Induction of Mixed Chimerism Depletes Pre-Existing and De Novo Developed Autoreactive B cells in Autoimmune NOD Mice

  1. Defu Zeng1,2,3
  1. 1Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA
  2. 2Department of Diabetes Research, The Beckman Research Institute, City of Hope, Duarte, CA
  3. 3Department of Hematology and Hematopoietic Cell Transplantation, The Beckman Research Institute, City of Hope, Duarte, CA
  1. Corresponding author: Defu Zeng, Email: dzeng{at}


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.

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