THE MECHANISMS OF IMMUNOSUPPRESSION BY CYCLOSPORIN A (CSA) (T-CELL, INTERLUKIN-2, T-LEUKEMIA)
Using a limited dilution analysis it was found that CsA impairs the T helper cell function in an in vitro MLC assay. As a consequence no proliferation (i.e., expansion) of cytolytic T cells (CTL) occurred, but CTL precursor cells remained intact. This suppression of CTL generation can be overcome by adding exogenous IL-2 into the culture. When mice were treated with CsA in vivo, it was found that a low dose of CsA treatment only T helper cell function is impaired; however, when the dose was increased, the CTL precursor cells are eliminated in an antigen nonspecific manner. The lymphokine production of spleen cells from CsA treated animals were quantified. Data show that the production of Interleukin-2 (IL-2), a T cell growth factor produced by T helper cells, was significantly decreased; but, the production of Interleukin-1 (IL-1), a T helper cell activator produced by macrophages, was not affected. These data confirm that CsA impairs T helper cell function. When the effect of CsA on cultured tumor cells was evaluated, it was found that CsA is cytostatic to T-cell tumors, regardless of whether they express the IL-2 receptors; however, for tumor cells which express the IL-2 receptor, their suppression by CsA can be overcome by the presence of IL-2 in the culture medium. On the other hand, for tumor cells expressing no IL-2 receptor, the exogenous IL-2 cannot overcome the CsA-induced suppression. These findings lead to the conclusion that CsA-induced suppression may not be a result of direct action on IL-2 receptors. For nonmalignant T cell clones, regardless of their classification and function, their alloantigen-driven but not IL-2-driven proliferation was found to be suppressed by CsA. However, the cytolysis reaction of both class I and class II cytolytic T cells was not affected by CsA. These data lead to the hypothesis that on the cellular level CsA induced suppression of T cells by either binding to the receptor(s) (cyclophilin) on both malignant or nonmalignant T cells, or alternatively, preventing nonmalignant T-cells from responding to the stimulating determinant on the histocompatibility antigen.
SHIH, CHIU-YANG (CHARLES), "THE MECHANISMS OF IMMUNOSUPPRESSION BY CYCLOSPORIN A (CSA) (T-CELL, INTERLUKIN-2, T-LEUKEMIA)" (1984). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI8502601.