Induction of Mixed Chimerism Depletes Pre-existing and De Novo–Developed Autoreactive B Cells in Autoimmune NOD Mice
- 1Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA
- 2Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA
- 3Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA
- Corresponding author: Defu Zeng, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1532/-/DC1.
See accompanying article, p. 1855.
- Received October 7, 2013.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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