Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma.
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 Groalpha/KC, MIP-2, GCP-2, and MIP-1alpha, 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.
Miura
Masayoshi
M
Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195-0001, USA.
El-Sawy
Tarek
T
Fairchild
Robert L
RL
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018946:Chemokine CCL5 / Q000032:analysis; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006650:Histocompatibility Testing; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology*; D013997:Time Factors; D014158:Transcription, Genetic; D016042:Transplantation, Heterotopic
D018946:Chemokine CCL5; D007371:Interferon-gamma