Regulatory T Cells and Extracorporeal Photochemotherapy: Correlation With Clinical Response and Decreased Frequency of Proinflammatory T Cells

Biaso, Iolanda Di; Maio, Lucia Di; Bugarin, Cristina; Gaipa, Giuseppe; Dander, Erica; Balduzzi, Adriana; Parma, Matteo; D’Amico, Giovanna; Perseghin, Paolo; Biondi, Andrea; Biagi, Ettore

doi:10.1097/tp.0b013e3181a27a5d

Cited by 72 publications

(56 citation statements)

References 10 publications

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“…Percentages of FOXP3-expressing T cells did not increase substantially in our GvHD patient cohort after ECP treatment. However, because of the lack of a more extensive Treg phenotyping 32,33 in our protocol, FOXP3-expressing T cells in our study cannot be equated with Tregs. Unexpectedly, percentages of IL-17-expressing T cells initially increased after ECP in GvHD patients, but dropped later to percentages lower than before ECP.…”

Section: Longitudinal Effects Of Ecp On Neutrophilic Mdscs In Gvhd Pamentioning

confidence: 94%

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

Rieber

Wecker

Neri

et al. 2014

Bone Marrow Transplant

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Extracorporeal photopheresis (ECP) is beneficial in patients with T-cell-mediated disorders, including GvHD, but the underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterized by their capacity to suppress T-cell proliferation. We quantified MDSCs by flow cytometry in peripheral blood from patients after BMT with GvHD before and after ECP treatment, patients after BMT but without GvHD and age-matched healthy controls. MDSC functionality was analyzed using T-cell proliferation, cytokine release and arginase activity. GvHD patients showed increased baseline percentages of neutrophilic MDSCs (PMN-MDSCs) compared with healthy controls and patients after BMT without GvHD. ECP treatment in GvHD patients rapidly increased circulating percentages of PMN-MDSCs. Functionally, PMN-MDSCs efficiently dampened Th1 and Th17 responses and were paralleled by an increase of cellular and extracellular arginase activity. Following ECP longitudinally over 16 weeks, two GvHD responder subgroups were identified, with group one continuously increasing PMN-MDSCs and group two with stable or decreasing PMN-MDSCs over time. This study demonstrates for the first time that ECP increases T-cell-dampening PMN-MDSCs in GvHD patients, a finding that should be confirmed in larger series of GvHD patients.

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Section: Longitudinal Effects Of Ecp On Neutrophilic Mdscs In Gvhd Pamentioning

confidence: 94%

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

Rieber

Wecker

Neri

et al. 2014

Bone Marrow Transplant

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“…Photopheresis is thought to ameliorate GVHD in part by increasing CD4 ϩ CD25 ϩ /FoxP3 ϩ Tregs. 35,36 The role of Tregs in controlling haploidentical GVHD after using this 2-step HSCT approach is an area of current inquiry.…”

Section: Discussionmentioning

confidence: 99%

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing

Grosso

Carabasi

Filicko-O'Hara

et al. 2011

Blood

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Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 ؋ 10 8 /kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143. (Blood. 2011;118(17): 4732-4739) IntroductionUntil recently, HLA haploidentical hematopoietic stem cell transplantation (HSCT) has often been associated with disappointing clinical outcomes, limiting the widespread application of this approach. Higher rates of infection and relapse, 2 consequences of the T-cell depletion required to prevent severe GVHD in recipients of HLA mismatched grafts, adversely affect long-term survival, particularly in patients receiving HSCT late in their disease course. Because only a subset of appropriate transplantation candidates has an HLA-identical sibling or unrelated donor, the development of safer, more efficacious transplantation approaches using haploidentical donors would provide potential transplantation options for patients who lack well-matched donors.Based on murine models, clinical approaches to haploidentical transplantation initially relied on aggressive T-cell depletion techniques. Ex vivo T-cell depletion with soybean agglutinin and E rosetting or the use of mAbs such as T10B9 resulted in BM products containing T-cell doses in the range of 10 4 -10 5 T cells/kg of recipient body weight. This degree of T-cell depletion was associated with the attenuation of severe GVHD and provided consistent engraftment, particularly when antithymocyte globulin was also administered. 1,2 The correlate of a high degree of T-cell depletion to avoid GVHD is delayed posttransplantation immune recovery, 3-9 mortality from infection and relapse, 1,10-16 and higher rates of graft rejection compared with T cell-containing regimens. 17 Ruggeri et al 18 demonstrated that the higher relapse rates associated with T-cell depletion can be moderated in part b...

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“…79 Regardless of the mechanism, responses in chronic GVHD patients have been associated with increased Treg cell counts, increased cellular activation, and inhibition of Tcon. 80,81 ECP has been evaluated in a phase 2 prospective randomized trial, with demonstrated efficacy in sclerodermatous chronic GVHD, including a reduction in steroid dose, meaningful decrease in skin sclerosis, and nonblinded investigator assessment of skin complete or partial responses. However, this study did not meet its prespecified primary end point.…”

Section: Inhibition Of Cytokine Receptor-mediated Signalingmentioning

confidence: 99%

Mechanistic approaches for the prevention and treatment of chronic GVHD

Cutler

Koreth

Ritz

2017

Blood

103

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Clinical outcomes for patients undergoing allogeneic hematopoietic stem cell transplantation continue to improve, but chronic graft-versus-host disease (GVHD) remains a common toxicity and major cause of nonrelapse morbidity and mortality. Treatment of chronic GVHD has previously relied primarily on corticosteroids and other broadly immune suppressive agents. However, conventional immune suppressive agents have limited clinical efficacy in chronic GVHD, and prolonged immune suppressive treatments result in additional toxicities that further limit clinical recovery from transplant and return to normal daily function. Recent advances in our understanding of the immune pathology of chronic GVHD offer the possibility that new therapeutic approaches can be directed in more precise ways to target specific immunologic mechanisms and pathways. In this review, we briefly summarize current standard treatment options and present new therapeutic approaches that are supported by preclinical studies and early-phase clinical trials suggesting that these approaches may have clinical utility for treatment or prevention of chronic GVHD. Further evaluation of these new therapeutic options in well-designed prospective multicenter trials are needed to identify the most effective new agents and improve outcomes for patients with chronic GVHD.

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Regulatory T Cells and Extracorporeal Photochemotherapy: Correlation With Clinical Response and Decreased Frequency of Proinflammatory T Cells

Abstract: In conclusion, our study shows that T-regs represent important immune mediators of the clinical benefits of ECP in patients affected by GvHD.

Cited by 72 publications

References 10 publications

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing

Mechanistic approaches for the prevention and treatment of chronic GVHD

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