title: Transient mixed chimerism for allograft tolerance.
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.
authors.affiliation: a Department of Surgery , Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Oura
authors.affiliation: a Department of Surgery , Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hotta
authors.affiliation: a Department of Surgery , Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
mesh_terms: D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation / Q000266:history*; D002417:Cattle; D046528:Chimerism; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D007108:Immune Tolerance; D009928:Organ Specificity / Q000276:immunology; D016377:Organ Transplantation / Q000266:history*; D014181:Transplantation Immunology
keywords: ATG; Donor BMT; Freemartin cattle; full chimerism; GVHD; HLA-match; HLA-mismatch; NHP; TBI; TI; TLI; TMEM; combined Kidney/BMT; mixed chimerism; multilineage chimerism; neonatal tolerance; nonmyeloablative; operational tolerance; persistent (durable) mixed chimerism; transient mixed chimerism