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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 1;99(3):396–402. doi: 10.1172/JCI119173

CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival.

P M Stuart 1, T S Griffith 1, N Usui 1, J Pepose 1, X Yu 1, T A Ferguson 1
PMCID: PMC507812  PMID: 9022072

Abstract

Although anatomical barriers and soluble mediators have been implicated in immune privilege, it appears that the apoptotic cell death of Fas+ cells by tissue-associated CD95 ligand (Fas ligand, FasL) is an important component. One clinical example of the function of an immune privileged site is the success of human corneal transplants, where a very high percentage of transplants accept without tissue matching or immunosuppressive therapy. Since the mouse cornea expresses abundant Fas ligand and immune privilege has been implicated in the success of these transplants, we examined the role of FasL in corneal transplantation. Our results show that human corneas express functional FasL capable of killing Fas+ lymphoid cells in an in vitro culture system. Using a mouse model for corneal allograft transplantation, FasL+ orthografts were accepted at a rate of 45%, whereas FasL- grafts, or normal grafts transplanted to Fas- mice, were rejected 100% of the time. Histological analysis found that FasL+ grafts contained apoptotic mononuclear cells indicating the induction of apoptosis by the graft, while rejecting FasL- corneas contained numerous inflammatory cells without associated apoptosis. Taken together our results demonstrate that FasL expression on the cornea is a major factor in corneal allograft survival and, thus, we provide an explanation for one of the most successful tissue transplants performed in humans.

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Selected References

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  1. Abbas A. K. Die and let live: eliminating dangerous lymphocytes. Cell. 1996 Mar 8;84(5):655–657. doi: 10.1016/s0092-8674(00)81042-9. [DOI] [PubMed] [Google Scholar]
  2. Bellgrau D., Gold D., Selawry H., Moore J., Franzusoff A., Duke R. C. A role for CD95 ligand in preventing graft rejection. Nature. 1995 Oct 19;377(6550):630–632. doi: 10.1038/377630a0. [DOI] [PubMed] [Google Scholar]
  3. Boisjoly H. M., Tourigny R., Bazin R., Laughrea P. A., Dubé I., Chamberland G., Bernier J., Roy R. Risk factors of corneal graft failure. Ophthalmology. 1993 Nov;100(11):1728–1735. doi: 10.1016/s0161-6420(93)31409-0. [DOI] [PubMed] [Google Scholar]
  4. Brady S. E., Rapuano C. J., Arentsen J. J., Cohen E. J., Laibson P. R. Clinical indications for and procedures associated with penetrating keratoplasty, 1983-1988. Am J Ophthalmol. 1989 Aug 15;108(2):118–122. doi: 10.1016/0002-9394(89)90003-2. [DOI] [PubMed] [Google Scholar]
  5. Brunner T., Mogil R. J., LaFace D., Yoo N. J., Mahboubi A., Echeverri F., Martin S. J., Force W. R., Lynch D. H., Ware C. F. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature. 1995 Feb 2;373(6513):441–444. doi: 10.1038/373441a0. [DOI] [PubMed] [Google Scholar]
  6. Ferguson T. A., Dube P., Griffith T. S. Regulation of contact hypersensitivity by interleukin 10. J Exp Med. 1994 May 1;179(5):1597–1604. doi: 10.1084/jem.179.5.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ferguson T. A., Fletcher S., Herndon J., Griffith T. S. Neuropeptides modulate immune deviation induced via the anterior chamber of the eye. J Immunol. 1995 Aug 15;155(4):1746–1756. [PubMed] [Google Scholar]
  8. Ferguson T. A., Hayashi J. D., Kaplan H. J. The immune response and the eye. III. Anterior chamber-associated immune deviation can be adoptively transferred by serum. J Immunol. 1989 Aug 1;143(3):821–826. [PubMed] [Google Scholar]
  9. Goldberg M. F., Ferguson T. A., Pepose J. S. Detection of cellular adhesion molecules in inflamed human corneas. Ophthalmology. 1994 Jan;101(1):161–168. doi: 10.1016/s0161-6420(94)31370-4. [DOI] [PubMed] [Google Scholar]
  10. Griffith T. S., Brunner T., Fletcher S. M., Green D. R., Ferguson T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science. 1995 Nov 17;270(5239):1189–1192. doi: 10.1126/science.270.5239.1189. [DOI] [PubMed] [Google Scholar]
  11. Griffith T. S., Herndon J. M., Lima J., Kahn M., Ferguson T. A. The immune response and the eye. TCR alpha-chain related molecules regulate the systemic immunity to antigen presented in the eye. Int Immunol. 1995 Oct;7(10):1617–1625. doi: 10.1093/intimm/7.10.1617. [DOI] [PubMed] [Google Scholar]
  12. Griffith T. S., Yu X., Herndon J. M., Green D. R., Ferguson T. A. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity. 1996 Jul;5(1):7–16. doi: 10.1016/s1074-7613(00)80305-2. [DOI] [PubMed] [Google Scholar]
  13. Joo C. K., Pepose J. S., Stuart P. M. T-cell mediated responses in a murine model of orthotopic corneal transplantation. Invest Ophthalmol Vis Sci. 1995 Jul;36(8):1530–1540. [PubMed] [Google Scholar]
  14. Ju S. T., Panka D. J., Cui H., Ettinger R., el-Khatib M., Sherr D. H., Stanger B. Z., Marshak-Rothstein A. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995 Feb 2;373(6513):444–448. doi: 10.1038/373444a0. [DOI] [PubMed] [Google Scholar]
  15. Kaplan H. J., Streilein J. W. Immune response to immunization via the anterior chamber of the eye. I. F. lymphocyte-induced immune deviation. J Immunol. 1977 Mar;118(3):809–814. [PubMed] [Google Scholar]
  16. Lau H. T., Yu M., Fontana A., Stoeckert C. J., Jr Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science. 1996 Jul 5;273(5271):109–112. doi: 10.1126/science.273.5271.109. [DOI] [PubMed] [Google Scholar]
  17. Mogil R. J., Radvanyi L., Gonzalez-Quintial R., Miller R., Mills G., Theofilopoulos A. N., Green D. R. Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo. Int Immunol. 1995 Sep;7(9):1451–1458. doi: 10.1093/intimm/7.9.1451. [DOI] [PubMed] [Google Scholar]
  18. Nagata S., Suda T. Fas and Fas ligand: lpr and gld mutations. Immunol Today. 1995 Jan;16(1):39–43. doi: 10.1016/0167-5699(95)80069-7. [DOI] [PubMed] [Google Scholar]
  19. Niederkorn J. Y., Callanan D., Ross J. R. Prevention of the induction of allospecific cytotoxic T lymphocyte and delayed-type hypersensitivity responses by ultraviolet irradiation of corneal allografts. Transplantation. 1990 Aug;50(2):281–286. doi: 10.1097/00007890-199008000-00023. [DOI] [PubMed] [Google Scholar]
  20. Rieux-Laucat F., Le Deist F., Hivroz C., Roberts I. A., Debatin K. M., Fischer A., de Villartay J. P. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995 Jun 2;268(5215):1347–1349. doi: 10.1126/science.7539157. [DOI] [PubMed] [Google Scholar]
  21. Singer G. G., Abbas A. K. The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity. 1994 Aug;1(5):365–371. doi: 10.1016/1074-7613(94)90067-1. [DOI] [PubMed] [Google Scholar]
  22. Sonoda Y., Streilein J. W. Impaired cell-mediated immunity in mice bearing healthy orthotopic corneal allografts. J Immunol. 1993 Mar 1;150(5):1727–1734. [PubMed] [Google Scholar]
  23. Stuart P. M., Beck-Maier B., Melvold R. W. Provocation of skin graft rejection across murine class II differences by non--bone-marrow-derived cells. Transplantation. 1984 Apr;37(4):393–396. doi: 10.1097/00007890-198404000-00016. [DOI] [PubMed] [Google Scholar]
  24. Wilbanks G. A., Mammolenti M., Streilein J. W. Studies on the induction of anterior chamber-associated immune deviation (ACAID). II. Eye-derived cells participate in generating blood-borne signals that induce ACAID. J Immunol. 1991 May 1;146(9):3018–3024. [PubMed] [Google Scholar]

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