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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Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice

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 12

Interactions among donor- and host-type Tregs and PD-L1hi pDCs in the periphery of Haplo-MC NOD mice.

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Interactions among donor- and host-type Tregs and PD-L1hi pDCs in the pe...
Depletion of Tregs in Haplo-MC NOD mice was described in Figure 9, and establishing of Haplo-MC with host-type PD-L1–/– hematopoietic cells was described in Figure 10. (A and B) Host-type pDCs and their expression of PD-L1 in the spleen (SPL) of Haplo-MC mice with or without depletion of donor- or host-type Tregs were compared. Representative pattern and mean ± SEM of percentage of host-type B220+PDCA-1+ pDCs among IgM–IgD–CD11c+ cells and their PD-L1 expression levels are shown (n = 5–9). (C and D) Host-type CD220+PDCA-1+ pDC, CD8+ DC, and CD11b+ DC subsets in the spleen of Haplo-MC mice with or without hematopoietic cell PD-L1 deficiency were measured. Representative pattern and mean ± SEM of DC subsets are shown (n = 6–8). (E) Percentage of Helios– pTregs among host- or donor-type Tregs in the spleen, PancLNs, and pancreas was measured. Helios–Nrp1+ pTregs among Helios– pTregs in the pancreas were also measured. Representative patterns and mean ± SEM are shown (n = 6–9). P values were calculated using 1-way ANOVA (A and B) or unpaired 2-tailed Student’s t tests (C–E); **P < 0.01, ***P < 0.001.