Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice
Yuqing Liu, Xiaoqi Wang, Yongping Zhu, Mingfeng Zhang, Ubaydah Nasri, Sharne S. Sun, Stephen J. Forman, Arthur D. Riggs, Xi Zhang, Defu Zeng
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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Research Article Autoimmunity

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 1

Induction of Haplo-MC prevents diabetes onset and reverses new-onset T1D in WT NOD mice, with clearing of insulitis.

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Induction of Haplo-MC prevents diabetes onset and reverses new-onset T1D...
Prediabetic 9- to 12-week-old NOD and new-onset diabetic NOD mice were conditioned with ATG + CY + PT, subjected to transplantation of BM (50 × 106) and spleen cells (30 × 106) from H-2b/g7 F1 or H-2s/g7 F1 donors, respectively, and coinjected with depleting anti-CD4 mAb (500 μg/mouse). Recipients were monitored for diabetes development for 100 days after HCT. (A) T1D development curves in prediabetic NOD mice (n = 20–37 from ≥3 experiments). P < 0.0001, conditioning-alone control vs. either H-2b/g7 or H-2s/g7 chimera using log-rank test. (B and C) One hundred days after HCT, residual nondiabetic mice were subjected to insulitis evaluation. Representative H&E histopathology photomicrographs are shown. Summary insulitis score is shown as mean (n = 9–12). (D) T1D relapse curves of new-onset diabetic NOD mice given conditioning alone or induction of either H-2b/g7 or H-2s/g7 Haplo-MC (n = 12–24 from ≥3 experiments). (E and F) Representative photomicrographs and summary (mean) of insulitis score of recipients with normal glycemia 100 days after HCT or control mice given conditioning alone (n = 6–12). Statistical comparison of insulitis was completed using χ2 test (B and F). Scale bars: 100 μm.