Extracorporeal Photophoresis Augments Function of CD4+CD25+FoxP3+ Regulatory T Cells by Triggering Adenosine Production

Schmitt, Sabrina; Johnson, Theron; Karakhanova, Svetlana; Näher, Helmut; Mahnke, Karsten; Enk, Alexander H.

doi:10.1097/tp.0b013e3181aed927

Cited by 43 publications

(37 citation statements)

References 21 publications

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“…In contrast to direct IL-10 inhibition in ECP-treated PBMC, many studies have demonstrated elevated IL-10 either in ECP-untreated DC/ monocytes being cocultured with ECP-exposed cells (12,49,50) or in ECP Tregs, and the requirement for IL-10 was demonstrated in IL-10-deficient mice (10). Furthermore, additional data have suggested that ECP promoted Treg expansion in recipients (51,52). In our view, these results support the hypothesis that ECP may have dual immunomodulatory activity: immunoregulatory activity of ECP-treated apoptotic lymphocytes interacting with ECP-unexposed host cells and possible immunostimulatory activity of directly ECP-exposed monocytes.…”

Section: Discussionmentioning

confidence: 99%

Extracorporeal Photopheresis Promotes IL-1β Production

Yakut

Jakobs

Peric

et al. 2015

The Journal of Immunology

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Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP.

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Section: Discussionmentioning

confidence: 99%

Extracorporeal Photopheresis Promotes IL-1β Production

Yakut

Jakobs

Peric

et al. 2015

The Journal of Immunology

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“…3,4 Despite its clinical effectiveness, the immunomodulatory mechanisms of ECP are not fully understood. 5 Previous studies proposed triggering of lymphocyte, monocyte and natural killer cell apoptosis, 6 the induction of regulatory T cells (Tregs), [7][8][9] including enhancement of Treg function, 10 modulation of pro-inflammatory cytokines and/ or induction of tolerogenic dendritic cells [11][12][13][14] as potential modes of ECP action. Immature B-cell subsets and levels of B-cell activating factor have been shown to serve as clinical ECPresponse markers.…”

Section: Introductionmentioning

confidence: 99%

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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“…This hypothesis is supported by the finding that transplant recipients of solid organs or with graftversus-host disease posthematopoietic stem cell transplants treated with ECP exhibited a higher frequency of peripheral T regs (CD41, CD251, FoxP31, and CD692) [12][13][14][15]. More recently, Schmitt et al [16] showed that ECP stimulates the conversion of adenosine triphosphate (ATP) to adenosine, a soluble immunosuppressive mediator of T-cell activation.…”

Section: What Is Ecp and Why Is It An Option In Heart And Lung Transpmentioning

confidence: 88%

Update on extracorporeal photopheresis in heart and lung transplantation

Marques

Schwartz

2010

J of Clinical Apheresis

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Transplant rejection of solid organs remains a threat to thousands of patients despite modern immunosuppressive regimens. The currently available drugs are associated with severe complications such as hypertension, diabetes mellitus, renal failure, risk of infections, and malignancies among many others and, often enough, still allow episodes of rejection. New and less-toxic immunologic measures are desperately needed to accomplish the desired tolerance to the transplant without the undesirable side effects. Extracorporeal photopheresis (ECP) has been shown to benefit especially patients with cardiac transplants, but also those who received lung allografts. ECP likely modulates the recipient's antigen-specific immune responses and inflammation in transplantation by in vivo generation of apoptotic leukocytes. This review will highlight the need for ECP, how it is thought to act, and the published evidence for its role in cardiac and pulmonary transplantation.

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Extracorporeal Photophoresis Augments Function of CD4+CD25+FoxP3+ Regulatory T Cells by Triggering Adenosine Production

Abstract: Our data indicate that ECP stimulates the conversion of ATP to adenosine by the ectonucleotiodase CD39, which acts as a novel soluble immunosuppressive reagent mediating immunosuppression of Treg.

Cited by 43 publications

References 21 publications

Extracorporeal Photopheresis Promotes IL-1β Production

Extracorporeal Photopheresis Promotes IL-1β Production

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

Update on extracorporeal photopheresis in heart and lung transplantation

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