Haploidentical mixed chimerism cures autoimmunity in established type 1 diabetic mice

摘要

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-2(g7)) 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-2(b/g7) F-1 donors that expressed autoimmune-resistant H-2(b) or from H-2(s/g7) F-1 donors that expressed autoimmune-susceptible H-2(s). 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-LP plasmacytoid DCs (pDCs). Depletion of donor- or host-type Tregs led to reduction of host-type PD-L1(hi) pDCs and recurrence of autoimmunity, whereas PD-L1 deficiency in host-type DCs led to reduction of host-type pDCs and Helios(-)Nrp1(+)t pTregs. Thus, induction of Haplo-MC reestablished both central and peripheral tolerance through mechanisms that depend on allo-MHC(+)donor-type DCs, PD-L1(hi) host-type DCs, and the generation and persistence of donor-and host-type tTregs and pTregs.