Colchicine inhibits cell microtubule assembly by binding to and preventing the polymerization ot tubulin monomers. Although there are data to indicate that colchicine inhibits a variety of cell-mediated immune responses, the effects and mechanisms of inhibiting cell microtubule assembly on the alloimmune response have not been thoroughly investigated. It has recently been shown that colchicine prevents acute rejection and promotes the long-term survival of rat renal allografts. In this study, the effects and mechanisms of inhibiting cell microtubule assembly by colchicine on the alloimmune response in vitro and in vivo were examined. First, the effects of colchicine on T lymphocyte response to alloantigen in vitro were tested. In the standard one-way mixed lymphocyte response (MLR), responder Lewis rat lymph node cells were cultured with irradiated Brown Norway stimulators. Colchicine inhibited the MLR in a dose-dependent manner, with 100% inhibition at a concentration of 25 ng/mL (6.25 x 10-8 M) and 50% inhibition at a concentration of approximately 5 to 10 ng/mL. Colchicine also inhibited the generation of cytotoxic T lymphocytes as well as cytotoxic T cell effector function in vitro in a dose-dependent fashion. Second, detailed immunohistologic studies of renal allografts harvested from unmodified control (acutely rejecting) and colchicine-treated rats (Day 15 or 30) were performed. These studies showed that grafts from colchicine-treated animals had significantly fewer mononuclear cell infiltrates and less edema, and moderately decreased deposition of immunoglobulin M, C3, and fibrin, as compared with acutely rejecting control grafts. In addition, grafts from colchicine-treated rats looked up-regulation of activation markers, including interleukin (IL)-2 receptor, major histocompatibility complex class II, and intercellular adhesion molecule-1, and showed essentially no expression ot the Th1-type activation and inflammatory cytokines IL-2, interferon-gamma, and tumor necrosis factor-alpha, respectively. By contrast, these grafts showed markedly increased labeling of intragraft mononuclear cells and associated endothelial cells for the Th2-related cytokine IL-4 and preservation of IL-6 expression, as compared with rejecting controls. These data indicate that blocking cell microtubule assembly down-regulates the alloimmune response in vitro, prevents acute rejection, and effects prolonged renal allograft survival by the selective inhibition of Th1 and the sparing of Th2 cell function in vivo. Understanding the mechanisms of how inhibiting cell microtubule assembly leads to such a state of immune deviation may lead to the development of novel therapies in organ transplantation as well as in autoimmune disease.
|Number of pages
|Journal of the American Society of Nephrology
|Published - Jan 1995
ASJC Scopus subject areas
- General Medicine