Induction of mixed chimerism depletes pre-existing and de novo-developed autoreactive B cells in autoimmune NOD mice.
Destruction of pancreatic islet β-cells in type 1 diabetes (T1D) is mainly mediated by autoimmune T and B lymphocytes. We reported that induction of major histocompatibility complex (MHC)-mismatched mixed chimerism reversed autoimmunity and reestablished thymic negative selection of autoreactive T cells in NOD mice, but it is still unclear how mixed chimerism tolerizes autoreactive B cells. The current studies were designed to reveal the mechanisms on how mixed chimerism tolerizes autoreactive B cells in T1D. Accordingly, mixed chimerism was induced in NOD mice through radiation-free nonmyeloablative anti-CD3/CD8 conditioning and infusion of donor CD4(+) T cell-depleted spleen and whole bone marrow (BM) cells or through myeloablative total body irradiation conditioning and reconstitution with T cell-depleted BM cells from donor and host. Kinetic analysis of percentage and yield of preplasma and plasma B cells, newly developed B-cell subsets, and their apoptosis was performed 30-60 days after transplantation. Induction of MHC-mismatched mixed chimerism results in depleting host-type pre-existing preplasma and plasma B cells as well as augmenting apoptosis of immature transitional T1 B cells, including insulin-specific B cells in a donor B cell-dependent manner. Therefore, induction of MHC-mismatched mixed chimerism depletes pre-existing and de novo-developed autoreactive B cells.
Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CADepartment of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CADepartment of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA.
Jeremy J
JJ
Racine
Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CADepartment of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA.
Miao
M
Wang
Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CADepartment of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA.
Mingfeng
M
Zhang
Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CADepartment of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CADepartment of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA dzeng@coh.org.
Defu
D
Zeng
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D016026:Bone Marrow Transplantation; D046528:Chimerism; D005260:Female; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology
D000911:Antibodies, Monoclonal