Cyclosporine (CsA), a natural 11 amino acid peptide with potent immunosuppressive properties, is widely used for the prevention of graft rejection and in the treatment of graft-versus-host disease (GVHD). The mode of action of this agent is still imprecisely understood but appears to be related to inhibition of early T cell activation, and most current investigations are directed towards elucidating manifestations of this drug in T cells. Functions of non-lymphocyte accessory cells are crucial in the early inductive phase of T cell activation. Accessory cells process and present antigens to the appropriate lymphocyte in association with products of class II major histocompatibility complex (Ia) genes expressed on their surface. Secondly, a variety of powerful immunomodulators, essential for the propagation and regulation of immunologic responsiveness are elaborated by these cells. It is postulated here that cyclosporine exerts at least part of its immunosuppressive action by altering accessory cell physiology and function. In this proposal, experiments designed to evaluate the effects of CsA on accessory cell physiology and function with respect to T cell initiation and activation will be described. In brief, this study will examine whether antigen (soluble and alloantigen) processing and presentation are impaired by CsA treatment of human monocytes and macrophages. The study will include attempts to examine whether CsA affects the expression and induction of Ia and the elaboration of immune mediators particularly interleukin-l, the prostaglandins, leukotrienes and thromboxanes. In addition, this proposed study will use CsA to probe the possibility of immune regulation at the level of monocyte antigen presentation. In order to circumvent problems inherent in routine monocyte/macrophage preparations (i.e. plastic adherence) relatively pure monocyte populations will be prepared using counterflow centrifugation elutriation. These monocytes will be studied for a) heterogeneity in cell surface markers such as Ia, Leu 10, Leu M3, and OKM-l expression, b) heterogeneity in function such as interleukin 1 production, arachidonic acid metabolism ability to present soluble and particulate antigens, and ability to preferentially activate suppressor or cytotoxic cells, and c) heterogeneity in sensitivity to Csa.
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