title: MHC-mismatched chimerism is required for induction of transplantation tolerance in autoimmune nonobese diabetic recipients.
abstract: In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II-dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1(+/+), but not from Rag1(-/-), NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010;
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA 91010;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Racine
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA 91010;
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010;
authors.forename: Ruishu
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA 91010;
authors.forename: Heather
authors.initials: H
authors.lastname: Johnston
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy of City of Hope, Duarte, CA 91010.
authors.forename: Christine
authors.initials: C
authors.lastname: Shen
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy of City of Hope, Duarte, CA 91010.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Siswanto
authors.affiliation: Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA 91010; dzeng@coh.org.
authors.forename: Defu
authors.initials: D
authors.lastname: Zeng
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007156:Immunologic Memory; D007328:Insulin / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D016377:Organ Transplantation; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D016038:Skin Transplantation; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: D017252:CD3 Complex; D016827:CD8 Antigens; D000949:Histocompatibility Antigens Class II; D018398:Homeodomain Proteins; D007328:Insulin; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; C064658:RAG-1 protein