Tolerance, mixed chimerism, and chronic transplant arteriopathy

Much evidence supports the conclusion that immunological responses to donor -specific incompatibilities are a major factor in producing "chronic" trans plant rejection, including the arteriopathy (atherosclerosis) commonly pres ent. Our experiments explored the effects of altered immunological responsi veness to these Ags on the formation of arteriopathy in transplanted mouse hearts. Specific immunological nonreactivity, or tolerance, was induced eit her by neonatal administration of allogeneic spleen cells (from F-1 donors between class 1-mismatched donor and recipient strains), resulting in "clas sical" immunological tolerance, or by bone marrow infusion to suitably prep ared adult recipients, either fully MHC mismatched or class I mismatched, y ielding "mixed chimerism." Both approaches obviated systemic graft-versus-h ost effects. In both groups, donor-specific skin grafts survived perfectly and donor cell chimerism persisted. Specific Abs were undetectable in all r ecipients. Most transplants to either group of tolerant recipients develope d striking vasculopathy in their coronary arteries (12 of 15 in neonatal to lerance and 15 of 23 in mixed chimeras). Neointimal infiltrates included CD 4 and CD8 T cells and macrophages. Only 2 of 29 contemporary isotransplants showed any evidence of vasculopathy. Recipients essentially incapable of T and B cell responses (C.B-17/SCED and RAG1(-/-)) were also used. Transplan ts into these animals developed vasculopathy in 16 of 31 instances. Accordi ngly, in this setting, vasculopathy develops in the presence of H-2 gene-de termined incompatibility even with minimal conventional immune reactivity. Perhaps innate responsiveness, that could include NK cell activity, can cre ate such arteriopathic lesions. More evidence is being sought regarding thi s process.