The allogeneic T and B cell response is strongly dependent on complement components C3 and C4

Background. The mechanisms controlling the production of antibodies against histocompatibility antigens are of prime importance in organ transplantati on. Methods. We investigated the role of complement in the response to allogene ic stimulation, using mice deficient in C3, C4, or C5 to dissect the role o f the alternative, classical, and terminal complement pathways. Results. After fully major histocompatibility complex disparate skin grafts , the allospecific immunoglobulin (Ig)G response was markedly impaired in C 3-and C4-, but not in C5-deficient mice. This defect was most pronounced fo r second set responses. C3-deficient mice also demonstrated a decreased ran ge of IgG isotypes. In contrast, there was no impairment of the allospecifi c IgM response. In functional T cell assays, the proliferative response and interferon-gamma secretion of recipient lymphocytes restimulated in vitro with donor antigen was decreased two- to threefold in C3-deficient mice. Conclusions. These data show impairment of allogeneic T cell and B cell fun ction in mice with defective complement activation and suggest a predominan t 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 na ive transplant recipients.