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ABSTRACT
Mixed chimerism discovered in Freemartin cattle by Ray Owen 70 years ago paved the way for research on immune tolerance. Since his discovery, significant progress has been made in the effort to induce allograft tolerance via mixed chimerism in various murine models. However, induction of persistent mixed chimerism has proved to be extremely difficult in major histocompatibility complex mismatched humans. Chimerism induced in humans tends to either disappear or convert to full donor chimerism, depending on the intensity of the conditioning regimen. Nevertheless, our studies in both NHPs and humans have clearly demonstrated that renal allograft tolerance can be induced by transient mixed chimerism. Our studies have shown that solid organ allograft tolerance via transient mixed chimerism 1) requires induction of multilineage hematologic chimerism, 2) depends on peripheral regulatory mechanisms, rather than thymic deletion, for long-term maintenance, 3) is organ specific (kidney and lung but not heart allograft tolerance are feasible). A major advantage of tolerance induction via transient mixed chimerism is exclusion of the risk of graft-versus-host disease. Our ongoing studies are directed toward improving the consistency of tolerance induction, reducing the morbidity of the conditioning regimen, substituting clinically available agents, such as Belatacept for the now unavailable anti-CD2 monoclonal antibody, and extending the protocol to recipients of deceased donor allografts.
Abbreviations
| AKI | = | acute kidney injury |
| ATG | = | antithymocyte globulin |
| BMT | = | bone marrow transplantation |
| CNI | = | calcineurin inhibitor |
| GVHD | = | graft-vs.-host disease |
| HLA | = | human leukocyte antigen |
| mAb | = | monoclonal antibody |
| MGH | = | Massachusetts General Hospital |
| MHC | = | major histocompatibility complex |
| NHP | = | nonhuman primate |
| TBI | = | total body irradiation |
| TI | = | thymic irradiation |
| TLI | = | total lymphoid irradiation |
| TMEM | = | memory T cell |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Funding
The present work was supported by grants from the Immune Tolerance Network (NIH/NIAID NO1 AI1541), NIH 5U01DK080653-04, and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) 1U19DK080652-01.