DIFFERENTIAL EFFECT OF CYCLOSPORINE ON LYMPHOCYTE SUBSET

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The hallmark of the immune system is its ability to distinguish "self" from "non-self"; failure to do so may result in autoimmune disease. Education of the immune system as to the concept of self takes place in the thymus wherein autoreactive lymphocytes are deleted, tolerized or actively suppressed. Clonal deletion is a major, albeit not the only, mechanism for self tolerance. The exact process by which clonal deletion takes place is not well understood although there are several autoimmune animal models in which the disease can be ameliorated by the adoptive transfer of normal thymocytes. This suggests that a thymocyte subset(s) may be involved in clonal deletion. The principal investigator has recently identified a novel murine thymocyte subset (NK1.1+, CD3+, CD4-, CD8-, CD5+, CD44+, Thy1+, TCR alpha/beta) which has a spontaneous lytic potential. Upon expansion with interleukin 2 (IL2), this population could kill fresh autologous CD4+, CD8+ thymocytes as well as PHA-activated mature thymocytes. These attributes are the basis of the hypothesis that NK1.1+, CD3+ thymocytes are important in the clonal deletion aspect of thymic selection. This hypothesis will be tested utilizing an in vivo and in vitro strategy. Major emphasis will be placed on examining the effect of neonatal cyclosporine (CSA) administration, which leads to the development of autoimmune disease, on the function and number of these thymocytes. Programmed cell death is another method by which self-tolerization is thought to be accomplished. Anti-CD3, in vivo, induces apoptosis in murine thymocytes. Preliminary data showed that, in addition to apoptosis, anti- CD3 causes near total depletion of CD4+, CD8+ thymocytes with a concomitant expansion of the NK1.1+, CD3+ subset and an insurgence of cytotoxic effector cells; CSA seems to abolish all these changes. The hypothesis to be tested is that the thymic effects of in vivo anti-CD3 are mediated, to a large extent, by cytokine-induced activation and expansion of NK1.1+, CD3+ thymocytes. T cell depletion, in vivo, is already being used clinically in certain autoimmune diseases and in treating organ transplant rejection. There is little known about the effects of such treatment on the immune system as a whole, with its interactive feedback mechanisms, and no attention has been given to the thymus. This proposal is expected to yield fruitful results clinically applicable in the autoimmunity and transplantation areas.