Efficient and Selective Prevention of Graft-Versus-Host Disease by Ag-Specific Induced Regulatory T Cells In Mice.

Abstract 3745

Naturally occurring regulatory T cells (nTregs) suppress the development of graft-versus-host disease (GVHD). The non-selective suppression against tumor associated antigens in some models severely dampened our enthusiasm for the application of nTregs in the control of GVHD after allogeneic hematopoietic cell transplantation (HCT). In this study, we used an alternative strategy to generate antigen-specific, induced Tregs (iTregs), and tested their potential in the prevention of GVHD in murine model of myeloablative BMT. CD4⁺CD25⁺Foxp3⁺ iTregs generated from OT-II TCR transgenic mice specific for OVA target antigen efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) in allogeneic recipients that express OVA protein but not in those that do not express OVA. The efficacy of these antigen-specific iTregs was significantly higher than polyclonal iTregs in preventing GVHD. As controls, OT-II CD4⁺Foxp3⁻ cells had no effect on GVHD development in OVA⁻ recipients and exacerbated GVHD in OVA⁺ recipients when transplanted together with polyclonal Teffs. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA⁺ recipients. In sharp contrast, OT-II iTregs failed to expand and had no effect on Teffs in OVA⁻ recipients. These results reveal the therapeutic potential of TGFβ-induced, antigen-specific iTregs to prevent GVHD efficiently and selectively.