Combinations of anti-GITR antibody and CD28 superagonist induce permanent allograft TOU

Combinations of anti-GITR antibody and CD28 superagonist induce permanent allograft
TOU

Combinations of anti-GITR antibody and CD28 superagonist induce permanent allograft

Abstract

Type 1 regulatory T (Tr1) cells represent a subset of IL-10–producing CD4

+

Foxp3



T cells and play key roles in promoting transplant tolerance. However, no effective pharmacological approaches have been able to induce Tr1 cells in vivo. We herein report the combined use of a CD28 superagonist (D665) and anti-glucocorticoid-induced tumor necrosis factor receptor–related protein monoclonal antibody (G3c) to induce Tr1 cells in vivo. Large amounts of IL-10/interferon-γ–co-producing CD4

+

Foxp3



Tr1 cells were generated by D665-G3c sequential treatment in mice. Mechanistic studies suggested that D665-G3c induced Tr1 cells via transcription factors

Prdm1

and

Maf

. G3c contributed to Tr1 cell generation via the activation of mitogen-activated protein kinase–signal transducer and activator of transcription 3 signaling. Tr1 cells suppressed dendritic cell maturation and T cell responses and mediated permanent allograft acceptance in fully major histocompatibility complex–mismatched mice in an IL-10–dependent manner. In vivo Tr1 cell induction is a promising strategy for achieving transplant tolerance.

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