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 concomit-
IntroductionPatients with chronic graft-versus-host disease (GVHD) suffer from considerable organ damage, leading to significant morbidity, frequent hospitalizations, and high mortality rates. [1][2][3] While potent immunosuppressive agents have been developed, a large number of patients either fail to respond or develop secondary treatment refractoriness. [4][5][6] Moreover, their prevalent side effects emphasize the need for innovative treatment strategies. Cellular therapy in the form of extracorporeal photopheresis (ECP) offers an interesting therapeutic option in terms of both efficacy and safety. It mostly utilizes 8-methoxypsoralen as a photosensitizer and ultraviolet illumination to provoke immune modulation. [7][8][9] The new-generation photosensitizer, 4,5-dibromorhodamine-123 (TH9402), is an attractive candidate for ECP because it demonstrates particularly potent cytotoxicity, uses visible light, and its unique ability to preferentially eliminate activated over resting T cells may translate into an appealing approach to eliminate pathogenic host-reactive T cells in patients with chronic GVHD. 10 Indeed, T cells activated upon exposure to mitogens or major histocompatibility complex (MHC)-disparate targets in a mixed lymphocyte reaction (MLR) are eliminated after TH9402 photodepletion. 11,12 Such photodepletion of alloreactive cells also prevents the development of GVHD after MHC-mismatched transplantation and preserves graft-versus-leukemia activity in a murine model. 13 Moreover, a phase I clinical trial of allogeneic MHC-mismatched transplantation, followed by infusion of donor lymphocytes depleted of their alloreactive component using TH9402 photodepletion, also provides evidence that such photodepletion can prevent the development of infections without causing GVHD. 14 Interestingly, some CD4 ϩ CD25 ϩ cells are resistant to TH9402 photodepletion, 11 and the fact that this cell subset is forkhead box protein 3 positive (FOXP3 ϩ ) further suggests that these cells might be regulatory T cells (Tregs), and could be used for the treatment of GVHD. 9,[15][16][17][18][19] However, these findings were obtained after the photodepletion of healthy donor cells activated in vitro, rather than cells from GVHD patients who demonstrate immune dysregulation. In addition, whether Tregs surviving photodepletion have preserved function, and how they exert their activity, has not been investigated.The aim of the present study was to determine whether TH9402 photodepletion could be...
