title: Targeting cells causing split tolerance allows fully allogeneic islet survival with minimal conditioning in NOD mixed chimeras.
abstract: Donor-specific tolerance induced by mixed chimerism is one approach that may eliminate the need for long-term immunosuppressive therapy, while preventing chronic rejection of an islet transplant. However, even in the presence of chimerism it is possible for certain donor tissues or cells to be rejected whereas others from the same donor are accepted (split tolerance). We previously developed a nonmyeloablative protocol that generated mixed chimerism across full major histocompatability complex plus minor mismatches in NOD (nonobese diabetic) mice, however, these chimeras demonstrated split tolerance. In this study, we used radiation chimeras and found that the radiosensitive component of NOD has a greater role in the split tolerance NOD mice develop. We then show that split tolerance is mediated primarily by preexisting NOD lymphocytes and have identified T cells, but not NK cells or B cells, as cells that both resist chimerism induction and mediate split tolerance. Finally, after recognizing the barrier that preexisting T cells impose on the generation of fully tolerant chimeras, the chimerism induction protocol was refined to include nonmyeloablative recipient NOD T cell depletion which generated long-term mixed chimerism across fully allogeneic barriers. Furthermore, these chimeric NOD mice are immunocompetent, diabetes free and accept donor islet allografts.
authors.affiliation: Department of Surgery and Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D P
authors.initials: DP
authors.lastname: Al-Adra
authors.forename: R
authors.initials: R
authors.lastname: Pawlick
authors.forename: A M J
authors.initials: AM
authors.lastname: Shapiro
authors.forename: C C
authors.initials: CC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D011828:Radiation Chimera / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous