Immunopathogenesis of accelerated allograft rejection in sensitized recipients: Humoral and nonhumoral mechanisms

Introduction. Accelerated rejection (AccR) in sensitized recipients (second-set rejection) is considered a classic humorally mediated form of allograft rejection, although additional effector mechanisms may be involved. Methods. We developed a model of AccR in which C57BL6 mice are sensitized by BALB/c skin grafts, followed 10 days later by transplantation of BALB/c hearts. We undertook analysis of various humoral and cellular components in this model using knockout or monoclonal antibody-treated allograft recipients. Results. Sensitized mice rejected cardiac allografts in 34+/-7 hr. AccR was accompanied by endothelial deposition of immunoglobulins, complement, and fibrin, but also by dense expression of multiple chemokines and a mixed polymorphonuclear and mononuclear cellular infiltrate. Whereas neutrophil or complement depletion had no significant effect on the tempo of AccR, surprisingly B cell-deficient recipients still underwent AccR (41+/-7 hr) in conjunction with T cell and macrophage recruitment. In contrast, T cell-deficient (nude) mice maintained functioning cardiac allografts for >720 hr despite prior skin engraftment. Conclusions. AccR in sensitized experimental recipients involves multiple effector pathways. Although most previous studies have emphasized the key role of humoral pathways in mediating AccR, our data indicate that T cell-dependent mechanisms can also promote AccR, alone or in conjunction with humoral responses.