Integrin Antagonists Prevent Costimulatory Blockade‐Resistant Transplant Rejection by CD8+ Memory T Cells

• Published in: American journal of transplantation Vol. 12; no. 1; pp. 69 - 80
• Main Authors: Kitchens, W. H., Haridas, D., Wagener, M. E., Song, M., Kirk, A. D., Larsen, C. P., Ford, M. L.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-01-2012; Wiley
• Subjects: Animal models; Animals; Antagonism; Antagonists; Biological and medical sciences; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell survival; Clinical trials; Costimulatory blockade; Graft rejection; Humans; Immunologic Memory; Immunological memory; Immunosuppression; Immunosuppressive agents; Integrins; Integrins - antagonists & inhibitors; Kidney transplantation; LFA-1 antigen; LFA‐1; Lymphocytes T; Male; Medical sciences; Memory cells; memory T cells; Mice; Mice, Inbred C57BL; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Renal function; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Transgenic mice; Translation; VLA-4 antigen; VLA‐4; Graft(material); LFA-1; Cell adhesion molecule; Transplantation; Lymphocyte function associated antigen 1; Homotransplantation; VLA-4; memory T cells; Memory lymphocyte; α4β1 integrin; Prevention; Rejection; Resistance; integrins; Treatment; Surgery; Costimulatory blockade; T-Lymphocyte; Graft; Antagonist; CD8 T lymphocyte
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2011.03762.x

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.
Using a transgenic mouse transplant system that models graft rejection by costimulation blockade‐resistant donor‐specific memory T cells, the authors demonstrate that immunosuppression regimens coupling costimulatory blockade with either LFA‐1 or VLA‐4 antagonism overcomes the “memory barrier” and significantly prolongs graft survival.