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Montréal, Canada

Bastien J.-P.,Rosemont Research Center | Bastien J.-P.,University of Montreal | Krosl G.,Rosemont Research Center | Therien C.,Rosemont Research Center | And 11 more authors.
Blood | Year: 2010

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.

Joyal J.-S.,University of Montreal | Joyal J.-S.,McGill University | Omri S.,Rosemont Research Center | Sitaras N.,Rosemont Research Center | And 5 more authors.
Acta Paediatrica, International Journal of Paediatrics | Year: 2012

Retinopathy of prematurity (ROP) is a major cause of severe visual deficits in children. This review focuses on the role of newly identified factors from retinal neurons, which through their opposing actions on vascular development contribute to ROP. These hypoxia-generated mediators include the Krebs cycle intermediate, succinate acting via GPR91, and the neuronal guidance molecule Semaphorin 3A.Conclusion: Neuron-derived factors guide retinal vascularization and are major contributors to the pathogenesis of ROP. © 2012 Foundation Acta Pædiatrica.

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