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Targeting Cells Causing Split Tolerance Allows Fully Allogeneic Islet Survival With Minimal Conditioning in NOD Mixed Chimeras
Author(s) -
AlAdra D. P.,
Pawlick R.,
Shapiro A. M. J.,
Anderson C. C.
Publication year - 2012
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2012.04260.x
Subject(s) - nod , chimera (genetics) , nod mice , immunology , immune tolerance , transplantation chimera , medicine , central tolerance , islet , transplantation , clonal deletion , cancer research , immune system , biology , stem cell , t cell , autoimmunity , microbiology and biotechnology , diabetes mellitus , haematopoiesis , genetics , t cell receptor , hematopoietic cell , gene , endocrinology
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.