Immunomodulation with donor regulatory T cells armed with Fas-ligand alleviates graft-versus-host disease

Esma S. Yolcu, Ayelet Kaminitz, Keren Mizrahi, Shifra Ash, Isaac Yaniv, Jerry Stein, Haval Shirwan, Nadir Askenasy

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)903-911
Number of pages9
JournalExperimental Hematology
Volume41
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

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