title: Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8(+)  memory T cells.
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.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Kitchens
authors.forename: D
authors.initials: D
authors.lastname: Haridas
authors.forename: M E
authors.initials: ME
authors.lastname: Wagener
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: M L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016023:Integrins