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Cancer Discov. 2014 May;4(5):578-91. doi: 10.1158/2159-8290.CD-13-0585. Epub 2014 Feb 18.

A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity.

Author information

1
Departments of 1Immunology, 2Computational Biology and Immunology, 3Pediatrics, and 4Medicine and Immunology, Memorial Sloan-Kettering Cancer Center; 5Department of Immunology, Weill-Cornell Medical Center, New York, New York; 6Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and 7Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida.

Abstract

Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

PMID:
24550032
PMCID:
PMC4011979
DOI:
10.1158/2159-8290.CD-13-0585
[Indexed for MEDLINE]
Free PMC Article

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