IL-4 Deficiency Prevents Eosinophilic Rejection and Uncovers a Role for Neutrophils in the Rejection of MHC Class II Disparate Skin Grafts

Background. Acute rejection of MHC class II-disparate bm12 skin grafts by C57BL/6 recipient mice is characterized by massive graft infiltration by eosinophils, together with increased intragraft amounts of IL-4 and IL-5 mRNA. IL-5 blockade prevents the intragraft eosinophil infiltration and prolongs the survival of skin allografts. As the differentiation of T cell precursors into Th2 cells is largely driven by IL-4, we investigated the role of IL-4 in MHC class II-disparate allograft rejection. Methods. We performed skin grafts from MHC class II incompatible bm12 mice into wild-type C57BL/6 mice (IL-4+/+) or C57BL/6 IL-4 deficient mice (IL-4−/−). Graft survival, in vitro T cell reactivity, and histology were compared. Results. We observed that 50% of IL-4−/− mice rapidly rejected their bm12 allograft, whereas the other 50% retained their graft 60 days after transplantation. Histological examination of bm12 allografts retained by IL-4−/− mice showed a normal appearance with no inflammatory infiltrate and no eosinophils. Among IL-4−/− mice that acutely rejected their bm12 skin graft, we observed a dense polymorphonuclear infiltrate. The depletion of neutrophils significantly prolonged bm12 graft survival. Conclusions. Eosinophil infiltrates, typical of MHC class II disparate acute skin graft rejection, are critically dependent on the availability of IL-4. IL-4−/− mice reject MHC class II disparate skin grafts by a pathway of rejection where neutrophils play a direct causal role.

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