Indication‐specific immunomodulatory effects of extracorporeal photopheresis: A pilot study in heart transplanted patients

Dieterlen, Maja‐Theresa; Garbade, Jens; Misfeld, Martín; Lehmann, Sven; Klaeske, Kristin; Borger, Michael A.; Barten, Markus J.

doi:10.1002/jca.21647

Cited by 7 publications

(11 citation statements)

References 27 publications

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“…2,6 In general, therapy of DSA-MR involves a combination of steroids, plasmapheresis, extracorporeal photopheresis, anti-T-lymphocyte IgG, and intravenous immunoglobulin (IVIG) applications. 4,6,7 While common therapeutic IVIG consist of IgG only, novel intravenous IgM-enriched immunoglobulin (IGM-IVIG) consist of a combination of 76% IgG, 12% IgM, and 12% IgA and can address DSA-MR by scavenging activated complement, neutralization of DSA, inhibition of the activation of cytotoxicity effector cells, inhibition of tissue migration granulocytes and monocytes, and activation of regulatory T cells. [8][9][10][11][12] IGM-IVIG are by now regularly used in the therapy of severe sepsis and showed first promising results in the therapy of DSA-MR in lung and heart transplantation.…”

Section: Introductionmentioning

confidence: 99%

Treatment of donor‐specific antibody‐mediated rejection after heart transplantation by IgM‐enriched human immunoglobulin

et al. 2021

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Antibody-mediated graft rejection caused by donor-specific antibodies (DSA-MR) remains a serious problem after heart transplantation (HTx). IgM-enriched human intravenous immunoglobulin (IGM-IVIG) consists of 76% IgG, 12% IgM, and 12% IgA and provides a new multifactorial approach for DSA-MR. Between 2017 and 2020, four (P1-4) of 102 patients developed DSA-MR after HTx in our department and were repetitively treated with IGM-IVIG in combination with anti-thymocyte globulin. While in P1 and P4, DSA-MR occurred within the early post-operative interval, P2 and P3 developed DSA-MR approximately 1 year after transplantation. An impairment of ventricular function was observed in three of four patients. Furthermore, P1 and P4 suffered from malign ventricular arrhythmias. After the application of IGM-IVIG, the ventricular function recovered, and all patients could be discharged from the hospital. As part of a multifactorial therapeutic approach, treatment with IGM-IVIG seems to be a safe and effective strategy to address DSA-MR.

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Section: Introductionmentioning

confidence: 99%

Treatment of donor‐specific antibody‐mediated rejection after heart transplantation by IgM‐enriched human immunoglobulin

et al. 2021

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“…One hypothesizes that the return of apoptotic T cells activates dendritic cells (DCs), which leads to cytokine alterations and results in an increase in regulatory T cells (T regs ) (6). The other hypothesizes that ECP presents an apoptotic stimulus that affects activated alloreactive T cells, which are preferentially processed and presented by DCs resulting in suppression of alloantigenresponding T cells (3). In particular, the effect of ECP on an increase of T regs in HTx was studied by different research groups (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…For example, questions remain about the best time point to initiate or reintroduce ECP therapy as well as about the optimal number of ECP treatments that are required for different indications, such as ACR or antibody-mediated rejection (AMR). Thus, a reliable monitoring tool for optimizing ECP therapy is required ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Monitoring Assay for Extracorporeal Photopheresis Treatment Optimization After Heart Transplantation

et al. 2021

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BackgroundExtracorporeal photopheresis (ECP) induces immunological changes that lead to a reduced risk of transplant rejection. The aim of the present study was to determine optimum conditions for ECP treatment by analyzing a variety of tolerance-inducing immune cells to optimize the treatment.MethodsTen ECP treatments were applied to each of 17 heart-transplant patients from month 3 to month 9 post-HTx. Blood samples were taken at baseline, three times during treatment, and four months after the last ECP treatment. The abundance of subsets of tolerance-inducing regulatory T cells (Tregs) and dendritic cells (DCs) in the samples was determined by flow cytometry. A multivariate statistical model describing the immunological status of rejection-free heart transplanted patients was used to visualize the patient-specific immunological improvement induced by ECP.ResultsAll BDCA+ DC subsets (BDCA1+ DCs: p < 0.01, BDCA2+ DCs: p < 0.01, BDCA3+ DCs: p < 0.01, BDCA4+ DCs: p < 0.01) as well as total Tregs(p < 0.01) and CD39+ Tregs(p < 0.01) increased during ECP treatment, while CD62L+ Tregs decreased (p < 0.01). The cell surface expression level of BDCA1 (p < 0.01) and BDCA4 (p < 0.01) on DCs as well as of CD120b (p < 0.01) on Tregs increased during the study period, while CD62L expression on Tregs decreased significantly (p = 0.04). The cell surface expression level of BDCA2 (p = 0.47) and BDCA3 (p = 0.22) on DCs as well as of CD39 (p = 0.14) and CD147 (p = 0.08) on Tregs remained constant during the study period. A cluster analysis showed that ECP treatment led to a sustained immunological improvement.ConclusionsWe developed an immune monitoring assay for ECP treatment after heart transplantation by analyzing changes in tolerance-inducing immune cells. This assay allowed differentiation of patients who did and did not show immunological improvement. Based on these results, we propose classification criteria that may allow optimization of the duration of ECP treatment.

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“…Monitoring of regulatory T cells frequencies during ECP treatment has been performed in several trials. Some reports describe an increase in circulating Treg percentages over the course of several months during ECP treatment, predominantly in the context of GVHD; however, stable or decreasing Treg frequencies were reported in other pathologic contexts . In most cases, Treg numbers display large inter‐individual heterogeneity and do not necessarily correlate with clinical responses .…”

Section: Introductionmentioning

confidence: 99%

“…Some reports describe an increase in circulating Treg percentages over the course of several months during ECP treatment, [11][12][13][14] predominantly in the context of GVHD; however, stable or decreasing Treg frequencies were reported in other pathologic contexts. 13,15 In most cases, Treg numbers display large inter-individual heterogeneity 16 and do not necessarily correlate with clinical responses. 17 In the context of CTCL treatment, it has been suggested that ECP could induce a cytotoxic response directed toward the malignant clone.…”

Section: Introductionmentioning

confidence: 99%

In vitro PUVA treatment triggers calreticulin exposition and HMGB1 release by dying T lymphocytes in GVHD: New insights in extracorporeal photopheresis

Coppard

Hannani

Humbert

et al. 2019

J of Clinical Apheresis

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Background Extracorporeal photopheresis (ECP) is an effective therapy for graft vs host disease (GVHD), based on infusion of UVA‐irradiated and 8 methoxy‐psoralen (PUVA)‐treated leukocytes. Reinfusion of these apoptosing cells affects the functionality of pathogenic T cells through poorly understood immunomodulatory mechanisms. Apoptosis is usually a silent, tolerance‐associated process, but can also be immunogenic, depending on death‐inducers and environmental context. Methods To understand ECP mechanisms of action, human alloreactive T cells generated in an in vitro model mimicking GVHD were used, as well as primary cells from GVHD patients. Cells were submitted to PUVA treatment and their phenotype and immunogenicity were analyzed, using cell culture and flow cytometry. Results In vitro PUVA treatment induced the expression of several damage‐associated molecular patterns (DAMPs) by dying T cells (calreticulin, high‐mobility group box‐1, and to a lesser extent heat shock proteins 70 and 90), especially upon T cell activation, leading to their phagocytosis by macrophages and dendritic cells (DCs). Allogeneic DCs preincubated with PUVA treated T cells induced comparable naive T cell proliferation and polarization as control allogeneic DC. Conclusion Altogether, in our experimental settings, in vitro PUVA‐treatment induces a partially immunogenic phenotype allowing phagocytosis of apoptotic cells by macrophages and DC, however not sufficient to induce dendritic cell maturation and T cell activation. These data refine current models of ECP‐mediated immune modulation and emphasize the need to further analyze PUVA‐treated cell interactions with immune cells.

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Indication‐specific immunomodulatory effects of extracorporeal photopheresis: A pilot study in heart transplanted patients

Cited by 7 publications

References 27 publications

Treatment of donor‐specific antibody‐mediated rejection after heart transplantation by IgM‐enriched human immunoglobulin

Treatment of donor‐specific antibody‐mediated rejection after heart transplantation by IgM‐enriched human immunoglobulin

Immune Monitoring Assay for Extracorporeal Photopheresis Treatment Optimization After Heart Transplantation

In vitro PUVA treatment triggers calreticulin exposition and HMGB1 release by dying T lymphocytes in GVHD: New insights in extracorporeal photopheresis

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