Chronic rejection of major histocompatibility complex class II-disparate skin grafts after anti-CD3 therapy - A model of antibody-independent transplant vasculopathy

Background. Chronic rejection remains a leading cause of allograft loss, Hi stologically, it is characterized by arterial intimal thickening and parenc hymal fibrosis, The immune mechanisms triggering chronic rejection are stil l uncompletely understood. Methods. We performed major histocompatibility complex (MHC) class II-incom patible skin grafts from C-H2(bm12) (bm12, H2(bm12)) into C57BL/6 (C57BL/6, H2(b)) recipients immunosuppressed with a short course of anti-CD3 monoclo nal antibodies to prevent acute rejection, Results. More than 80% of grafts survived for prolonged periods, but eventu ally all displayed macroscopic and microscopic evidence of chronic rejectio n. At histology, there was a progressive arterial intimal thickening as wel l as intense dermal fibrosis. This was accompanied by an inflammatory infil trate consisting of lymphocytes and macrophages, but also of a considerable number of eosinophils, Mice with chronic rejection were unable to generate anti-donor MHC class II cytotoxic T lymphocyte activity at either 20 or 60 days after transplant. Furthermore, transplantation of bm12 skins on C57BL /6-congenic, Ig knock-out mice was associated with the development of a chr onic rejection that was identical to that occurring in wildtype C57BL/6 ani mals, indicating that alloantibodies are not necessary in this model. Conclusions. (1) Skin grafts may undergo chronic rejection with the charact eristic lesions of vasculopathy and fibrosis; (2) chronic rejection of MHC class II-disparate shins may occur in the absence of direct cytotoxic T lym phocyte activity or alloantibodies.