Immunobiology of allograft rejection in the absence of IFN-γ:: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions

Both wild-type (WT) and IFN-gamma -deficient (IFN-gamma (-/-)) C57BL/6 mice can rapidly reject BALB/c cardiac allografts, When depleted of CD8(+) cells, both WT and LFN-gamma (-/-) mice rejected their allografts, indicating that these mice share a common CD4-mediated, CD8-independent mechanism of rejection. However, when depleted of CD4(+) cells, WT mice accepted their allografts, while IFN-gamma (-/-) recipients rapidly rejected them. Hence, IFN-gamma (-/-), but not WT mice developed an unusual CDS-mediated, CD4-independent, mechanism of allograft rejection, Allograft rejection in IFN-gamma (-/-) mice was associated with intragraft accumulation of IL-4-producing cells, polymorphonuclear leukocytes, and eosinophils. Furthermore, this form of rejection was resistant to treatment with anti-CD40 ligand (CD40L) mAb, which markedly prolonged graft survival in WT mice. T cell depletion studies verified that anti-CD40L treatment failed to prevent CDS-mediated allograft rejection in IFN-gamma (-/-) mice. However, anti-CD40L treatment did prevent CD4-mediated rejection in IFN-gamma (-/-) mice, although grafts were eventually rejected when CD8(+) T cells repopulated the periphery, The IL-4 production and eosinophil influx into the graft that occurred during CD8-mediated rejection were apparently epiphenomenal, since treatment with anti-IL-4 mAb blocked intragraft accumulation of eosinophils, but did not interfere with allograft rejection. These studies demonstrate that a novel, CDS-mediated mechanism of allograft rejection, which is resistant to experimental immunosuppression, can develop when LFN-gamma is Limiting. An understanding of this mechanism is confounded by its association with Th2-like immune events, which contribute unique histopathologic features to the graft but are apparently unnecessary for the process of allograft rejection.