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      Survival of Allografted Pancreatic Islets in the Subretinal Space in Rats

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          Abstract

          The purpose of this study was to determine whether the subretinal space would provide immune privilege for pancreatic islet transplantation. Islets from outbred Sprague Dawley (SD) rats were isolated by collagenase digestion, and about 200 handpicked islets were transplanted into the subretinal space of SD rats. Similar grafts were transplanted into the subconjunctival space of SD rats as controls. Transplanted eyes were enucleated after 2 to 60 days, fixed and embedded in paraffin for immunoperoxidase staining of insulin, glucagon, and CD8+ lymphocytes. Clinical examination of rat eyes revealed minimal or no inflammation in the anterior chamber or vitreous at any time point. Fifteen of 19 subretinal allografts survived up to 60 days. Few CD8+ lymphocytes were present in the subretinal grafts and the endocrine cells stained intensely for insulin and glucagon at all time points. In contrast, CD8+ lymphocytes were present in subconjunctival grafts in rats by day 14 and all grafts were destroyed by day 21. These results suggest that the subretinal space provides immune privilege for islet allotransplantation by preventing massive lymphocyte infiltration.

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          A role for CD95 ligand in preventing graft rejection.

          Testis is a remarkable immune-privileged site, long known for its ability to support allogeneic and xenogeneic tissue transplants. Here we have investigated the molecular basis for testis immune privilege. Testis grafts derived from mice that can express functional CD95 (Fas or Apo-1) ligand survived indefinitely when transplanted under the kidney capsule of allogeneic animals, whereas testis grafts derived from mutant gld mice, which express non-functional ligand, were rejected. Further analysis of testis showed that CD95 ligand messenger RNA is constitutively expressed by testicular Sertoli cells, and that Sertoli cells from normal mice, but not gld mice, were accepted when transplanted into allogeneic recipients. CD95 ligand expression in the testis probably acts by inducing apoptotic cell death of CD95-expressing, recipient T cells activated in response to graft antigens. These findings indicate that CD95 ligand could be used to create immune-privileged tissue for a variety of transplant uses.
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            CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance.

            We examined the relationship between cell death and tolerance induction following antigen injection into the anterior chamber of the eye. Our data show that when inflammatory cells undergo apoptosis following infection with HSV-1, tolerance to the virus was observed. In contrast, when cell death was absent due to defects in Fas or FasL, immune tolerance was not observed. Further studies revealed that cell death and tolerance required that the lymphoid cells be Fas+ and the eye be FasL+. Additionally, we show that while Fas/FasL-mediated apoptosis occurred in the eye, it was apoptotic cell death that was critical for tolerance induction. Our results further demonstrate immune privilege is not a passive process involving physical barriers, but is an active process that employs an important natural mechanism to induce cell death and immune tolerance.
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              Immunologic consequences of intraocular implantation of retinal pigment epithelial allografts.

              Immune rejection is a major concern for potential therapeutic RPE transplantation. The purpose of this study is to determine the pattern and consequences of immune responses to intraocular retinal pigment epithelial (RPE) allografts. RPE allografts which derive from C57BL/6 newborn mice were implanted into the subretinal space (SR), anterior chamber (AC) and subconjunctival space (SCon) of the eyes of adult BALB/c mice. After implantation, clinical, histological and immunological examinations were conducted. Results revealed that RPE allografts implanted into SR and AC had a prolonged survival which is associated with a suppression of donor-specific delayed hypersensitivity (DH) for at least 12 days. In contrast, similar RPE grafts implanted into the SCon induced conventional DH and grafts were rejected. Moreover, previously healthy intraocular RPE grafts were rejected 2 weeks after a donor-specific challenge and rejection was accomplished with extensive cell infiltration which subsequently damaged intraocular tissue of the host eye. These results suggested that intraocular RPE allografts enjoyed immune privilege and induced a down-regulation of immune responses. However, this privilege is not absolute and static--DH was able to emerge and grafts were rejected in a cell-mediated fashion.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2003
                February 2003
                30 January 2003
                : 35
                : 1
                : 48-53
                Affiliations
                aDuke University Eye Center, DUMC, and bThe Veterans Affair Medical Center, Durham, N.C., USA
                Article
                68197 Ophthalmic Res 2003;35:48–53
                10.1159/000068197
                12566863
                978bb915-5fd9-49a8-bbd2-17c078de9d42
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 27 March 2002
                : 20 September 2002
                Page count
                Figures: 5, Tables: 1, References: 17, Pages: 6
                Categories
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Islet transplantation,Subretinal transplant,Immune privilege,Islet of Langerhans

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