Human CD8+ regulatory T cells inhibit GVHD and preserve general immunity in humanized mice

#The subject matter described herein relates to various aspects associated with inhibiting graft-versus-host disease while preserving general immunity of the host/recipient and graft versus tumor effects.

#Bone marrow transplantation (BMT) is now widely accepted as an effective treatment for malignant and nonmalignant hematologic diseases. However, graft-versus-host disease (GVHD) is a lethal complication of allogeneic BMT. GVHD is a condition that can occur after an allogeneic transplant. In GVHD, the immune cells in the donated bone marrow attacks the recipient's tissue and organs as foreign invaders. Treating GVHD relies on the general suppression of the immune system, but this treatment leads to severe side effects like tumor reoccurrence or opportunistic infection.

#The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the invention. It is intended to neither identify key or critical elements of the invention nor delineate the scope of the invention. Rather, the sole purpose of this summary is to present some concepts of the invention in a simplified form as a prelude to the more detailed description that is presented hereinafter.

#FIGS. 1A-1E depict a GVHD model including illustrating the effects of CD8hi Treg on inflammatory cytokine production by CD4+ and CD8+ T cells from donor PBMC in vitro.

#FIGS. 2A-2C depict a graphical illustration of recipient-specific donor CD8hi Treg suppressing the acute proliferation of donor T cells in target organs after donor hPBMC transplantation.

#FIGS. 3A-3D depict data demonstrating that the concentration of human TGF-β and IL-10 does not increase in the target organs of CD8hi Treg-treated humanized GVHD mice.

#The current strategy of controlling GVHD by depletion (1) or general inhibition (2) of donor T cells using immunosuppressive agents may cause general immune suppression, resulting in tumor relapse or opportunistic infection, and limiting the effectiveness of BMT (2). The ideal for BMT would be to induce a sustained state of specific tolerance to alloantigen with minimal or no conventional immunosuppressive drugs.

#Alloantigen-specific regulatory T cells (Treg), as the negative regulators of immune responses to alloantigen, are critical for maintaining alloantigen-specific tolerance (3-5). In addition to the well-described role of CD4+ Treg in suppressing excessive immune responses (6, 7), CD8+ Treg has also been reported to play important roles in maintaining immune tolerance (8-12). Adoptive transfer of murine alloantigen-specific Treg can prevent GVHD and allograft rejection in mouse models (5, 13), indicating that Treg-based therapy has a great therapeutic potential for these diseases in humans. However, the clinic application of Treg-based therapy is limited by the low frequency of human Treg and the lack of a reliable model to evaluate their therapeutic effects in vivo.

#Although several protocols have been developed for generation of human CD8+ Treg (14-19), none has been robust in terms of being of a practical scale for clinical use. Recently, using allogeneic CD40-activated B cells as the tolerogenic antigen presenting cells (20-22) to stimulate naïve CD8+CD25− T cells, we developed a simple, cost-effective novel protocol to rapidly induce and expand large numbers of functional human alloantigen-specific CD8+ Treg. The induced CD8+ Treg expressed higher levels of CD8 on their surface than their precursors and are thus identified as CD8hi Treg (23).