title: Immunomodulation with donor regulatory T cells armed with Fas-ligand alleviates graft-versus-host disease.
abstract: Infusion of large numbers of donor regulatory T cells (Tregs) is an effective approach to suppress graft-versus-host disease (GvHD). We have reported previously that enhancing the killing activity of CD25(+) Tregs by decoration with short-lived Fas-ligand (FasL) protein (killer Tregs) is effective in abrogation of autoimmunity. In this study, we assessed the therapeutic efficacy of killer Tregs in murine models of lethal GvHD. In a model in which disease-associated mortality was not prevented by infusion of naive donor Tregs (3 days after transplant) at an effector:suppressor ratio of 10:1, killer Tregs rescued 70% of the mice and improved the clinical and histologic scores. We found that both effector lymphocytes and therapeutic Tregs migrate to and proliferate in the mesenteric lymph nodes of irradiated recipients; however, only killer Tregs increased fractional apoptosis of effector lymphocytes. Although the lymphoid organs were primarily reconstituted from the bone marrow with little contribution of the infused effector and suppressor subsets, immunomodulation with FasL caused a durable rise in fractions of CD4(+)FoxP3(+) Tregs. Our findings demonstrate that a short-lived apoptotic protein increases the suppressive activity of Tregs and ameliorates GvHD severity.
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Ayelet
authors.initials: A
authors.lastname: Kaminitz
authors.forename: Keren
authors.initials: K
authors.lastname: Mizrahi
authors.forename: Shifra
authors.initials: S
authors.lastname: Ash
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000276:immunology*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy*; D056747:Immunomodulation; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*
chemical_list: D053222:Fas Ligand Protein