Tolerance, Mixed Chimerism, and Chronic Transplant Arteriopathy

Abstract

Much evidence supports the conclusion that immunological responses to donor-specific incompatibilities are a major factor in producing “chronic” transplant rejection, including the arteriopathy (atherosclerosis) commonly present. Our experiments explored the effects of altered immunological responsiveness to these Ags on the formation of arteriopathy in transplanted mouse hearts. Specific immunological nonreactivity, or tolerance, was induced either by neonatal administration of allogeneic spleen cells (from F1 donors between class I-mismatched donor and recipient strains), resulting in “classical” immunological tolerance, or by bone marrow infusion to suitably prepared adult recipients, either fully MHC mismatched or class I mismatched, yielding “mixed chimerism.” Both approaches obviated systemic graft-versus-host effects. In both groups, donor-specific skin grafts survived perfectly and donor cell chimerism persisted. Specific Abs were undetectable in all recipients. Most transplants to either group of tolerant recipients developed striking vasculopathy in their coronary arteries (12 of 15 in neonatal tolerance and 15 of 23 in mixed chimeras). Neointimal infiltrates included CD4 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/SCID and RAG1−/−) were also used. Transplants into these animals developed vasculopathy in 16 of 31 instances. Accordingly, in this setting, vasculopathy develops in the presence of H-2 gene-determined incompatibility even with minimal conventional immune reactivity. Perhaps innate responsiveness, that could include NK cell activity, can create such arteriopathic lesions. More evidence is being sought regarding this process.

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

“…One could surmise that researchers in the field have a pre-determined bias (full tolerance is the preferred outcome clinically), as evidenced by the numerous studies that chose to use clinically irrelevant MHC-congenic donors (minor antigen-matched) that are likely to give a false impression of full tolerance (skin acceptance) [16,[38][39][40][41][42][43][44], including in protocols very similar to our own [45]. No explanation is given in such studies for the unusual choice of donor/recipient combination.…”

The fate of transplanted xenogeneic bone marrow‐derived stem cells in rat intervertebral discs

“…As such, they play an important role in the rejection of xenograft cells. 41,42 In our xenogeneic cell transplantation model, the infiltrated macrophages (CD68 þ cells) were observed only at the border region of the outer annulus and the endplate in the early stages following transplantation. The increased CD68 þ cells on days 1 and 10 suggest that macrophages are involved with the graft response, which is not normally associated with inflammatory cells.…”

T-Cell Depletion Eliminates the Development of Cardiac Allograft Vasculopathy in Mice Rendered Tolerant by the Induction of Mixed Chimerism

“…We previously demonstrated that cardiac allografts to mixed chimeric mice developed cardiac allograft vasculopathy (CAV), even though they were tolerant of donor antigens confirmed by donor strain skin graft survival (1). These findings suggested that innate immune responses might be involved in the process.…”

“….A/B6 mixed chimeric mice were created by receiving injections of anti-CD4/CD8 mAbs and CD40L mAb, 3Gy WBI, and bone marrow cells from B10.A (H-2 k ) mice given to C57BL/ 6 (B6; H-2 b ) mice as previously described (1,8,9). At 8 weeks after the induction of mixed chimerism, B10.A skin grafts were placed onto B6/B10.A chimeric recipients to confirm that they were tolerant of donor antigens in vivo.…”