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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kitchens, WH; Haridas, D; Wagener, ME; Song, M; Kirk, AD; Larsen, CP; Ford, ML

Published Date

  • January 2012

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 69 - 80

PubMed ID

  • 21942986

Pubmed Central ID

  • 21942986

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

Digital Object Identifier (DOI)

  • 10.1111/j.1600-6143.2011.03762.x

Language

  • eng

Conference Location

  • United States