期刊
JCI INSIGHT
卷 2, 期 19, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.89381
关键词
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资金
- TRIAD [FP7-281493]
- KRUK [SF1/2014]
- NIHR, Wellcome Trust Programme [082519/Z/07/Z]
- Academy of Medical Sciences Sister Grant for Clinical Lecturers
- Restore Research Trust.
- Wellcome Trust [082519/Z/07/Z] Funding Source: Wellcome Trust
- Academy of Medical Sciences (AMS) [AMS-SGCL11-Issa] Funding Source: researchfish
- Kidney Research UK [SF1/2014] Funding Source: researchfish
- National Institute for Health Research [CL-2013-13-005] Funding Source: researchfish
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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