Photodepletion differentially affects CD4+ Tregs versus CD4 + effector T cells from patients with chronic graft-versus-host disease

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Abstract

Even the most potent immunosuppressive drugs often fail to control graftversus-host disease (GVHD), the most frequent and deleterious posttransplantation complication.We previously reported that photodepletion using dibromorhodamine (TH9402) eliminates T cells from healthy donors activated against major histocompatibility complex-incompatible cells and spares resting T cells. In the present study, we identified photodepletion conditions selectively eradicating endogenous proliferating T cells from chronic GVHD patients, with the concomittant sparing and expansion of CD4 +CD25+ forkhead box protein 3-positive T cells. The regulatory T-cell (Treg) nature and function of these photodepletion-resistant cells was demonstrated in coculture and depletion/repletion experiments. The mechanism by which Tregs escape photodepletion involves active P-glycoprotein - mediated drug efflux. This Treginhibitory activity is attributable to interleukin-10 secretion, requires cell-cell contact, and implies binding with cytotoxic T-lymphocyte antigen 4 (CTLA-4). Preventing CTLA-4 ligation abrogated the in vitro generation of Tregs, thus identifying CTLA-4 - mediated cell-cell contact as a crucial priming event for Treg function. Moreover, the frequency of circulating Tregs increased in chronic GVHD patients treated with TH9402 photodepleted cells. In conclusion, these results identify a novel approach to both preserve and expand Tregs while selectively eliminating CD4+ effector T cells. They also uncover effector pathways that could be used advantageously for the treatment of patients with refractory GVHD. © 2010 by The American Society of Hematology.

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Bastien, J. P., Krosl, G., Therien, C., Rashkovan, M., Scotto, C., Cohen, S., … Roy, D. C. (2010). Photodepletion differentially affects CD4+ Tregs versus CD4 + effector T cells from patients with chronic graft-versus-host disease. Blood, 116(23), 4859–4869. https://doi.org/10.1182/blood-2010-03-273193

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