Immunobiology of allograft rejection in the absence of IFN-gamma: 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(+) cell s, both WT and LFN-gamma (-/-) mice rejected their allografts, indicating t hat these mice share a common CD4-mediated, CD8-independent mechanism of re jection. However, when depleted of CD4(+) cells, WT mice accepted their all ografts, while IFN-gamma (-/-) recipients rapidly rejected them. Hence, IFN -gamma (-/-), but not WT mice developed an unusual CDS-mediated, CD4-indepe ndent, mechanism of allograft rejection, Allograft rejection in IFN-gamma ( -/-) mice was associated with intragraft accumulation of IL-4-producing cel ls, polymorphonuclear leukocytes, and eosinophils. Furthermore, this form o f rejection was resistant to treatment with anti-CD40 ligand (CD40L) mAb, w hich markedly prolonged graft survival in WT mice. T cell depletion studies verified that anti-CD40L treatment failed to prevent CDS-mediated allograf t rejection in IFN-gamma (-/-) mice. However, anti-CD40L treatment did prev ent CD4-mediated rejection in IFN-gamma (-/-) mice, although grafts were ev entually rejected when CD8(+) T cells repopulated the periphery, The IL-4 p roduction and eosinophil influx into the graft that occurred during CD8-med iated rejection were apparently epiphenomenal, since treatment with anti-IL -4 mAb blocked intragraft accumulation of eosinophils, but did not interfer e with allograft rejection. These studies demonstrate that a novel, CDS-med iated 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 ev ents, which contribute unique histopathologic features to the graft but are apparently unnecessary for the process of allograft rejection.