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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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7685732 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.

Liu Yuqing Y Wang Xiaoqi X Zhu Yongping Y Zhang Mingfeng M Nasri Ubaydah U Sun Sharne S SS Forman Stephen J SJ Riggs Arthur D AD Zhang Xi X Zeng Defu D

The Journal of clinical investigation 20201201 12

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 ...[more]

PMID: 32817590

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Project description:IntroductionWe previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.MethodsCD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored.ResultsHLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline.DiscussionThese results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.

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Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.

Publications

Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice.

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