title: A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity.
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.
authors.affiliation: 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.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: Tuckett
authors.forename: Samedy
authors.initials: S
authors.lastname: Ouk
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Grégoire
authors.initials: G
authors.lastname: Altan-Bonnet
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Oyler
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Mallory L
authors.initials: ML
authors.lastname: West
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Singer
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Doubrovina
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pankov
authors.forename: Chandresh V
authors.initials: CV
authors.lastname: Undhad
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Zakrzewski
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D020569:Proto-Oncogene Proteins c-rel; D011948:Receptors, Antigen, T-Cell; D054852:Small Molecule Libraries