The purpose of this proposal is to investigate the role of 1,25(OH)2D3 in the regulation of T-lymphocyte mediated immunity. We have discovered that peripheral human lymphocytes express 1,25(OH)2D3 receptors upon activation and that the hormone, probably acting via this receptor, is a very potent suppressor of the lymphokine interleukin-2 (IL-2) and it inhibits the generation of cytotoxic T-lymphocytes. We have also obtained preliminary evidence to suggest that 1,25(OH)2D3 is involved in the intrathymic differentiation of lymphocytes. Using in vitro activated T-lymphocytes from normal donors as well as two continuous T cell lines, one that constitutively produces IL-2 (MLA-144) and a second that produces IL-2 upon stimulation with mitogens (Jurkat-clote 71) we shall investigate in detail the mechanism of and the cellular and biochemical events which are associated with the 1,25(OH)2D3 induced suppression of IL-2 and inhibition of generation of cytotoxic T-lymphocytes. In addition we shall investigate the role of 1,25(OH)2D3 in intrathymic T-cell differentiation, using lymphocytes isolated from rat thymuses. There is ample evidence that calcium plays a central role in the activation of lymphocytes and the production of lymphokines. In view of this and the well documented calcitropic actions of 1,25(OH)2D3 in its classical target tissues, we shall examine whether the 1,25(OH)2D3 effects on T-lymphocytes are dependent on calcium and whether they can be influenced by either the mineral itself or by ionophores. Finally we shall also examine the influence of Glucocorticosteroids on the 1,25(OH)2D3 effects on T-lymphocytes; the former hormone also suppresses immune responses including IL-2 production and cytotoxic lymphocyte generation. The proposed studies should provide a comprehensive insight on the involvement of 1,25(OH)2D3 in cellular immunity both at the T-lymphocyte differentiation level and at the level of the effector function of these cells. Moreover they might provide the basis for subsequent exploitation of the effects of 1,25(OH)2D3, either alone or in combination with Glucocorticoids or Calcitropic agents, in the therapeutic manipulation of immune responses.
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