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The specific anti-T lymphocyte immunosuppressive drugs cyclosporine A (CsA), FK-506 (FK) and rapamycin (RPM) have revolutionized the field of allograft transplantation and have recently been evaluated for use in autoimmune diseases. Effects of immunosuppressive drugs on adhesion molecule expression in the putative autoimmune conditions psoriasis, through the use of keratinocyte (KC) cell culture techniques, and alopecia areata were investigated. In the Dundee Experiment Bald Rat, a model of alopecia areata, hair regrowth was only apparent with CsA therapy and FK had a high toxicity profile. <I>In vivo</I> the observed cutaneous reduction of ICAM-1 and LFA-1 expression particularly around the hair bulbs was due to the effects of CsA and FK on the inflammatory cell infiltrate, especially since the associated cutaneous lymphocyte populations were reduced with drug. This is corroborated by the results obtained from <I>in vitro</I> culture of human KC, since cytokine-induced expression and release of ICAM-1 by KC was unaffected by CsA, RPM or FK treatment. CsA and RPM, but not FK, however, had an observable cytostatic effect on unstimulated and more especially, cytokine-stimulated KC proliferation and may, therefore, clinically inhibit KC hyperplasia, which is characteristic of psoriasis. This study shows that CsA, FK and RPM may inhibit either directly but more likely in an indirect manner, cellular adhesion molecule expression during immune reactions. This effect will lower the possible number of cellular interactions and furthermore, reduce intracellular co-signalling events necessary for cellular activation which accounts for the overall inhibition of cell-mediated immune responses by these novel immunosuppressive drugs.

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This thesis aims to place corneal allograft rejection in the context of general transplantation immunology, examine the role of lymphocyte subsets in the rejection process and consider the potential application of monoclonal antibody therapy in clinical corneal graft rejection. The literature relating to the current clinical practice of corneal grafting, with particular reference to corneal allograft rejection, is reviewed in chapter 1 to present the extent of the problem. Chapter 2 then reviews the mechanisms of allograft rejection from the literature of transplantation immunology, much of which has arisen from studies of kidney, heart, pancreatic islets and liver in animal models. The materials and methods are described in detail in chapter 3, and only the relevant experimental design is detailed in the Materials and Methods sections of the succeeding chapters. The experimental mouse model of transplanting corneal tissue into the renal subcapsular is evaluated in chapter 4, demonstrating that isografts survive indefinitely whereas allografts are rejected typically by 30 days. Pretransplant sensitisation decreased allograft survival time to 10 days. Immunohistochemistry demonstrated the presence of CD4⁺ and CD8⁺ lymphocytes and macrophages at the rejection site. Heterotopic corneal graft recipients were then treated with various monoclonal antibody regimes. Chapter 5 demonstrates that allograft survival can be increased by either anti-CD4 or anti-CD8 therapy, providing near total depletion of the respective lymphocyte subset is achieved. Xenograft rejection is shown to depend on mainly CD4⁺ lymphocytes in chapter 6, with no benefit being found of depleting the CD8⁺ subset in addition. A mild immunosuppressive effect of anti-Vβ8 monoclonal antibody is demonstrated and discussed in chapter 7. The final chapter discusses these results in the light of recent, related work in other transplant systems, and presents a case for a trial of intracameral pan-T-cell monoclonal antibody treatment.