HUMAN CD8+ REGULATORY T CELLS INHIBIT GVHD AND PRESERVE GENERAL IMMUNITY IN HUMANIZED MICE

摘要

Graft-versus-host disease (GVHD) is a lethal complication of allograft transplantation. The current strategy of using immunosuppressive agents to control GVHD may cause general immune suppression and limit the effectiveness of allograft transplantation. Adoptive transfer of regulatory T cells (Treg) can prevent GVHD in rodents, indicating the therapeutic potential of Treg for GVHD in humans. However, the clinical application of Treg-based therapy is hampered by the low frequency of human Treg and the lack of a reliable model to test their therapeutic effects in vivo. Human alloantigen-specific Treg are generated from antigenically-naïve precursors in a large scale ex vivo using allogeneic activated B cells as stimulators. Here, a human allogeneic GVHD model is established in humanized mice to mimic GVHD after allograft transplantation in humans. The ex vivo-induced CD8hi Treg can control GVHD in an allo-specific manner by reduction of alloreactive T-cell proliferation, and inflammatory cytokine and chemokine secretion within target organs through a CTLA-4-dependent mechanism in humanized mice. Importantly, the Tregs can induce long-term tolerance effectively without compromising general immunity and graft-versus-tumor (GVT) activity.

主权项

1. A method for inhibiting graft-versus-host disease (GVHD) in a patient-recipient due to bone marrow transplantation, comprising:
obtaining a sample of naïve T cells from a donor of bone marrow; co-culturing activated B cells from a patient-recipient of bone marrow with naïve T cells from the donor in a ratio of 1:2 to 1:25 for a period of time sufficient to generate alloantigen-specific human regulatory T cells; and administering the alloantigen-specific human regulatory T cells to the patient-recipient of bone marrow.