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(American Journal of Pathology. 2003;162:509-519.)
© 2003 American Society for Investigative Pathology

Regular Articles

Neutrophils Mediate Parenchymal Tissue Necrosis and Accelerate the Rejection of Complete Major Histocompatibility Complex-Disparate Cardiac Allografts in the Absence of Interferon-{gamma}

Masayoshi Miura*{dagger}, Tarek El-Sawy{dagger}{ddagger} and Robert L. Fairchild*{dagger}{ddagger}

From the Urological Institute * and Department of Immunology,{dagger} Cleveland Clinic Foundation, Cleveland; and the Department of Pathology,{ddagger} Case Western Reserve University School of Medicine, Cleveland, Ohio

A major feature of acute rejection of cardiac allografts is an intense mononuclear cell infiltration accompanied by interferon (IFN)-{gamma} production. In the current study we tested the role of IFN-{gamma} in acute rejection of allografts by comparing the histopathology of rejection in wild-type versus IFN-{gamma}-/- recipients of major histocompatibility complex-mismatched cardiac grafts. Wild-type recipients rejected the allografts at days 8 to 9 after transplant but rejection was accelerated 2 to 3 days in IFN-{gamma}-deficient recipients. During rejection in wild-type recipients, the allografts were heavily infiltrated with CD8+ T cells and other mononuclear cells. In contrast, allografts in IFN-{gamma}-deficient recipients had few T cells but an intense neutrophil infiltration accompanied by extensive graft parenchymal necrosis. No difference in expression levels of neutrophil chemoattractants including Gro{alpha}/KC, MIP-2, GCP-2, and MIP-1{alpha}, was observed in allografts retrieved from wild-type and IFN-{gamma}-/- recipients. Depletion of neutrophils from IFN-{gamma}-deficient recipients delayed rejection until days 8 to 10 after transplant and restored the histopathology of acute allograft rejection to that observed in allografts rejected by wild-type recipients. These results indicate the potent regulatory properties of IFN-{gamma} during acute rejection directed at neutrophil infiltration into allografts and mediating graft tissue necrosis.




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