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Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses.

Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses.
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Zaitsu M, Issa F, Hester J, Vanhove B, Wood KJ,


Zaitsu M, Issa F, Hester J, Vanhove B, Wood KJ, (click to view)

Zaitsu M, Issa F, Hester J, Vanhove B, Wood KJ,

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JCI insight 2017 10 052(19) doi 10.1172/jci.insight.89381
Abstract

T cells are central to the detrimental alloresponses that develop in autoimmunity and transplantation, with CD28 costimulatory signals being key to T cell activation and proliferation. CTLA4-Ig molecules that bind CD80/86 and inhibit CD28 costimulation offer an alternative immunosuppressive treatment, free from some of the chronic toxicities associated with calcineurin inhibition. However, CD80/86 blockade by CTLA4-Ig also results in the loss of coinhibitory CTLA4 signals that are critical to the regulation of T cell activation. Here, we show that a nonactivating monovalent anti-CD28 that spares CTLA4 signaling is an effective immunosuppressant in a clinically relevant humanized mouse transplant model. We demonstrate that selective CD28 blockade prolongs human skin allograft survival through a mechanism that includes a reduction in the cellular graft infiltrate. Critically, selective CD28 blockade promotes Treg function in vivo and synergizes with adoptive Treg therapy to promote transplant survival. In contrast to CTLA4-Ig treatment, selective CD28 blockade promotes regulation of alloimmune responses and facilitates Treg-based cellular therapy.

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