Authorship：Last author,　Corresponding author   Language：English  

DOI： 10.1186/s12348-020-00234-y

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Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

DOI： 10.1038/s42003-020-01185-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called 'immune privilege'. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.

DOI： 10.3390/ijms21113962

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Purpose: V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel immune checkpoint receptor and ligand for regulating T cell proliferation and cytokine production. The purpose of the present study was to determine the role of VISTA in the immune privilege of corneal allografts. Methods: Expression of VISTA mRNA in mouse eyes was assessed with reverse-transcription PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c wild-type recipients treated with anti-VISTA mAb, and graft survival was assessed. A separate set of BALB/c mice treated with anti-VISTA mAb or rat IgG received injection of C57BL/6 splenocytes into the anterior chamber, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. CD4+ and CD8+ T cells in the spleen were assessed with flow cytometry. Results: VISTA mRNA was constitutively expressed in the cornea, and the expression of VISTA was localized to CD11b+ cells on the corneal stroma. Survival of allografts treated with anti-VISTA mAb was less than that of the control. ACAID was induced less efficiently in BALB/c mice treated with VISTA mAb. The proportions of CD8+ T cells and CD8+ CD103+ T cells (CD8+ T regulatory cells) in the spleen of BALB/c mice treated with anti-VISTA mAb were significantly lower than those of the control. Conclusions: VISTA may play an essential role in the acceptance of corneal allografts via involvement with allospecific ACAID, which suppresses T cell infiltration into the cornea.

DOI： 10.1167/iovs.19-27322

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Corneal transplantation is the most successful solid organ transplantation performed in humans. The extraordinary success of orthotopic corneal allografts, in both humans and experimental animals, is related to the phenomenon of "immune privilege". Inflammation is self-regulated to preserve ocular functions because the eye has immune privilege. At present, three major mechanisms are considered to provide immune privilege in corneal transplantation: 1) anatomical, cellular, and molecular barriers in the cornea; 2) tolerance related to anterior chamber-associated immune deviation and regulatory T cells; and 3) an immunosuppressive intraocular microenvironment. This review describes the mechanisms of immune privilege that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, and its relevance for the clinic. An update on molecular, cellular, and neural interactions in local and systemic immune regulation is provided. Therapeutic strategies for restoring immune privilege are also discussed.

DOI： 10.1016/j.preteyeres.2019.04.002

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Language：English   Publisher：KOREAN DERMATOLOGICAL ASSOC  

DOI： 10.5021/ad.2017.29.2.239

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. Corneal endothelial cell density undergoes a progressive decrease for many years after transplantation, eventually threatening patients with late endothelial failure. The purpose of this study was to investigate the possibility of an immunologic response in successfully grafted corneal endothelium.
METHODS. The corneal endothelium of patients who had undergone corneal transplantation was evaluated by specular microscopy. Rabbit models were subjected to penetrating keratoplasty (PK) with either syngeneic or allogeneic corneal transplants and Descemet's stripping endothelial keratoplasty (DSEK) with allogeneic corneal transplants. The presence of immune cells and expression of proinflammatory cytokines were determined by immunostaining. The corneal endothelium and immune cells were also evaluated by scanning electron microscopy.
RESULTS. Scanning slit contact specular microscopy of patients with no features of graft rejection revealed cell-like white dots on the grafted corneal endothelium. The corneal endothelium of the allogeneic PK and DSEK rabbit models displayed the presence of immune cells, including CD4(+) T-helper cells, CD8(+) cytotoxic T cells, CD20(+) B lymphocytes, CD68(+) macrophages, and neutrophils, but these immune cells were rarely observed in the syngeneic PK model. These immune cells also produced proinflammatory cytokines. Notably, some of the corneal endothelial cells situated near these immune cells exhibited features of apoptosis.
CONCLUSIONS. T lymphocytes, B lymphocytes, macrophages, and neutrophils are present on the grafted corneal endothelium in both PK and DSEK allogeneic rabbit models. The potential involvement of immune cells as an underlying pathophysiology for late endothelial failure deserves further examination.

DOI： 10.1167/iovs.16-20019

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. The interaction between the inducible costimulatory molecule (ICOS) and ICOS ligand (ICOSL) has been implicated in the differentiation and functions of T cells. The purpose of the present study was to determine the role of ICOS-ICOSL in the immune privilege of corneal allografts.
METHODS. Expression of ICOS and ICOSL mRNA from mouse eyes was assessed by RT-PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of ICOS-/- BALB/c recipients and BALB/c wild-type (WT) recipients treated with anti-ICOSL mAb, and graft survival was assessed. A separate set of WT and ICOS-/- BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. In vitro, cornea was incubated with T cells from WT and ICOS-/- BALB/c mice, and destruction of corneal endothelial cells (CECs) and the population of Foxp3(+) CD25(+) CD4(+) T cells was assessed.
RESULTS. Inducible costimulatory molecule ligand mRNA was constitutively expressed in the cornea, iris-ciliary body, and retina. Allograft survival in ICOS-/- recipients and WT recipients treated with anti-ICOSL mAb was significantly shorter than in control recipients. Anterior chamber-associated immune deviation was induced less efficiently in ICOS-/- mice. Destruction of CECs by alloreactive ICOS-/- T cells was enhanced compared with WT T cells. After coincubation with allogeneic corneal tissue, the proportion of regulatory T cells was significantly greater among WT T cells than in ICOS-/- T cells.
CONCLUSIONS. The expression of ICOSL in the cornea and the ICOS-mediated induction of Foxp3(+) CD4(+) regulatory T cells may contribute to successful corneal allograft survival.

DOI： 10.1167/iovs.16-20644

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Rheumatology S.A.S.  

Objective. Behçet's disease (BD) is a systemic inflammatory disorder polarised to the Th1 and Th17 immune systems. Allergic diseases are polarised to the Th2 immune system. The aim of the present study is to investigate the prevalence of allergic diseases in patients who have BD. Methods. The study involved a largescale interview survey of Japanese patients with BD at 21 institutes of ophthalmology
353 patients (255 males and 98 females) were recruited for this study. We analysed the history of allergic diseases such as atopic dermatitis (AD), allergic rhinitis (AR), bronchial asthma (BA) and drug/food allergies (FA). Results. Oral aphthous ulcers, ocular lesions, skin lesions, genital ulcers, arthritis, neurological lesions, intestinal lesions, deep vein thrombosis and epididymitis were reported in 95.8%, 98.6%, 72.5%, 44.8%, 13.9%, 6.8%, 6.2%, 3.7% and 1.4% of the patients, respectively. It was also reported that 73 patients (20.7%) had histories of allergic diseases: AD (5 cases, 1.4%), AR (36 cases, 10.2%), BA (19 cases, 5.4%) and FA (30 cases, 8.5%). This percentage was significantly lower than in a survey that Japan's Ministry of Health, Labour and Welfare conducted for healthy population (47.6%) (odds ratio = 0.29, 95% confidence interval = 0.22-0.38, p=4.9×10-22). Frequencies of posterior/pan-uveitis, relatively severe ocular findings, and visual prognosis were not affected by a history of allergic diseases in BD. Conclusion. Patients with BD had fewer complications from allergic diseases than did the entire population of Japan.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Purpose: To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behcet's disease (BD).
Design: Retrospective multicenter study using a questionnaire.
Participants: A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6 +/- 11.7 years, and the mean treatment duration was 32.9 +/- 14.4 months.
Methods: Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-&lt;24 months), group B (n = 62, 24-&lt;36 months), group C (n = 42, 36-&lt;48 months), and group D (n = 17, &gt;= 48 months).
Main Outcome Measures: Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy.
Results: The frequency of ocular attacks decreased in all groups (from 5.3 +/- 3.0 to 1.0 +/- 0.3 in group A, 4.8 +/- 4.6 to 1.4 +/- 0.3 in group B, 4.1 +/- 2.9 to 0.9 +/- 0.3 in group C, and 9.5 +/- 5.8 to 1.6 +/- 0.5 in group D; all P &lt; 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79 +/- 1.04 to 0.59 +/- 0.94 in group A, 0.59 +/- 1.07 to 0.41 +/- 1.04 in group B, and 1.15 +/- 1.77 to 0.92 +/- 1.73 in group C; all P &lt; 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy.
Conclusions: Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events. (C) 2014 by the American Academy of Ophthalmology.

DOI： 10.1016/j.ophtha.2014.04.042

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

DOI： 10.1371/journal.pone.0063620

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Inflammation and Regeneration  

DOI： 10.2492/inflammregen.33.274

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Language：Japanese  

Purpose: To report a case of bilateral panuveitis who was later diagnosed with scleroderma. Case: A 55-year-old female presented with hyperemia and pain in the left eye since 10 days before. Findings: Corrected visual acuity was 1.0 right and 0.5 left. The left eye showed signs of iridocyclitis and papillitis. Fluorescein angiography showed hyperpermeability of retinal vessels. Optic coherence tomograph (OCT) showed serous retinal detachment. The right eye developed similar symptoms 2 months later. She gradually developed Raynaud phenomenon with hardening of skin of hands and fingers. These findings led to the diagnosis of scleroderma. Ocular lesions subsided after topical treatment with corticosteroid 10 months after her initial visit. Conclusion: This case illustrates that panuveitis may develop before clinical manifestations of underlying collagen disease including scleroderma.

DOI： 10.11477/mf.1410104090

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Language：English   Publisher：SPRINGER TOKYO  

DOI： 10.1007/s10384-011-0058-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. The pathway between the glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) and GITR ligand (GITRL) has been shown to control the function of regulatory T cells (Treg). The present study was conducted to investigate the role of this pathway and Treg in establishing immune privilege status for corneal allografts.
METHODS. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c mice, and graft survival was assessed. A separate set of BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allo-specific anterior chamber-associated immune deviation was assessed. Recipients were intraperitoneally administrated anti-GITRL, anti-CD25 monoclonal antibodies (mAb), or control immunoglobulin (IgG). Expressions of GITRL, GITR, and Foxp3 in the allografts were assessed. In vitro, cornea pretreated with anti-GITRL mAb or control IgG was incubated with T cells, and destruction of corneal endothelial cells and the population of Foxp3(+)CD25(+)CD4(+) T cells were assessed.
RESULTS. GITRL was expressed constitutively in the cornea and iris-ciliary body. GITRL-expressing allografts were infiltrated with Foxp3+GITR+CD25+CD4(+) T cells. Blockade of GITRL did not affect allo-specific ACAID but led to infiltration of Foxp3(-)CD4(+) T cells and allograft rejection. Depletion of CD25+CD4(+) Treg also accelerated allograft rejection. Destruction of corneal endothelial cells by T cells was significantly enhanced in GITRL-blocked cornea compared with control cornea. Foxp3+CD25+CD4(+) T cells were increased after incubation with GITRL-expressing cornea, but not with GITRL-blocked cornea.
CONCLUSIONS. Presence of Foxp3+CD25+CD4(+) Treg in the allograft is necessary for allograft survival. GITRL-dependent expansion of Treg within the cornea is one mechanism underlying immune privilege in corneal allografts. (Invest Ophthalmol Vis Sci. 2010; 51: 6556-6565) DOI:10.1167/iovs.09-4959

DOI： 10.1167/iovs.09-4959

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

The original evidence for the existence of immunologically privileged sites in the body was based on the prolonged survival of genetically disparate transplanted tissue in the anterior chamber of the eye. The failure of the immune system to elicit an immune response in this and other such sites constitutes the hallmark of the immune privilege status. The remarkably successful field of corneal transplantation in clinical practice is undoubtedly associated with corneal immune privilege. Several investigations have addressed the regulatory mechanisms governing this phenomenon, which involves a complex interplay between multiple molecular and cellular pathways. Furthermore, the use of various transgenic mouse models has facilitated the identification of critical pathways, which upon disruption can modify the immune privileged status of the eye. Understanding these pathways not only reveals the mechanisms underlying various ocular inflammatory disease conditions, but also has clinical implications for the transplantation field and for the treatment of autoimmunity.

DOI： 10.3109/09273948.2010.512696

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

DOI： 10.1007/s10384-009-0727-y

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (international conference proceedings)  

The eye, along with the brain and reproductive organs, possesses inherent immune privilege
therein, inflammation is self-regulated so as to preserve organ function. At present, 3 major mechanisms of immune privilege in the eye are thought to exist. These are: (1) anatomical, cellular, and molecular barriers in the eye
(2) eye-derived immunological tolerance known as anterior chamber-associated immune deviation
and (3) immune suppressive intraocular microenvironment. In this review, the mechanisms of immune privilege that have been learned from animal models of corneal transplantation are described. Also, the role of new B7 family molecule inducing T-cell apoptosis is discussed as a mechanism of local immune suppressive microenvironment in the cornea. © 2009 by Lippincott Williams &amp
Wilkins.

DOI： 10.1097/ICO.0b013e3181ae9b8b

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The eye, like the brain and reproductive organs, possesses inherent immune privilege, and inflammation is self-regulated so as to preserve the organ functions. Studies over the past 30 years have provided insights of the multiple mechanisms of immune privilege. At present, three major lines of thought prevail regarding the molecular mechanisms of immune privilege in the eye: there are (1) anatomical, cellular, and molecular barriers in the eye; (2) eye-derived immunological tolerance, the so-called anterior chamber-associated immune deviation; and (3) immune suppressive intraocular microenvironment. In this review, the mechanisms of immune privilege that have been learned from ocular inflammation animal models, especially corneal transplantation, are described. Roles of new B7 family molecules on local immune regulation within the cornea are also introduced.

DOI： 10.1007/s12177-008-9010-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

The present study determined whether topical latanoprost, a prostaglandin (PG) F-2 alpha analog, influences the induction of anterior chamber-associated immune deviation (ACAID), corneal neovascularization (NV) or survival of corneal allografts in mice. BALB/c mice received topical latanoprost or PGE(2) once or multiple times daily starting 4 weeks prior to or the day of anterior chamber injection of C57BL/6 splenocytes. Induction of allo-specific ACAID was assessed by ear challenge with C57BL/6 splenocytes I week after subcutaneous immunization. In a separate experiment, orthotopic corneal transplantation was performed using C57BL/6 mice as donors and BALB/c mice as recipients. Recipients were randomized in a masked fashion to receive topical latanoprost or PGE(2) Graft fate was assessed clinically under surgical microscopy. Presence of MHC class II+ CD11c(+) or CD11b(+) cells in normal BALB/c mouse eyes following latanoprost or PGE(2) administration was assessed immunohistochemically. Control mice received topical 20% dimethyl sulfoxide or no treatment. Allo-specific ACAID was induced after 2 or 6 weeks of once daily treatment with latanoprost, and was induced even after 6 weeks of multiple treatments with latanoprost. Conversely, mice receiving PGE(2) failed to develop ACAID. Opacity and corneal NV scores for allografts treated with latanoprost were statistically indistinguishable from those for control allografts (p &gt; 0.05), whereas all allografts treated with PGE(2) were rejected. Opacity and NV scores were significantly higher in these allografts than in controls (p &lt; 0.05). A number of MHC class II+ CD11c(+) cells were present in the central cornea after PGE(2) treatment. Topical application of latanoprost does not influence induction of ACAID or graft outcomes including opacity and NV, whereas PGE, does. Immune privilege of corneal allograft is maintained after topical latanoprost application in mice. (C) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.exer.2007.11.012

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DOI： 10.1272/jnms.75.56

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Language：English   Publisher：TAYLOR & FRANCIS INC  

Purpose: To determine the extent to which each layer of the mouse cornea displays alloimmuno-genicity or immune privilege. Methods: Intact corneas or individual or combined layers of corneas from normal or cauterized eyes of BALB/c, C57BL/6, and CD95L-deficient B6-gld mice were grafted beneath the kidney capsule of normal BALB/c, B10.D2, BALB.B mice or of BALB/c mice presensitized to donor antigens. Graft fate was assessed clinically and histologically and acquisition of donor-specific delayed hypersensitivity (DH) was assessed at selected intervals after grafting. Results: Full-thickness allogeneic corneas induced vigorous DH and were rejected acutely. Similar results were obtained with allografts of corneal epithelium alone (if supported by syngeneic viable stroma), allografts of epithelium from cauterized corneas (containing Langerhans' cells), and stromal allografts deprived of endothelium. Grafts comprised of stroma plus endothelium (without epithelium) were not rejected, nor did they induce DH unless the graft had no CD95L expression. If stroma-endothelium grafts had no CD95L expression, DH directed against major histocompatibility complex (MHC), but not minor histocompatibility, alloantigens was induced. Moreover, CD95L expressed on stroma-endothelium grafts protected endothelial cells, but not stromal cells, from rejection in presensitized recipients. Conclusions: When grafted to a heterotopic site, the alloimmunogenicity of the normal cornea resides within its epithelial and stromal layers, whereas immune privilege arises from the endothelium. In normal mice, CD95L-expressing endothelium can inhibit the stroma from inducing immunity directed at MHC alloantigens, but in presensitized mice the endothelium can protect itself only from immune rejection.

DOI： 10.1080/09273940701382374

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Language：English   Publisher：INFORMA HEALTHCARE  

Multipotent, self-renewing stem and progenitor cells isolated from the mammalian central nervous system (CNS) have been shown to survive as allografts following transplantation to sites throughout the neuraxis. However, studies of this type shed little light upon the immunologic properties of the cells themselves, primarily because little is learned about the intrinsic immunogenic properties of a cell when it is grafted into an immune-privileged site. We have therefore investigated the immunogenic and antigenic properties of CNS progenitor cells by grafting them into a conventional (i.e., non-immune-privileged) site, namely, beneath the kidney capsule. Our results indicate that allogeneic CNS progenitor cells survive at least 4 weeks in a conventional site, during which time they neither sensitize their hosts nor express detectable levels of major histocompatibility complex (MHC) class I or II. These in vivo data are in accord with flow cytometric results showing that CNS progenitor cells do not express MHC class I or class II, either at baseline or upon differentiation in 10 serum. Exposure to interferon gamma, however, reversibly upregulates expression of these key transplantation antigens. Together, these results reveal CNS progenitor cells to possess inherent immune privilege. Since CNS progenitor cell allografts were rejected beneath the kidney capsule following specific sensitization of the host, CNS progenitor cells were able to display alloantigens, albeit not in an immunogenic form.

DOI： 10.1080/09273940701382242

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Corneal allografts enjoy a remarkable success rate when compared to all other forms of organ transplants. In routine keratoplasties, HLA matching and systemic immunosuppressive drugs are not employed, yet 90% of the uncomplicated transplants survive. The success of corneal allografts was recognized over half a century ago and led to the term 'immune privilege'. The original explanation for the immune privilege of corneal allografts attributed the escape of immune rejection to the avascular and alymphatic nature of the corneal graft bed, which sequestered the corneal allograft from the immune apparatus. In the past 20 years, the widespread use of animal models of keratoplasty has shed light on the mechanisms of corneal immune privilege and has revealed that the success of corneal allografts is due to a combination of properties of the corneal graft bed and the cornea itself. © 2007 S. Karger AG, Basel.

DOI： 10.1159/000099279

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Degenerative diseases of the retina afflict millions of Americans, and very few effective treatments are available at present. Transplantation of solid tissue or stem cell grafts represents a promising, albeit challenging, approach to replace photoreceptor cells lost due to injury or disease. However, there remain a number of formidable obstacles to be overcome before these techniques can be applied in a clinical setting. Foremost of these challenges is immunological acceptance and survival of the graft. We will refer to studies performed in collaboration with J. Wayne Streilein over the past decade that address this issue. The immune-privileged status of the subretinal space, as well as the inherent immune privilege of retinal pigment epithelium, neuronal retina and neural stem cells will be described. The goal of these studies is to gain a better understanding of the immunological properties of both the donor tissues and recipient graft site in retinal transplantation. This information will allow for the development of strategies to improve graft outcome and lead to successful repair of the diseased eye. © 2007 S. Karger AG, Basel.

DOI： 10.1159/000099280

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

We review recent experimental evidence of the immunosuppressive and immunogenic potential of amniotic epithelial cells. Since cryopreserved amniotic membrane (AM) has been used in clinical applications,, much research has focused on the beneficial effects of amniotic stromal matrix rather than on the function of viable amniotic cells. However, viable human amniotic epithelial cells (HAECs) have been shown to elicit beneficial effects on secretion of anti-inflammatory factors. Topical application Of Culture supernatant from HAECs leads to profound suppression of suture-induced neovascularization in cornea and fewer major histocompatibility complex (MHC) class II+ antigen-presenting cells (APCs) in inflamed cornea after thermal cautery. Furthermore, expression of interleukin (IL)-1 beta mRNA was suppressed in cauterized cornea. These results suggest that HAECs are a source of Soluble anti-inflammatory factors that suppress corneal inflammation. However, viable amniotic epithelial cells display antigenicity and immunogenicity as allografts. Fresh allogeneic amniotic epithelium (AE) expresses MHC class I antigens and sensitizes recipients when placed in the eye, although long-term memory of allo-specific delayed hypersensitivity (DH) was not acquired. Allogeneic AE was clearly vulnerable to acute immune rejection in specifically sensitized recipients and recipients of repeated AE transplantation. We therefore suggest that immunogenicity of AE should not be ignored, and use of AM from different donor placentas should be emphasized when repeated AM transplantation is required in patients clinically.

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The programmed death-1 (PD-1) costimulatory pathway has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in establishing an immune privilege status of corneal allografts in mice. B7-H1, but not B7-DC or PD-1, was expressed constitutively in the eye, i.e., cornea, iris-ciliary body, and retina. After corneal allografting, PD-1(+)CD4(+) T cells infiltrated and adhered with B7-H1(+) corneal endothelium. Blockade of PD-1 or B7-H1, but not B7-DC, led to accelerated corneal allograft rejection. In B7-H1-expressing corneal allografts, apoptosis of the infiltrating PD-1(+)CD4(+) or CD8(+) T cells was observed, after which there was allograft acceptance. In contrast, B7-H1 blockade suppressed apoptosis of infiltrating PD-1(+) T cells, which led to allograft rejection. In vitro, destruction of corneal endothelial cells by alloreactive T cells was enhanced when the cornea was pretreated with anti-B7-H1 Ab. This is the first demonstration that the constitutive expression of B7-H1 plays a critical role in corneal allograft survival. B7-H1 expressed on corneal endothelial cells maintains long-term acceptance of the corneal allografts by inducing apoptosis of effector T cells within the cornea.

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PURPOSE: To determine the usefulness of the Pentacam corneal volume assay in the assessment of corneal endothelial damage caused by phacoemulsification and aspiration (PEA).
DESIGN: Prospective, comparative, observational case series.
METHODS: PEA was performed in 85 eyes by three surgeons under different conditions. Central cell density (CD) was determined using a specular microscope before and one month after surgery. Pentacam was used before and one day, one week, and one month after surgery to determine 3- and 10,mm corneal volumes.
RESULTS: For all surgeons, no significant differences in the 3-mm corneal volumes were noted between the before and one-month after surgery values. However, 10-mm corneal volumes at one month were significantly higher than preoperative levels. No correlation was noted between the increasing rate of the 10-mm corneal volume and decreasing rate of CD.
CONCLUSIONS: Pentacam-determined corneal volumes may be useful in assessing PEA-caused corneal damage.

DOI： 10.1016/j.ajo.2006.04.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To determine the immunogenic characterization of amniotic epithelium (AE), by examining the fate of allogeneic AE grafts heterotopically transplanted in the eye.
METHODS. Intact AE from enhanced green fluorescence protein (EGFP) transgenic mice (C57BL/6 background) and wild-type C57BL/6 mice were transplanted onto cornea or conjunctiva, or inserted into the anterior chamber (AC) of normal BALB/c mice, C57BL/6 mice, or BALB/c mice presensitized to donor antigens. For repeated AE transplantation experiments, AE was grafted in the other eye 7 days after the first grafting. Graft fate was assessed clinically and histologically at selected intervals after grafting. Infiltrating inflammatory cells were examined immunohistochemically. Sensitization to alloantigens by AE was assessed by the delayed hypersensitivity (DH) response.
RESULTS. In normal recipients, GFP(+) cells were absent in EGFP donor-derived AE grafts by day 21 on cornea and by day 7 on conjunctiva. AE grafts implanted in the AC survived for &gt;8 weeks. In presensitized recipients and recipients that underwent repeated AE implantation, graft survival was markedly shorter than in normal recipients. DH was induced at 2 weeks, but faded to be induced at 4 weeks after grafting on cornea or at 8 weeks after grafting on conjunctiva and in the AC of normal recipients.
CONCLUSIONS. Fresh allogeneic AE expressed immunogenicity when placed on the ocular surface, although no memory of allospecific DH was acquired. Allogeneic AE is clearly vulnerable to immune rejection in specifically sensitized recipients.

DOI： 10.1167/iovs.05-0787

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

Human amniotic epithelial cells (HAEC) may be a source of soluble anti-inflammatory factors. The purpose of this study is to determine the effect of topically applied HAEC culture supernatant on corneal inflammatory reactions. HAEC were obtained from a placenta and cultured for 48 hr, and the supernatant was collected. The conditioned medium from HAEC contained small amounts of human interleukin-1 receptor antagonist (IL-1ra). Intrastromal sutures were placed in the cornea of BALB/c mice to induce corneal neovascularisation. Superficial cauterisation was applied to induce recruitment or activation of antigen presenting cells (APCs) in the cornea without neovascularisation. HAEC conditioned medium, placebo, or recombinant human IL-1ra was topically applied three times daily for 2 weeks. Suture-induced corneal neovascularisation was evaluated microscopically for 8 weeks. The cauterised corneas were harvested at 2 weeks, and the MHC class II+ APCs were quantified by immunofluorescent staining and confocal microscopy. Inflammatory cytokine gene expression in the cauterised corneas was analyzed by a multiprobe ribonuclease protection assay. Conditioned medium from HAEC led to a profound suppression of corneal neovascularisation and fewer MHC class II+ APCs in the epithelium. In contrast, human IL-1ra was only slightly effective in suppressing corneal inflammatory reactions. mRNA expression of murine IL-1ra and IL-1beta in the cauterised corneas was markedly suppressed after application of the conditioned medium. These results suggest that HAEC are a source of soluble anti-inflammatory factors and that conditioned medium from HAEC contains factors other than IL-1ra that suppress corneal inflammation. (c) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.exer.2004.11.018

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Publishing type：Research paper (scientific journal)  

Background: Because immunological mechanisms are thought to be involved in scleritis associated with rheumatoid arthritis, topical or systemic administration of a corticosteroid drug is the standard treatment for this condition. We report a case of scleritis associated with malignant rheumatoid arthritis in which local administration of corticosteroid therapy resulted in minimal remission but topical cyclosporine was effective. Case Report: A 68-year-old female with malignant rheumatoid arthritis developed anterior diffuse scleritis in her left eye. Because a month of corticosteroid therapy, by instillation or subconjunctival injection, resulted in little change and her general condition precluded systemic administration, instillation of 2% cyclosporine was started. A week after the start of this therapy the condition of the conjunctiva improved and diffuse scleral injection and ocular pain disappeared within 1 month. Conclusion: Instillation of cyclosporine may be an option for the treatment of intractable scleritis.

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Background: We report a case of a rare association of ocular pemphigoid and herpes simplex keratitis that were diagnosed based on immunofluorescence and polymerase chain reaction (PCR), respectively, occurring in a patient with immunofluorescence-confirmed bullous pemphigoid. Case Report: A 57-year-old male who had been treated with oral corticosteroid medication for bullous pemphigoid complained of redness of the conjunctiva in the right eye. After topical fluorometholone was started, conjunctival erosion appeared. Immunofluorescence showed the presence of linear deposits of complement C3 on the basement membrane, suggesting ocular pemphigoid. Topical betamethasone was prescribed and the conjunctival lesion improved. However, a dendritic ulcer appeared in the peripheral cornea and PCR analysis of corneal epithelium revealed herpes simplex virus DNA. Topical corticosteroid medication was stopped immediately and acyclovir ointment was started, which resulted in healing of the corneal lesion. Conclusion: This case appears to represent a rare case of bullous and ocular pemphigoid in which herpes simplex keratitis was induced by corticosteroid therapy.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. In low-risk eyes of mice, most of the composite corneal grafts composed of slngeneic epithelium layered on allogeneic stroma and endothelium are accepted indefinitely. The study was undertaken to determine the fate of similar composite corneal grafts placed in high-rids mouse eyes.
METHODS Epithelium-deprived allogeneic corneas (C57BL/6) were reconstituted in vitro with BALB/c epithelium, and then transplanted orthotopically into high-risk eyes of RALBc mice. Graft survival was assessed clinically and evaluated histologically. Acquisition of donor-specific delayed hypersensitivity (DH) was also assessed in recipient mice. Recipients bearing healthy composite grafts were immunized subcutaneously with injected C57BL/6 spleen cells at 2 or weeks after grafting, after which the fate of the grafts was evaluated.
RESULTS. Virtually all epithelium-deprived corneal allografts reconstituted in vitro with normal BALB/c corneal epithelium survived indefinitely when paced in high-risk eyes of BALB/c mice. Recipients of these composite grafts failed to acquire donor-specific DH when tested at both 2 anti 8 weeks after grafting. Moreover, these recipients did not acquire the capacity to actively suppress donor-specific D. Within 1 to 3 weeks of sensitization of recipient mice with spleen cells of donor origin, healthy composite grafts in residence for 2 or 8 weeks were rejected.
CONCLUSIONS. Replacement of donor epithelium with syngeneic epithelium protects orthotopic allogeneic corneal grafts (stroma plus endothelium) placed in high-risk eyes front sensitizing their recipients and froth immune-mediated rejection. Recipients of composite corneal grafts containing syngeneic epithelial layers act as though they are immunologically ignorant of the graft's presence.

DOI： 10.1167/iovs.02-0399

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

Multipotent, self-renewing stem and progenitor cells isolated from the mammalian central nervous system (CNS) have been shown to survive as allografts following transplantation to sites throughout the neuraxis. However, studies of this type shed little light upon the immunologic properties of the cells themselves, primarily because little is learned about the intrinsic immunogenic properties of a cell when it is grafted into an immune-privileged site. We have therefore investigated the immunogenic and antigenic properties of CNS progenitor cells by grafting them into a conventional (i.e., non-immune-privileged) site, namely, beneath the kidney capsule. Our results indicate that allogeneic CNS progenitor cells survive at least 4 weeks in a conventional site, during which time they neither sensitize their hosts nor express detectable levels of major histocompatibility complex (MHC) class I or II. These in vivo data are in accord with flow cytometric results showing that CNS progenitor cells do not express MHC class I or class II, either at baseline or upon differentiation in 10% serum. Exposure to interferon gamma, however, reversibly upregulates expression of these key transplantation antigens. Together, these results reveal CNS progenitor cells to possess inherent immune privilege. Since CNS progenitor cell allografts were rejected beneath the kidney capsule following specific sensitization of the host, CNS progenitor cells were able to display alloantigens, albeit not in an immunogenic form.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Transplantation of immature retinal tissues may offer a solution for restoring sight to individuals afflicted with degenerative retinal diseases. Promising results have recently demonstrated that neonatal retinal grafts placed in the eye can survive, differentiate into photoreceptor cells, and respond to evoked electrical stimuli. These transplants, however, were performed in immunologically immature recipients. Since it is important to know whether neonatal neuronal retina (NNR) tissue is immunogenic in immune-competent recipients, and whether this tissue displays inherent immune privilege, we have examined the fate of such grafts placed in a non-immune-privileged site of adult recipient mice. We found that typical, photoreceptor-dominated rosettes formed in differentiating NNR grafts, and that these allografts survived beyond 12 days, whereas genetically identical skin grafts were rejected earlier. Class II MHC-bearing cells of recipient origin were observed along the edge of NNR allografts as early as day 5. Donor-specific delayed hypersensitivity was not detected at 12 days, but did emerge on day 20, coincident with rejection of NNR allografts. Lymph nodes, but not spleens, of mice bearing NNR grafts at 12 days contained regulatory lymphoid cells that suppressed delayed hypersensitivity in naive recipients. We conclude that NNR grafts accommodate and even differentiate in the non-immune-privileged space beneath the kidney capsule. Survival beneath the kidney capsule of NNR allografts, but not skin allografts, at 12 days and beyond implies that NNR tissue possesses inherent immune privilege. The vulnerability of these grafts to rejection by 20 days reveals this privilege to be partial and temporary.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

The purpose of this study was to investigate the role of CD80 and CD86 costimulatory molecules in corneal allograft rejection. Anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) were administered after orthotopic corneal allograft transplantation. Graft rejection was observed by biomicroscopy. Population and localization of CD80(+) and CD86(+) cells in the cornea, cervical lymph nodes, and spleen were examined by flow cytometry and immunohistochemistry, The combined use of anti-CD80 and anti-CD86 mAbs was effective in prolonging corneal allograft survival. In the untreated mice bearing rejected graft, many CD86(+) and CD80(+) cells were found around the host-graft junctional area in the cornea. and CD86 high cells were found in the cervical lymph node and spleen. In contrast, few CD86(+) or CD80(+) cells were observed in the cornea, cervical lymph node, and spleen from the mice treated with antiCD80/CD86 mAbs. These results demonstrated a significant role of CD80 and CD86 costimulatory molecules in corneal allograft rejection. (C) 2002 Elsevier Science Ltd.

DOI： 10.1006/exer.2001.1109

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. TO determine the extent to which donor cells persist and recipient cells repopulate each of the three cell layers of orthotopic corneal grafts in mice.
METHODS. BALB/c, C57BL/6, and enhanced green fluorescence protein (EGFP) transgenic mice (Bb background) were used as donors and recipients for orthotopic syngeneic and allogeneic corneal grafts. Graft-bearing eyes were harvested at 5, 10, 15, 28, and 56 days, stained with propidium iodide, and observed (layer by layer) by confocal microscopy. Bone marrow- derived cells in the grafts were assessed immunohistochemically.
RESULTS. Donor epithelium was totally replaced by recipient epithelial cells within 15 days in both syngeneic and allogeneic grafts, whereas donor stromal keratocytes and endothelial cells were retained virtually intact in syngeneic grafts and in accepted allografts. In rejected allografts, neither donor-derived keratocytes nor endothelial cells were detected, and, instead, recipient-derived stromal fibroblasts, neovessels, and infiltrating leukocytes were heavily represented. The posterior surface of rejected grafts was devoid of corneal endothelium and was covered incompletely with bone marrow-derived cells of recipient origin.
CONCLUSIONS. Whereas in mice graft-derived epithelium is largely irrelevant to corneal allograft outcome, persistence of donor-derived endothelium and keratocytes correlates perfectly with graft acceptance. Recipient endothelium is incapable of covering the posterior surface of accepted or rejected corneal grafts, whereas bone marrow-derived cells of recipient origin come to occupy this site in rejected grafts.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To determine whether epithelium-deprived corneal allografts covered with syngeneic epithelium display immune privilege in orthotopic transplantation and whether syngeneic epithelium containing antigen-presenting cells nullifies this effect.
METHODS. Epithelium-deprived allogeneic corneas (C57BL/6) and epithelium-deprived allogeneic corneas reconstituted with syngeneic (BALB/c) epithelium (containing or deprived of Langerhans' cells) were transplanted orthotopically into normal eyes of BALB/c mice. Graft survival was assessed clinically and evaluated histologically.
RESULTs. Epithelium-deprived corneal grafts survived in syngeneic recipients but were swiftly rejected in allogeneic recipients. These allografts incited intense stromal inflammation and neovascularization. Epithelium-deprived allografts that were resurfaced in vivo by syngeneic epithelium derived from immune-incompetent SCID mice also underwent intense acute rejection when placed in normal eyes of BALB/c mice. The epithelium of in vivo resurfaced grafts was replete with Langerhans' cells. By contrast, most of the epithelium-deprived allografts reconstituted in vitro with fresh, normal BALB/c corneal epithelium survived indefinitely when placed in eyes of BALB/c mice. Similar grafts reconstituted with BALB/c epithelium containing Langerhans' cells were swiftly rejected.
CONCLUSIONS. Replacement of donor epithelium with Langerhans' cell-deficient syngeneic epithelium protects orthotopic allogeneic cornea grafts (stroma plus endothelium) from immune-mediated rejection. The presence of an intact, histocompatible layer of corneal epithelium has two important effects on orthotopic corneal allografts: It suppresses nonspecific inflammation and neovascularization within the graft, and it blunts the alloimmunogenicity of the histoincompatible stroma and endothelium.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Purpose. To review recent experimental evidence of the immunogenic potential of each layer of the cornea as an allograft placed in a heterotopic, nonimmune-privileged site. Methods, Each layer of allogeneic cornea and composite corneal tissue was transplanted heterotopically beneath the kidney capsule of normal and presensitized mice. The graft fate was assessed clinically and histologically. Sensitization to alloantigens by each layer of the cornea was assessed by delayed hypersensitivity (DH) responses. Results. Allogeneic full-thickness corneas induced a DH response and were rejected acutely in heterotopic sites. Epithelium-deprived allogeneic corneas failed to induce a DH response and survived indefinitely unless the grafts lacked CD95 ligand (CD95L) expression. CD9SL-deficient grafts of stroma-endothelium induced a major histocompatibility complex (MHC)-specific DH response. Viable allogeneic epithelium alone, which was supported by syngeneic stroma, induced a DH response. Allogeneic stroma alone also induced a DH response and was rejected. Endothelium nullified the DH response induced by allogeneic stroma and protected allogeneic stroma from rejection via CD95L expression. CD95L protected allogeneic endothelial cells from rejection, even in presensitized recipients. Conclusion. Both the epithelium alone and the stroma alone display immunogenic potential, whereas the endothelium confers immune privilege through constitutive expression of CD95L. CD95L acts by preventing direct sensitization of MHC-specific T cells and by inhibiting destruction of target cells during rejection.

DOI： 10.1097/00003226-200000003-00009

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. To determine the extent to which each layer of the mouse cornea displays alloimmunogenicity or immune privilege.
METHODS. Intact corneas or individual or combined layers of corneas from normal or cauterized eyes of BALB/c. C57BL/b, and CD95L-deficient B6-gld mice were grafted beneath the kidney capsule of normal BALB/c, B10.D2, BALB.B mice or of BALB/c mice presensitized to donor antigens. Graft fate was assessed clinically and histologically and acquisition of donor-specific delayed hypersensitivity (DH) was assessed at selected intervals after grafting.
RESULTS. Full-thickness allogeneic corneas induced vigorous DH and were rejected acutely. Similar results were obtained with allografts of corneal epithelium alone (if supported by syngeneic viable stroma), allografts of epithelium from cauterized corneas (containing Langerhans' cells), and stromal allografts deprived of endothelium. Grafts comprised of stroma plus endothelium (without epithelium) were not rejected, nor did they induce DH unless the graft had no CD95L expression. if stroma- endothelium grafts had no CD95L expression, DH directed against major histocompatibility complex (MHC), but not minor histocompatibility, alloantigens was induced. Moreover, CD95L expressed on stroma- endothelium grafts protected endothelial cells, but not stromal cells, from rejection in presensitized recipients.
CONCLUSIONS. When grafted to a heterotopic site, the alloimmunogenicity of the normal cornea resides within its epithelial and stromal layers, whereas immune privilege arises from the endothelium. In normal mice, CD95L-expressing endothelium can inhibit the stroma from inducing immunity directed at MHC alloantigens, but in presensitized mice the endothelium can protect itself only from immune rejection.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD  

To determine whether preservation of the donor cornea prevents allograft rejection, orthotopic corneal transplantation was performed using corneas preserved in storage medium (Optisol-GS(R)). Donor corneas harvested from C3H/He (H-2(k)) mice and B10.D2 (H-2(d)) mice were preserved in storage medium for 0, 3, 7 and 14 days, and then transplanted into the corneal beds of the recipient BALB/c (H-2(d)) mice. Graft survival was determined clinically and histologically. The expression of major histocompatibility complex (MHC) molecules in the preserved corneas was analysed by immunohistochemistry and Western blotting. Donor-specific cytotoxic T lymphocyte (CTL) and delayed-type hypersensitivity (DTH) responses were assessed 3 weeks after grafting. Active suppression of DTH in the recipient mice was also examined 3 weeks after grafting. The survival of 14 day preserved allografts was significantly higher than that of the non-preserved allografts in both MHC and minor histocompatibility (H) antigens, and minor H only disparate combination. The recipients of the preserved allografts failed to induce both CTL and DTH. The active suppression of DTH was not acquired in these recipients. The expression of donor-derived MHC class I antigens was markedly reduced in the corneas after preservation. Preservation of the donor cornea had a remarkable effect on the prevention of corneal allograft rejection. Since the preserved allografts failed to induce donor-specific CTL and DTH, and active suppression of DTH was not acquired in the recipients, the prevention of allo-rejection is due to a failure of allo-sensitization, These results indicate that the reduction of MHC class I antigens and minor H antigens expression in the preserved grafts induces a failure of allo-sensitization and leads to the high rate of acceptance in corneal allografts. (C) 2000 Academic Press.

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Authorship：Corresponding author   Language：English   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

DOI： 10.1006/exer.2000.0841

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

PURPOSE. TO determine whether corneal tissue as an allograft displays immune privilege in a nonprivileged site and, if so, whether CD95 ligand expression contributes to the privileged status.
METHODS. Syngeneic and allogeneic corneal tissues deprived of epithelium were transplanted beneath the kidney capsule of normal mice. Syngeneic BALB/c, allogeneic C57BL/6, and allogeneic B6Smn.C3H-gld (CD95 ligand-deficient) mice were used as donors for BALB/c recipients, and syngeneic C3H/HeJ-gld (CD95 ligand-deficient) mice were used for normal C3H/HeJ recipients. Allogeneic conjunctival segments served as positive grafting controls. Graft fate was assessed by visual inspection at 4, 7, 14, and 21 days and was confirmed by histologic study. Viability of graft endothelium was assessed by immunocytochemical analysis
RESULTS. Syngeneic corneas and C57BL/6 corneas survived almost indefinitely beneath the kidney capsule. Both the stroma and the endothelial layers remained healthy and intact. Allogeneic conjunctiva evoked a strong inflammatory response attended by neovascularization. Similarly, B6-gld corneas deficient in CD95 ligand expression showed acute destruction beneath the kidney capsule. Circumstantial evidence implicates alloimmune rejection as the mechanism.
CONCLUSIONS. Epithelium-deprived corneas from normal mice possess inherent immune privilege that protects them from alloimmune rejection even at nonprivileged sites. Constitutive expression of CD95 ligand contributes to the privileged status. It is inferred that the extraordinary success of orthotopic corneal allografts owes as much to the qualities of the graft as an immune-privileged tissue as to the qualities of the rye as an immune-privileged site.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0041-1345(99)00491-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background. Cytokine profile is a key in understanding the mechanisms of allograft rejection. Cytokine expression in the aqueous humor and the correlation between the aqueous humor cells and corneal infiltrating cells are not fully understood in corneal transplantation.
Methods. Orthotopic mouse corneal transplantation was performed using BALB/c (H2(d)) mice as recipients, and C3H/He (H2(k)) and BALB/c mice as donors for allografts and isografts, respectively. Immunocytochemistry was performed on aqueous humor cells. Corneal graft was studied immunohistochemically. Cytokine gene expressions of the cells infiltrating the aqueous hunter and corneal grafts were determined by the semiquantitative reverse transcription and polymerase chain reaction method.
Results Interferon-gamma, interleukin (IL)-2, IL-4, and IL-10 were detected in the cells infiltrating the aqueous humor and corneal grafts at both the protein and gene expression levels. T helper 1 (Th1) cytokine expressions at the protein level, however, were consistently predominant in the rejected allografts compared to those of Th2 cytokines. The cytokine and surface marker profiles of the cells in the aqueous humor corresponded well to those of the cells infiltrating the corneal grafts. Cytokine protein and mRNA expression levels in the aqueous humor decreased rapidly.
Conclusions. Allorejection in corneal transplantation is Th1 cytokine-predominant. Infiltrating cells do not express Th2 cytokine so much in allograft rejection,as compared with Th1 cytokine, The cell infiltration patterns of the aqueous humor were well correlated with those of the cornea.

DOI： 10.1097/00007890-199812150-00014

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Authorship：Lead author   Language：English  

DOI： 10.1016/S0041-1345(97)01230-X

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Language：English   Publisher：SPRINGER-VERLAG BERLIN  

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Purpose The purpose of this study is to investigate effects of cornea! preservation in Optisol® on the survival rate of corneal grafts after penetrating keratoplasty (PK) in mice Methods PK was performed using C3H/He (H-2k) mice as donors and BALB/c (H-2d) mice as recipients Both the donor and the recipient corneas were excised using a trephine of 2 0 mm in diameter The donor corneas were preserved in Optisol GS® at 4 C for 0, 3. 7, 14 or 21 days and they were transplanted to the recipient corneal beds by 8 interrupted 11-0 nylon sutures The corneal allografts were observed using an operating microscope for 4 weeks after PK The transparency of the corneal allografts were scored. The cornea! allografts were defined as rejected when they became so opaque with stromal edema that the iridial vessels could not be discerned clearly Results: The rates of corneal allograft survival 4 weeks after PK were 19 % in 0-day preservation (n=l 1), 29 % in 3-day (n=7), 50 % in 7-day (n=10), 63 % in -i4 day (n=8) and 56 % in 2l-day(n=9) preservation Conclusion The period of corneal graft preservation in Optisol GSK affects the survival rates of corneal allografts after PK in mice The preservation of the corneal graft in Optisol® may be effective in suppression of corneal allograft rejection in PK.

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Purpose: To investigate effects of anti-αβT cell receptor monoclonal antibody (antiαβTcR mAb) on corneal allograft rejection after penetrating keraloplasty (PK) in rats. Methods: We performed PK using Fischer rats (F344) as donors and Lewis rats (Lew/Crj) as recipients. Both donor and recipientcomeas were excised with a 3. 0 mm trephine and they were sutured with 11-0 nylon. The rats were divided into 2 groups: rats treated with anti-αβTcR mAb (Treated group, n=20) and those without antibody treatment (Control group, n=14). The antibody was administered intraperitoneally2 mg/kg daily from 0 to 12th day after PK in Treated group. The corneal grafts were examined by an operating microscope. The corneal grafts were defined to be rejected when they became so opaque that the pupil margins could not be discerned. The corneas were excised 14 days after PK and they were examined histologically. Results: In the Control group, all of the corneal grafts were rejected in 14 days after PK. In the Treated group, on the contrary, no allograft rejection occurred. Histological examination demonstrated marked lymphocyte infiltration, stromal edema and vessel invasion into the grafts in the Control group. In the Treated group, however, lymphocyte infiltration and vessel invasion were mild and no stromal edema was observed. Conclusion: Treatment with anti-αβTcR mAb is effective in suppression of corneal allograft rejection.

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Purpose The best characterized co-stimulatory molecules on antigen presenting cells are B7-1 (CD80) and B7-2 (CD86). Recent studies have demonstrated that blocking these molecules may induce immunosupprcssion effectively. We have shown previously that administration of monoclonal antibodies (mAbs) to some intercellular adhesion molecules such as VLA-4 and LFA-1 lead to prolonged allograft survival in murine conical allograft model. In this study, we investigate the effect of anti B7-1 (CD80), B7-2 (CD86) mAbs in mice. Methods Orthotopic peneirating keratoplasty (PK) was pcrfoimcd using C3H/He (H-2k) mice as donors and BALB/c (H-2d) mice as recipients. Recipients mice were intraperitoneally injected mixture of 0. 1 mg each of antibodies staning immediately after surgery and on days 2, 4, 6, 8. HE staining and immunohislological examonations of B7-1 and B7-2 molecules are performed on day 14 after PK. Results The survival rates of allografts in the untreated mice 2 weeks after PK uere 18%. In contiast, 89% of allografts ot treated mice were remained transparent. Three weeks after surgery, 66. 7% were rejected and all were rejected within 5 weeks. Histological examination showed that no apparent cell infiltration and graft edema were founi in the treated mice. Conclusion Anti B7-1 (CD80), anti B7-2 (CD86) mAbs were effective in suppressing the allograft rejection in mice.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD  

It has been reported that allograft rejection is mediated by a variety of adhesion molecules. Using a corneal allograft model in mice, we studied the role of very late antigen (VLA)-4 and leukocyte function-associated antigen (LFA)-1 adhesion molecules in corneal allograft rejection and the effects of monoclonal antibodies (mAbs) to them in suppressing corneal rejection. C3H/He donor corneas were transplanted into BALB/c corneal beds. The allografted mice were treated with a control mAb (M18/2), mAbs to VLA-4, or LFA-1 or their combination by i.p. injection until day 7. The expression of VLA-4, LFA-1, major histocompatibility complex (MHC) class II antigens, interleukin (IL)-2, IL-2 receptor and interferon gamma (IFN gamma) in the grafted cornea were studied immunohistochemically. Cytotoxic T lymphocyte (CTL) responses to donor alloantigens were assessed. The skins from a syngeneic donor or a third-part strain were transplanted 8 weeks after the initial keratoplasty onto the mice treated with anti-LFA-1 plus anti-VLA-4 mAbs. Fourteen of 16 allografts in non-treated mice and control mAb-treated mice became opaque by 2 weeks after transplantation. At 2 weeks, non-treated allografts showed expression of MHC class II antigens on keratocytes and mononuclear cells at the host-graft junction. Also, mononuclear cells expressing VLA-4, LFA-1, IL-2, IL-2 receptor and IFN gamma were present in the stroma at the host-graft junction. The allografts treated with either anti-VLA-4 or anti-LFA-l alone, or anti-VLA-4 plus anti-LFA-1 remained transparent for more than 2 weeks, and the survival rates at 14 weeks was 0%, 16.7%, and 75.0%, respectively. The combined use of anti-VLA-4 and anti-LFA-1 mAbs prolonged graft survival significantly (P &lt;0.05) at 14 weeks as compared with anti-LFA-1 mAb alone, At 3 weeks, CTL responses to donor alloantigens were depressed in mice treated with either anti-LFA-1 alone or anti-LFA-1 plus anti-VLA-4. Specific prolongation of donor-syngeneic skin was observed after treatment with the combination of these two mAbs. These results indicate that VLA-4 and LFA-1 have important roles in rejection process of corneal allografts, and that the combined use of mAbs to these molecules has remarkable effects on inducing alloantigen-specific immunosuppression in corneal transplantation. (C) 1997 Academic Press Limited.

DOI： 10.1006/exer.1997.0316

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILLIAMS & WILKINS  

Background. The mechanisms of corneal xenogeneic immunoreaction, as well as the potential role of immunosuppressive therapy in the suppression of corneal xenograft rejection, have not been thoroughly explored.
Methods. BALB/c mice who received orthotopic corneal transplants (Lewis rats donors) were administered intraperitoneally anti-leukocyte function associated antigen-1 (LFA-1) monoclonal antibody (mAb) or FK506 (3 mg/kg/day) or both of these immunosuppressants during a 12-day postoperative period. Histological (hematoxylin-eosin stain) and immunohistochemical evaluations of enucleated eyes were performed. Humoral immune response and delayed-type hypersensitivity (ear-swelling assay) were evaluated.
Results. The mean (+/-SD) graft survival time in the untreated control, FK506-treated, anti-LFA-1 mAb-treated, and combined-treatment groups was 5.8+/-0.8, 9.4+/-4.0, 8.7+/-5.0, and 67.7+/-16.4 days, respectively. In the untreated control group, mouse IgG, IgM, and C3 were expressed on the rat corneal grafts during the early postoperative phase, Flow cytometry studies revealed high titers of xenoreactive IgG and IgM antibodies, T helper 1 cytokines were expressed on xenografted corneal beds, and delayed-type hypersensitivity was induced. However, local expression of IgM, C3 and T helper 1 cytokines, serum antibodies of IgG and IgM, and delayed-type hypersensitivity were suppressed in the anti-LFA-1 mAb- plus FK506-treated group.
Conclusions. Both humoral and cell-mediated immune reaction play an important role in the initial rejection in rat-to-mouse corneal xenotransplantation. The treatment with anti-LFA-1 mAb in combination with FK506 synergistically suppresses concordant corneal xenogeneic reaction.

DOI： 10.1097/00007890-199707150-00009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0041-1345(97)00331-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0041-1345(96)00269-2

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Corneal transplantation was performed by grafting C3H/He donor corneas into BALB/c corneal beds. The allografted mice were injected either with 0.5 mg/day of anti-very late antigen (VLA)-4 antibody, anti-leukocyte function- associated antigen (LFA)-1 antibody, or 0.25 mg/day each of both antibodies on days -2, 0, 1, 3, 5, and 7. After 3 weeks, cytotoxic T lymphocyte (CTL) responses to donor alloantigens were assessed. Splenocytes in the allografted mice without treatment demonstrated greater CTL responses than those in naive mice. CTL responses were depressed in mice treated with either anti-LFA-1 alone or a combination of anti-LFA-1 and anti-VLA-4 antibodies as compared with splenocytes from allografted mice without treatment. These data suggest that CTLs play significant roles in eliciting immune response to corneal allografts.

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PubMed

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：APPLETON & LANGE  

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Language：English   Publisher：LIPPINCOTT-RAVEN PUBL  

Purpose: To investigate expressions of MHC class II antigen and cytokines in the corneal allograft at the early period after transplantation, immunohistochemical study was performed in the murine model. Methods: Penetrating keratoplasty was performed using C3H/He (H-2k) mice as donors and BALB/c (H-2d) mice as recipients. The grafted eyes were enucleated 4, 7, 11 days after transplantation, and immunoperoxidase staining for MHC class II antigen, IL-2, IFN-γ, and IL-10 were performed. Results: MHC class II antigen was expressed on keratocytes in host cornea, especially near the limbal area at the 4th day. The expression was enhanced on keratocytes in both host-graft junction and graft at the 7th day, and corneal endothelium was also stained at the 11th day when allograft rejection occurred clinically. IL-2 and IFN-γ expressing cells were present in the stroma at the host-graft junction at the 4th day. These expressions were extended to both graft and host stroma at the 7th day, and to the epithelium at the 11th day. IL-10 was expressed mainly in the epithelium of both graft and host at the 4th day. It was also expressed in the stroma, especially at the host-graft junction at the 7th day, in both graft and host cornea at the 11th day. Conclusion: Expressions of MHC class II antigen, IL-2, IFN-γ, and IL-10 were shown to be changing their distributions and enhanced before rejection developed clinically.

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Language：English   Publisher：LIPPINCOTT-RAVEN PUBL  

Purpose. Our purpose is to investigate the humoral immune response in rat to mouse concordant corneal xenograft penetrating keratoplasty Methods. We performed orthotopic penetrating keratoplasties using Lewis rats as donors and BALB/c mice as recipients. Mice were divided into treated and non-treated groups. Treated group: FK506 3mg/kg plus anti-mouse LFA-1 monoclonal antibody (anti-LFA-1 mAb) 18mg/kg were administered intraperitoneally. FK506 was injected daily until 12th day and anti-LFA-1 mAb was injected on days 0,1,3,5,7,9 after surgery. HE staining and immunohistochemical examinations were performed on days 6th and 10th in those animals which rejected the xenograft in the non-treated group and on the 70th day in animals from the postoperatively treated group. Sera were collected from the postoperative 70th day treated group. The levels of IgG and IgM in the treated mice sera to Lewis rat spleen cells on the postoperative 70th day after rejection were compared with those of naive mice sera using flow cytometry. Results. Cell infiltration was not found in the stroma on the 6th day in the non-treated group when the grafted corneal became opaque after surgery. Immunofluorescence staining of opaque cornea in the non-treated group demonstrated deposits of IgG, IgM and C3 on the epithelium and the stroma. On the 10th day, marked cell infiltration and stromal edema were seen in the non-treated group. In treated group which survived for 67 days (average value), immunofluorescence staining showed deposits of IgG and IgM, however deposits of C3 were not detected in the rejected cornea. The reactivity to antibodies of anti-mouse IgG alone in the treated group was highly detectable, however IgM was suppressed to the level of the naive mice sera. Conclusions. Complement-dependent cytotoxicity is theorized to be the initial rejection mechanism in rat to mouse corneal xenotransplantation in the non-treated group. Late onset rejection in the group which was treated with FK506 in combination with anti-LFA-1 mAb was associated with the antibody-dependent cell cytotoxicity.

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Language：English   Publisher：LIPPINCOTT-RAVEN PUBL  

Purpose. We previously reported FK506 and anti-mouse LFA-1 monoclonal antibody (anti-LFA-1 mAb) had some effects for suppressing rejection in rat to mouse xenograft penetrating keratoplasty. In the present study, we investigated the effect of a combination of these immunosuppresive agents and assessed on humoral immune response by flow cytometry. Methods. We performed orthotopic penetrating keratoplasties using Lewis rats as donors and BALB/c mice as recipients. Mice were divided into four groups according to the treatment protocol. Group A was a control xenograft (n=13). Group B treated by anti-LFA-1 mAb 18mg/kg (n=7); Group C: FK506 3mg/kg (n=8) and Group D: FK506 3mg/kg plus anti-LFA-1 mAb (n=7) were administered intraperitoneally. FK506 was injected daily until 12th day and anti-LFA-1 mAb was injected on day 0,1,3,5,7,9 after surgery. The corneal grafts were defined as rejected immunologically when they became opaque so that the iris vessel could not be observed. Recipient mice sera on the 12th postoperative day in the four groups were collected. The levels of IgG and IgM in the mice sera to Lewis rat spleen cell were compared with those of naive mouse serum. Results. The average periods of rejection in Groups A, B and C were 5.8, 8.7 and 9.4 days after surgery, respectively. In contrast, Group D (FK506 3mg/kg plus anti-LFA-1 mAb) survived for 67.0 days in average. The reactivity to antibodies of anti-mouse IgG and IgM in Group A was highly detected, however those in Group D were suppressed to the level of naive mouse serum. Conclusions. Treatments with FK506 in combination with anti-LFA-1 mAb significantly suppress the corneal xenograft rejection in animal model.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER VERLAG  

Background: There is a lack of studies focusing on differences in visual field damage between normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) in the late stage of the disease. This problem was addressed in 34 NTG cases and 63 POAG cases with a mean deviation (STATPAC)less than or equal to-15 dB. Age, refraction, mean deviation, best corrected visual acuity and sex ratio showed no significant between-group differences. Methods: Total deviation (STATPAC), the difference between the measured threshold and the age-corrected normal reference at each test point of the Humphrey 30-2 or 10-2 program (TD30 or TD10) was used for pointwise between-group comparisons: (I) difference in the TD30 or TD10 at the examination point due to the difference of disease type was examined using logistic discriminant analysis; (2) a relatively spared point in a given visual field was defined as a test point of TD30 or TD10&gt;mean deviation/3 and the incidence was compared pointwise between the two groups. Further, (TD30-mean TD30) or (TD10-mean TD30) was used to compare the diffuseness of the visual field damage. Results and conclusion: The two methods of pointwise between-group comparison gave similar results. In late-stage disease, the inferior ceco-central field was found to be significantly less depressed in NTG than in POAG. Between-group difference was also suggested in the damage in the superior field and the lower Bjerrum area and in the diffuseness of the visual field damage.

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We reviewed 120 eyes with open angle glaucoma treated by trabeculectomy and subconjunctival 5-fluorouracil. Longstanding postoperative hypotony, defined as intraocular pressure (IOP) lower than 5 mmHg for 6 months, developed in 14 eyes, 12%. Reduction in visual acuity not due to cataract was significantly associated with postoperative hypotony (p &lt; 0.05). Among the factors studied, mean IOP during the 2nd postoperative week lower than 5 mmHg was associated with higher incidence of longstanding postoperative hypotony.

DOI： 10.11477/mf.1410904398

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J-GLOBAL

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:単純ヘルペスウイルス(HSV)脳炎治療後に急性網膜壊死(ARN)を発症し,治療寛解の3年後に僚眼に重篤な閉塞性血管炎を伴うHSV-ARNを生じた1例を経験したので報告する。症例:68歳,女性。2020年5月にHSV脳炎の治療歴があった。2020年10月に左視力低下を主訴に日本医科大学多摩永山病院(当院)を受診した。前房水ポリメラーゼ連鎖反応(PCR)検査でHSVが検出され左眼HSV-ARNと診断した。アシクロビルとプレドニゾロンの全身投与および網膜剥離予防目的で硝子体茎離断術,強膜輪状締結術,シリコーンオイル留置を行い,その後は再燃なく経過していた。2023年4月に右眼の飛蚊症を主訴に当院を受診した。初診時視力は右(0.6),左(0.2)であった。右前房炎症と出血斑の散在,蛍光眼底造影検査でびまん性血管漏出と閉塞性血管炎を認めた。前房水PCR検査でHSVが検出され右眼HSV-ARNと診断した。左眼には再発は認めなかった。アシクロビル全身投与が反応不良であり,ホスカルネットとバラシクロビル投与に変更したが効果不十分であった。ビダラビンとバラシクロビル投与に切り替えたところ,速やかに滲出病変が消退した。第64病日に網膜分離の拡大を認め,水晶体再建術,硝子体茎離断術,強膜輪状締結術,シリコーンオイル留置を行った。右眼の最終視力は光覚弁となった。左眼には再発は認めず矯正視力0.2を維持している。結論:HSV脳炎とHSV-ARNの寛解から3年後に,僚眼に重篤な閉塞性網膜血管炎を伴う急性網膜壊死を生じた。後発眼でより重篤に進行することがあるため,アシクロビル耐性を念頭に置いた薬剤選択が必要である。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01537&link_issn=&doc_id=20240926030018&doc_link_id=10.11477%2Fmf.1410215303&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410215303&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞目的:日本医科大学多摩永山病院(以下,当院)の5年間の内眼炎患者の統計的観察および既報との比較。対象と方法:2018年4月～2023年3月に当院眼炎症外来を初診した内眼炎患者621例(男性248例,女性373例)を後方視的に診療録の観察研究を行った。結果:初診時年齢は55.7±19.5歳。男性248例(39.9%),女性373例(60.1%)。強膜炎151例(24.3%),サルコイドーシス60例(9.7%),Vogt-小柳-原田病32例(5.2%),ヘルペス性角膜ぶどう膜炎32例(5.2%),ベーチェット病24例(3.9%),急性前部ぶどう膜炎22例(3.5%)の順に多く,31.2%は疾患カテゴリー分類不能であった。続発緑内障は238例(38.3%)で,そのうちステロイド緑内障は52例(21.8%)であった。生物学的製剤使用は43例(6.9%)で,そのうちアダリムマブ使用は27例(62.8%)であった。全国多施設眼炎症疾患統計(JJO 2021)と疾患頻度上位6疾患の内訳は一致していたが,本研究は強膜炎が最多であることが異なっていた。筆者らの既報(日眼会誌2015)と比べても,強膜炎が17.0%から24.3%に増え,続発緑内障の発生率も本研究が高かった。結論:当院では他報告と比べて強膜炎が多く,続発緑内障の併発率も高かった。全体で生物学的製剤使用は7%弱であった。

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Language：Japanese   Publisher：眼科臨床紀要会  

背景:新型コロナウイルス感染症(COVID-19)では神経眼科的障害が報告されている.しかし,その多くは神経内科からの報告であり,眼科的経過の詳細についての知見に乏しい.症例:26歳女性.両眼眼瞼下垂と頭痛で初診,その1週間後に複視,左眼外転障害も生じた.4ヵ月前にCOVID-19に罹患していた.全身神経所見では他の異常はなく,髄液オリゴクローナルバンド陽性であった.頭部画像所見でも異常はなかった.1ヵ月後も自覚症状,異常所見が残存していたため,ステロイドパルス療法を施行し,速やかに自覚症状,異常所見は改善した.結論:COVID-19罹患後,遅発性に眼瞼下垂と眼球運動障害を発症し,ステロイドパルス療法が有用であった症例を経験した.本症例の病態は不明であり,今後の経過観察を要する.(著者抄録)

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：眼科臨床紀要会  

背景:MIRAgelは、長期間を経て、変性、膨化することが報告されているが、その機序は不明な点が残る。今回、我々が経験した1例について、摘出検体を病理組織学的に検討したので報告する。症例:82歳、男性。右網膜剥離手術22年後に外斜視、眼球運動障害を生じた。所見:右眼球結膜下に隆起性病変があり、MRIでは境界明瞭な腫瘤がみられた。被膜の一部とその内部の半透明のゼリー状の脆い異物を摘出した。病理組織所見では眼瞼結膜の下に、血管増生を伴う膠原線維層がみられ、細胞浸潤は血管周囲に少量であった。また、CD68抗体陽性細胞が、異物の表面だけでなく、粒子の間隙を通って深部まで浸潤し、異物を貪食していた。結論:CD68抗体陽性細胞が、加水分解によって生じた粒子の間隙を通って深部にも広がり、MIRAgelを破壊、膨化する可能性が示唆された。(著者抄録)

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Language：Japanese   Publisher：(株)メディカル葵出版  

背景:近年、生物学的製剤の投与によるパラドキシカルリアクションが報告されている。今回、関節リウマチ(RA)に対してCTLA4Igを導入され、パラドキシカルリアクションとして強膜炎の発症が疑われた2症例を経験したので報告する。症例:症例1は64歳、女性。RAに対しアバタセプト(ABT)を導入した3ヵ月後に左眼周辺部角膜浸潤を伴うびまん性強膜炎を発症し、眼瞼炎、続発緑内障を合併した。ABTは投与継続とし、ステロイド眼局所治療で強膜炎は消炎した。症例2は76歳、女性。RAに対しABT投与歴があり、右眼びまん性強膜炎を発症し遷延化したため、内科から重症感染症のリスクが低いABTが再度選択された。ABT導入後1週間で強膜炎は増悪し黄斑浮腫も併発し10週後も改善せず、ゴリムマブへ変更後1ヵ月で速やかに鎮静化した。考察:RA患者に対するCTLA4Ig投与はパラドキシカルリアクションとして強膜炎を発症することがあり、強膜炎の鎮静化にはステロイド治療の追加やTNF-α阻害薬への変更が有用であった。(著者抄録)

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Language：Japanese   Publisher：(公財)日本眼科学会  

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J-GLOBAL

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J-GLOBAL

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01049&link_issn=&doc_id=20190214220005&doc_link_id=%2Fdz1nigan%2F2019%2F012302%2F004%2F0128-0134%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz1nigan%2F2019%2F012302%2F004%2F0128-0134%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Vogt-小柳-原田病(VKH)の再発率、再発部位、再発時の治療内容について観察した。2008年1月〜2016年8月に日本医科大学付属病院眼科を受診したVKH患者(n=33)を対象に、診療録より後ろ向きに検討した。初診時の状態は、初発例が24例、再発例が1例、遷延例が4例、他院で加療後の経過観察が4例であった。治療経過中の再発は初発例の24例中6例(25.0%)、再発・遷延例の5例中4例(80%)に認め、再発・遷延例では再発を繰り返す症例が高頻度であった。再発部位は前眼部型6例、後眼部型4例であった。前眼部型に対しては2例を除いてステロイドの眼局所療法が有効であった。後眼部型に対してはステロイドとシクロシポリンの併用や、アダリムマブが有効であった。(著者抄録)

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DOI： 10.18888/J00293.2016240698

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2016240698

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Language：Japanese   Publisher：医歯薬出版(株)  

眼には過剰な炎症を自動制御し組織の恒常性を維持する免疫特性があり、この性質は従来から免疫特権(immune privilege)とよばれている。角膜移植の高い生着率も免疫特権の恩恵である。近年、角膜移植モデルを用いることで、免疫特権の分子機構が解明されつつある。角膜から前房、虹彩にかけて多くの免疫制御因子が発現し、免疫抑制性眼内微小環境が維持されていることは、免疫特権の重要な機序のひとつと考えられている。免疫抑制性眼内微小環境を維持する分子のなかでもFas ligand、B7H1、GITR ligand、Galectin-9などは、エフェクターT細胞へのアポトーシス、制御性T細胞の誘導などを介して、それぞれ眼内の免疫抑制に大きく寄与し、角膜移植片の生着に必須な分子と考えられている。(著者抄録)

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PubMed

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Other Link： http://search.jamas.or.jp/link/ui/2015239987

Purpose: To report a case of Vogt-Koyanagi-Harada disease (VKH) who developed choroidal neovascularization (CNV) that responded to intravitreal ranibizumab. Case: A 56-year-old female was referred to us before. She had been treated by topical and systemic corticosteroid. Findings: Corrected visual acuity was 0.6 right and 0.4 left. Both eyes showed signs of chronic iritis and sunset-glow fundus. Clinical Course: Visual acuity improved to 1.2 in either eye following cataract surgery. Metamorphopsia developed 4 years later with visual acuity of 0.2 right and 0.5 left. Fluorescein angiography and optical coherence tomography showed findings of CNV. Right visual acuity improved to 0.5 following 3 sessions of intravitreal ranibizumab injection over 6 months. She has been doing well for 6 months until present. Conclusion: Repeated sessions of intravitreal ranibizumab was effective for CNV as late complication of VKH.

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Other Link： http://search.jamas.or.jp/link/ui/2015284435

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DOI： 10.11477/mf.1410104491

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Language：Japanese   Publisher：(株)医学書院  

目的:両眼の汎ぶどう膜炎で発症し,その後強皮症と診断された症例の報告。症例:55歳女性が10日前からの左眼充血と疼痛で受診した。所見:矯正視力は右1.0,左0.5で,左眼に虹彩毛様体炎の所見と乳頭発赤があった。蛍光眼底造影で網膜血管の透過性亢進,光干渉断層計(OCT)で漿液性網膜剥離があった。2ヵ月後に右眼に同様の病変が生じた。次第に手指皮膚の硬化とRaynaud現象が出現し,強皮症と診断された。副腎皮質ステロイドの局所投与で眼所見は10ヵ月後に寛解した。結論:膠原病としての全身症状が顕在化する前に,これと原因的に関連する汎ぶどう膜炎が発症することを本症例は示している。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01537&link_issn=&doc_id=20120224160016&doc_link_id=10.11477%2Fmf.1410104090&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410104090&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(公財)日本眼科学会  

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DOI： 10.11477/mf.1410103969

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2011002375

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CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2010218611

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Purpose : To report the incidence of endogenous intraocular inflammation in our department. Cases : This retrospective study was made on 433 new cases of endophthalmitis during 4 years through 2008. The series comprised 208 males and 225 females. The age averaged 51 years. Results : There were anterior uveitis 47%, panuveitis 27%, posterior uveitis 19% and intermediate uveitis 4%. Definitive diagnosis was made in 272 cases (63%). They comprised sarcoidosis 19%, scleritis 14%, Vogt-Koyanagi-Harada (VKH) disease 5%, herpetic uveitis 5%, acute anterior uveitis 4% and Behçet disease 3%. Juvenile iridocyclitis was the most frequent among children, and sarcoidosis among adults. Secondary glaucoma, including steroid glaucoma, was present in 30% of cases. Conclusion : About 37% of cases could not be classified in the present series. Sarcoidosis, VKH and Behçet diseasse were major clinical entities. Rinsho Ganka (Jpn J Clin Ophthalmol) 63(5): 701-705,2009.

DOI： 10.11477/mf.1410102706

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Publisher：The Society of Japanese Women Scientists  

The normal eye possesses immune privilege. When grafted orthotopically to the eye of experimental animals, allogeneic corneas enjoy a relatively high level of acceptance, compared to orthotopic grafts of other types of solid tissue. Each layer of the cornea displays different potentials of alloimmunogenicity or immune privilege. Immunogenicity of the cornea as an allograft resides within its epithelium and stroma, whereas immune privilege arises from endothelium. Corneal endothelium confers immune privilege on the corneal allografts through constitutive expression of CD95L and B7-H1. These molecules induce apoptosis of effector T cells by binding to CD95 and PD-1 expressed on T cells. These two key molecules play a role on peripheral deletion of allo-reactive effector T cells within corneas to maintain immune privilege of corneal allografts. To reduce allogeneic donor epithelium-derived immunogenicity in transplantation, a reconstituted corneal tissue, eliminating the risk of immune rejection, was created. Replacement of donor epithelium with syngeneneic epithelium protects orthotopic corneal allografts from allo-sensitization and rejection even in high risk recipients.

DOI： 10.5939/sjws.07002

CiNii Books

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Other Link： https://jlc.jst.go.jp/DN/JALC/00379518991?from=CiNii

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2008051814

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Background: After corneal endothelial injury, adjacent cells migrate to cover the wounded area, which results in equalization of cell density (CD) over the entire cornea. We report a case of blunt corneal injury in which we used specular microscopy to follow the course of endothelial CD changes in many local areas of the cornea. Case Report: A 13-year-old boy was injured in both eyes by explosion of a plastic bottle containing dry ice. At the initial examination, his right eye was found to have hyphema, central corneal erosion, stromal edema, and folds in Descemet's membrane in the center, inferior, and nasal areas of the cornea. The left eye was found to have a fold in Descemet's membrane in the inferior cornea. Follow-up specular microscopy examinations were performed weekly until 13 weeks after the injury. In the right eye, CD in the central area was appreciably decreased compared to CD in the left eye at 1 week after injury, and at 3 to 4 weeks after injury there was obvious decrease in CD over the whole area except for the uninjured superior portion of the cornea. However, CDs in the injured areas became equal to CD over the entire cornea during weeks 7 to 13. Similar trends were observed in the population of hexagonal cells and the coefficient of variance in various areas. Conclusion: In this case, regular follow-up specular microscopy examinations documented equalization of CD in injured areas and over the entire cornea by 13 weeks after injury.

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2006258715

Language：Japanese  

DOI： 10.11477/mf.1410100353

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2006141030

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Language：Japanese  

DOI： 10.11477/mf.1410100169

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2006050987

Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2006004499

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CiNii Books

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Language：Japanese   Publisher：(公財)日本眼科学会  

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DOI： 10.11477/mf.1410904468

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DOI： 10.11477/mf.1410904407

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Language：Japanese  

CiNii Books

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Language：Japanese   Publishing type：Research paper (scientific journal)  

To compare the visual field defects in the late stage of disease between normal-tension glaucoma (NTG) and primary open angle glaucoma (POAG), measurements taken with the 30-2 and 10-2 threshold program of the Humphrey Visual Field Analyzer were analysed by statistical methods including logistic discriminant analysis. Thirty-four eyes of 34 NTG cases and 63 eyes of 63 POAG cases whose mean deviation (MD) given by STATPAC was equal to or less than -15 dP were included and there was no significant difference in MD, refraction, or age between the two groups. The analyses demonstrated that the upper arcuate area was significantly more depressed in POAG and the inferior Bjerrum area was significantly more depressed in NTG eyes. It was also shown that the lower papillo-macular area was less affected in NTG than in POAG eyes.

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PubMed

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DOI： 10.11477/mf.1410901986

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Total pages：xxiii, 1143p   Language：Japanese  

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Total pages：279p   Language：Japanese  

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Responsible for pages：286-290  

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Language：Japanese   Publisher：(一社)日本小児リウマチ学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：Japanese   Publisher：眼科臨床紀要会  

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：眼科臨床医報会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：Japanese   Publisher：眼科臨床医報会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT-RAVEN PUBL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：LIPPINCOTT-RAVEN PUBL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ASSOC RESEARCH VISION OPHTHALMOLOGY INC  

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Language：English  

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Venue：Gold Coast, Australia   Country：Australia  

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Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：Charles University in Prague Czech Republic.   Country：Czech Republic  

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Presentation type：Oral presentation (general)  

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Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2022.10

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Event date： 2022.10

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Event date： 2022.10

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Event date： 2022.10

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Event date： 2022.4

Presentation type：Oral presentation (general)  

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Event date： 2020.10

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Event date： 2020.10

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Event date： 2020.10

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Event date： 2020.10

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