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- Title
Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.
- Authors
Yuqing Liu; Xiaoqi Wang; Yongping Zhu; Mingfeng Zhang; Nasri, Ubaydah; Sun, Sharne S.; Forman, Stephen J.; Riggs, Arthur D.; Xi Zhang; Defu Zeng; Liu, Yuqing; Wang, Xiaoqi; Zhu, Yongping; Zhang, Mingfeng; Zhang, Xi; Zeng, Defu
- Abstract
Clinical trials are currently testing whether induction of haploidentical mixed chimerism (Haplo-MC) induces organ transplantation tolerance. Whether Haplo-MC can be used to treat established autoimmune diseases remains unknown. Here, we show that established autoimmunity in euthymic and adult-thymectomized NOD (H-2g7) mice was cured by induction of Haplo-MC under a non-myeloablative anti-thymocyte globulin-based conditioning regimen and infusion of CD4+ T cell-depleted hematopoietic graft from H-2b/g7 F1 donors that expressed autoimmune-resistant H-2b or from H-2s/g7 F1 donors that expressed autoimmune-susceptible H-2s. The cure was associated with enhanced thymic negative selection, increased thymic Treg (tTreg) production, and anergy or exhaustion of residual host-type autoreactive T cells in the periphery. The peripheral tolerance was accompanied by expansion of donor- and host-type CD62L-Helios+ tTregs as well as host-type Helios-Nrp1+ peripheral Tregs (pTregs) and PD-L1hi plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type PD-L1hi pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and Helios-Nrp1+ pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-MHC+ donor-type DCs, PD-L1hi host-type DCs, and the generation and persistence of donor- and host-type tTregs and pTregs.
- Subjects
CHIMERISM; AUTOIMMUNITY; PEOPLE with diabetes; AUTOIMMUNE diseases; T cells; TREATMENT of diabetes; RESEARCH; BONE marrow transplantation; HOMOGRAFTS; ANIMAL experimentation; RESEARCH methodology; DIABETES; TYPE 1 diabetes; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; RESEARCH funding; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p6457
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI131799