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Donor MHC class II mRNA combined with rapamycin programs Th1-like regulatory T cells and induces donor-specific alloimmune hyporesponsiveness

ABSTRACT: Donor-specific immune tolerance remains a major goal in transplantation. In this study, we investigated whether donor major histocompatibility complex (MHC) class II could be delivered as an mRNA-encoded alloantigen to modulate donor-reactive T-cell responses. Using the B6.C-H2bm12–C57BL/6 model, mice were treated with donor MHC class II I-Aβ mRNA, rapamycin, or their combination. Donor MHC mRNA elicited alloimmune responses, whereas combination treatment promoted regulatory T-cell features and donor-specific hyporesponsiveness. Bulk RNA sequencing of splenic CD4+ T cells revealed a mixed effector- and regulatory-associated transcriptional response to donor MHC mRNA, with rapamycin modifying inflammatory transcriptional programs in a context-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE346892 | GEO | 2026/09/15

REPOSITORIES: GEO

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Donor MHC class II mRNA combined with rapamycin programs Th1-like regulatory T cells and induces donor-specific alloimmune hyporesponsiveness

Project description:Donor MHC class II mRNA combined with rapamycin programs Th1-like regulatory T cells and induces donor-specific alloimmune hyporesponsiveness

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Project description:We report our results of RNA-seq analysis on flow sorted Tr1 cells Immune tolerance to allografts has been pursued as an important goal in transplantation for decades. Administration of apoptotic donor splenocytes effectively induced antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor, and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and 1 MHC class II DRB allele- matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric, and translatable method for inducing antigen- specific tolerance in transplantation.

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Peri-transplant Glucocorticoids Redistribute Donor T-cells to the Bone Marrow and Prevent Relapse after haploidentical SCT

Project description:Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency.

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Preoperative Administration of Donor-derived Human M regs to Kidney Transplant Recipients (Agilent RISET 2.0)

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Project description:Despite significant improvements in solid organ transplant outcomes over the past several decades, our limited understanding of the immune interface between donor organs and recipient immune systems has hindered the development of strategies to expand immunoregulatory cell populations and induce immune tolerance in transplant recipients. Given that group 2 innate lymphoid cells (ILC2s) are resident in transplanted solid organs, play a role in wound healing, and coordinate immunoregulatory cell populations, we sought to investigate their function in the alloimmune response. Using a murine heterotopic cardiac transplant model, we demonstrate that recipient ILC2s replace donor ILC2s and upregulate MHC class II (MHCII) without expressing costimulatory molecules. These recipient-derived ILC2s process and present alloantigens, inducing CD4+ T cell anergy through the Caspase-3-dependent pathway. In the absence of recipient-derived ILC2s, we observed a marked increase in infiltrating donor-reactive CD4+ T cells and significantly reduced allograft survival. Furthermore, in vivo expansion of ILC2s via IL-33 administration prolonged murine heart allograft survival. Collectively, these findings reveal a critical and previously unrecognized immunoregulatory role of host-derived ILC2s in solid organ transplantation, where they promote alloimmune tolerance by inducing anergy in alloreactive CD4+ T cells.

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