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Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.
- Source :
-
Journal of Clinical Investigation . Dec2020, Vol. 130 Issue 12, p6457-6476. 20p. - Publication Year :
- 2020
-
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. [ABSTRACT FROM AUTHOR]
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- 147508894
- Full Text :
- https://doi.org/10.1172/JCI131799