Abstract
Abstract Description
Induction of mixed chimerism (MC) with bone marrow (BM) from another strain of mice in non-autoimmune neonatal mice is well established. However, induction of MC with donor BM only in autoimmune neonatal mice has not been reported. Autoimmune NOD mice remain the best model reflecting pathogenesis of human type 1 diabetes (T1D), in which autoimmune lymphocytes (i.e., T cells) destroy insulin+ β cells. In the current studies, we observed that >60% of Foxp3+ Treg cells in NOD mice were pathogenic IL-10-IFN-g+TNF-α+ or IFN-g-TNF-α+, and overactivated CD4+CD8+ BDC2.5-tetramer+ autoreactive T cells were present in the pancreas but not lymph nodes. Haploidentical F1 donor BM with CD4+ T-depleted spleen cells were required to induce MC in neonatal NOD mice, although BM alone induced MC in non-autoimmune mice. The haplo-MC totally prevented T1D in WT NOD and Rag-1-/-BDC2.5 NOD mice that can develop lethal T1D at ∼25 days of age. The MC depleted CD4+CD8+ BDC2.5-tetramer+ autoreactive T cells in the pancreas, with marked reduction in ratio of IL-10-IFN-g+TNF-α+ or IFN-g-TNF-α+ versus CTLA4hiIFN-g-TNF-α- Treg cells, increase of CD103+CD69+tetramer+ pTreg cells, and formation of tertiary lymphoid structures (TLS) containing donor-type PD-L1hi gp38+ fibroblastic reticular cells and host-type pTreg cells. Therefore, formation of TLS that deplete autoreactive T cells and transdifferentiate the residuals into CTLA4hiIFN-g-TNF-α- pTreg cells may contribute to prevention of T1D in MC NOD mice.
Funding Sources
Arthur Riggs Diabetes & Metabolism Research Institute Innovative Award
Topic Categories
Therapeutic Approaches to Autoimmunity (THER)