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, The Beckman Research Institute, City of Hope, Duarte, CA
- 3Department of Hematology and Hematopoietic Cell Transplantation, The Beckman Research Institute, City of Hope, Duarte, CA
- Corresponding author: Defu Zeng, Email:
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 MHC-mismatched mixed chimerism reversed autoimmunity and re-established thymic negative selection of autoreactive T cells in NOD mice; but it is still unclear how mixed chimerism tolerizes the 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 non-myeloablative anti-CD3/CD8 conditioning and infusion of donor CD4+ T cell-depleted spleen and whole bone marrow cells, or through myeloablative total body irradiation conditioning and reconstitution with T cell-depleted bone marrow cells from donor and host. Kinetic analysis of percentage and yield of pre-plasma 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 pre-plasma 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.
- Received October 7, 2013.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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