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Am J Transplant. 2012 Jan;12(1):69-80. doi: 10.1111/j.1600-6143.2011.03762.x. Epub 2011 Sep 22.

Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+) memory T cells.

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1
Emory Transplant Center, Emory University, Atlanta, GA, USA.

Abstract

The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T-cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study the mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8(+) T-cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T-cell trafficking to the graft but not memory T-cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials.

PMID:
21942986
PMCID:
PMC3467016
DOI:
10.1111/j.1600-6143.2011.03762.x
[Indexed for MEDLINE]
Free PMC Article
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