title: IL-7 receptor blockade following T cell depletion promotes long-term allograft survival.
abstract: T cell depletion is commonly used in organ transplantation for immunosuppression; however, a restoration of T cell homeostasis following depletion leads to increased memory T cells, which may promote transplant rejection. The cytokine IL-7 is important for controlling lymphopoiesis under both normal and lymphopenic conditions. Here, we investigated whether blocking IL-7 signaling with a mAb that targets IL-7 receptor α (IL-7Rα) alone or following T cell depletion confers an advantage for allograft survival in murine transplant models. We found that IL-7R blockade alone induced indefinite pancreatic islet allograft survival if anti-IL-7R treatment was started 3 weeks before graft. IL-7R blockade following anti-CD4- and anti-CD8-mediated T cell depletion markedly prolonged skin allograft survival. Furthermore, IL-7 inhibition in combination with T cell depletion synergized with either CTLA-4Ig administration or suboptimal doses of tacrolimus to induce long-term skin graft acceptance in this stringent transplant model. Together, these therapies inhibited T cell reconstitution, decreased memory T cell numbers, increased the relative frequency of Tregs, and abrogated both cellular and humoral alloimmune responses. Our data suggest that IL-7R blockade following T cell depletion has potential as a robust, immunosuppressive therapy in transplantation.
authors.forename: Hoa-Le
authors.initials: HL
authors.lastname: Mai
authors.forename: Françoise
authors.initials: F
authors.lastname: Boeffard
authors.forename: Julie
authors.initials: J
authors.lastname: Longis
authors.forename: Richard
authors.initials: R
authors.lastname: Danger
authors.forename: Bernard
authors.initials: B
authors.lastname: Martinet
authors.forename: Fabienne
authors.initials: F
authors.lastname: Haspot
authors.forename: Bernard
authors.initials: B
authors.lastname: Vanhove
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
mesh_terms: D000069594:Abatacept; D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D006085:Graft Survival / Q000276:immunology*; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D018796:Immunoconjugates / Q000008:administration & dosage; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors*; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D016559:Tacrolimus / Q000008:administration & dosage; D014181:Transplantation Immunology; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D020395:Receptors, Interleukin-7; D000069594:Abatacept; D016559:Tacrolimus