Induction of Haploidentical Mixed Chimerism Cures Autoimmune Type 1 Diabetes

Autor: Yuqing Liu, Mingfeng Zhang, Arthur Riggs, Xi Zhang, Defu Zeng
Rok vydání: 2018
Předmět:
Zdroj: The Journal of Immunology. 200:176.16-176.16
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.200.supp.176.16
Popis: Type 1 diabetes is an autoimmune disease in association with particular MHC, and induction of MHC-matched mixed chimerism cannot reverse autoimmunity. Haploidentical HCT has gradually become a common practice for treating non-malignant diseases, but it remains unknown whether induction of haploidentical mixed chimerism can reverse autoimmunity. In the current studies, we induced mixed chimerism in NOD mice (H2-Ag7) by transplanting bone marrow and CD4+ T-depleted spleen cells from haploidentical (B6 × B6g7) F1 donors (H2-Ab/g7). We found that haploidentical mixed chimerism eliminated insulitis as well as prevented in pre-diabetic and cured diabetes in new-onset WT NOD mice. Interestingly, although I-As was thought to be autoimmune susceptible, induction of haploidentical mixed chimerism with I-Ag7/s transplants also effectively eliminate insulitis. Furthermore, the mixed chimerism markedly reduced the percentage of host-type but not donor-type CD4+CD8+ thymocytes and increased CD11c+CD8−SIRPα+CD11b+ migratory DC that can mediate thymic negative selection in the chimeric thymus. In the peripheral, percentage of tetramer+ autoreactive host-type Tcon cells was markedly reduced and part of the residual T cells became PD-1hiIL-7Rαlo anergic/exhausted, while percentage of host-type CD4+Foxp3+ Treg cells significantly increased. Additionally, in the pancreas of mixed chimeric BDC2.5 NOD mice, Treg cells among tetramer+ autoreactive T cells increase 5–10 fold. Taken collectively, haploidentical mixed chimerism reverses autoimmunity and eliminating insulitis in NOD mice by enhancing DC mediated negative selection in thymus and augmenting expansion of Treg, especially antigen specific Treg cells, in the periphery.
Databáze: OpenAIRE
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