In vivo characterization of rabbit anti-mouse thymocyte globulin: a surrogate for rabbit anti-human thymocyte globulin.

摘要

BACKGROUND: Polyclonal rabbit anti-human thymocyte globulin (Thymoglobulin) is used clinically for immunosuppression in solid organ transplantation; however, it is difficult to fully characterize the effects of this agent in humans. METHODS: A surrogate rabbit anti-murine thymocyte globulin (mATG) was generated analogously to the commercial product Thymoglobulin and in vivo activities were evaluated, including pharmacokinetics, T-cell depletion, dose response and kinetics, depletion/sparing of T-cell subsets or other leukocyte populations, and depletion in different lymphoid organs. RESULTS: Within 1 day, T cells are depleted by mATG in the blood, spleen, lymph node, and bone marrow down to doses of 1 mg/kg. Although mATG binds and depletes thymocytes in vitro, there is no thymocyte depletion in vivo at any dose level, suggesting decreased antibody accessibility to the thymus. After two doses of mATG given 3 days apart, T-cell reconstitution begins as early as day 9 and returns to basal levels by day 21 and 29 for CD4 and CD8 T cells, respectively. There is also preferential depletion of naive T cells that results in increased ratios of regulatory and memory T cells within 1 day after mATG administration. Depletion of natural killer-T cells, natural killer cells, plasma cells, and plasmablasts occurs, but is modest and more transient compared with T cells. B cells, macrophages, dendritic cells, hematopoetic stem cells, and bone marrow stromal cells seem resistant to mATG depletion. CONCLUSIONS: These studies characterize the depletive effects of mATG in normal mice and provide insight into mechanisms of action of Thymoglobulin.