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Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice
Yuqing Liu, … , Xi Zhang, Defu Zeng
Yuqing Liu, … , Xi Zhang, Defu Zeng
Published August 20, 2020
Citation Information: J Clin Invest. 2020;130(12):6457-6476. https://doi.org/10.1172/JCI131799.
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Research Article Autoimmunity Article has an altmetric score of 5

Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice

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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.

Authors

Yuqing Liu, Xiaoqi Wang, Yongping Zhu, Mingfeng Zhang, Ubaydah Nasri, Sharne S. Sun, Stephen J. Forman, Arthur D. Riggs, Xi Zhang, Defu Zeng

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Figure 5

Haplo-MC increases percentage of total CD73hiFR4hi anergic CD4+ T cells and Nrp1+CD73hiFR4hi anergic cells among host-type CD44hiCD62L–CD4+ Tem cells.

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Haplo-MC increases percentage of total CD73hiFR4hi anergic CD4+ T cells ...
Sixty to 80 days after HCT, samples of PancLNs and pancreas MNCs were analyzed by flow cytometry for their expression of CD45.2 (donor marker), TCRβ, CD4, Foxp3, CD62L, CD44, CD73, FR4, and Nrp1. Representative patterns of flow cytometry and mean ± SEM of percentage of CD73hiFR4hi anergic cells among total host-type Foxp3–CD62L–CD44hiCD4+ Tem cells and percentage of Nrp1+CD73hiFR4hi cells among total CD73hiFR4hi anergic cells are shown (n = 4–8). P values were calculated using 1-way ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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