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The mechanisms controlling the production of antibodies against histocompatibility antigens are of prime importance in organ transplantation.We investigated the role of complement in the response to allogeneic stimulation, using mice deficient in C3, C4, or C5 to dissect the role of the alternative, classical, and terminal complement pathways.After fully major histocompatibility complex disparate skin grafts, the allospecific immunoglobulin (Ig)G response was markedly impaired in C3- and C4-, but not in C5-deficient mice. This defect was most pronounced for second set responses. C3-deficient mice also demonstrated a decreased range of IgG isotypes. In contrast, there was no impairment of the allospecific IgM response. In functional T cell assays, the proliferative response and interferon-γ secretion of recipient lymphocytes restimulated in vitro with donor antigen was decreased two- to threefold in C3-deficient mice.These data show impairment of allogeneic T cell and B cell function in mice with defective complement activation and suggest a predominant role for the classical pathway in stimulating alloimmunity. The terminal pathway seems unimportant in this regard. This extends the results reported for soluble protein antigens and demonstrates a surprisingly marked effect on the alloresponse despite the presence of a stringent antigenic stimulus. These results have implications for the prevention of sensitization in naïve transplant recipients.