Identification of the immunological profile in rejection-free heart transplantation

Klaeske, Kristin; Lehmann, Sven; Büttner, Petra; R, Palitzsch; Fischer, Julia; Jawad, Khalil; Garbade, Jens; Borger, Michael A.; Barten, Markus J.; Dieterlen, Maja‐Theresa

doi:10.1016/j.trim.2019.101259

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…Induction and maintenance of donor-specific allo-immune tolerance is dependent on the balance of effector T cells and regulatory CD4 + T cells (T reg cells) 1 . The latter play an essential role in the development of long-term allograft acceptance 2 and tolerance 3 . Hence, establishing protocols for immunotherapies targeting T reg cells in the setting of solid organ transplantation has gained an intense interest.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Lehmann

Wang

et al. 2021

Sci Rep

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Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.

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Section: Introductionmentioning

confidence: 99%

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Lehmann

Wang

et al. 2021

Sci Rep

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“…The hierarchical cluster analysis of the dataset reported by Klaeske et al. ( 14 ) formed two clusters. The first cluster included 75% long-term HTx patients and the second cluster included 67% pre-HTx patients ( Supplementary Figure 1 ).…”

Section: Methodsmentioning

confidence: 97%

“…Klaeske et al. used hierarchical clustering and principle component analyses to show that this immune phenotype of long-term HTx patients differed from that of pre-HTx patients ( 14 ). A hierarchical cluster analysis including the dataset of the previous study from Klaeske et al.…”

Section: Methodsmentioning

confidence: 99%

“…It can be assumed that stable long-term transplanted patients who never suffered from transplant rejection received an optimal immunosuppression and have an immune phenotype promoting transplant tolerance. Klaeske et al used hierarchical clustering and principle component analyses to show that this immune phenotype of long-term HTx patients differed from that of pre-HTx patients (14). A hierarchical cluster analysis including the dataset of the previous study from Klaeske et al and measurements of an ECPtreated patient will allow to evaluate if the immune phenotype of the ECP-treated patients changes to the transplant tolerance immune phenotype during ECP treatment by changes of the position in the heat map of the cluster analysis towards the cluster consisting of long-term HTx patients.…”

Section: Classification Of Immunological Effects Induced By Ecpmentioning

confidence: 99%

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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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“…Immunoregulatory function of MSCs is also mediated by the secretion of immunosuppressive factors such as 2, 3-diioxygenase, Prostaglandin E2, IL-10, TGFβ, and induction of regulatory T cell (Treg) (Soleymaninejadian et al 2012). Tregs play a key role in the immune tolerance of heart transplantation, and it induces immune tolerance by secreting cytokines TGF-β/IL-10 and inhibiting IL-2/INF-γ transcription (Klaeske et al 2020). The TGF-β-induced Treg cells migration to transplanted heart surface enables to prolong the life-span of allograft survival in mice (Ozdemir et al 2006).…”

Section: Introductionmentioning

confidence: 99%

TIPE2 Improves the immune tolerance of human amniotic mesenchymal stem cells

et al. 2020

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Tumor necrosis factor-α induced protein 8 like 2 (TIPE2) is one of the newly discovered negative regulators for body's immune balance. The present study aimed to investigate the effect of TIPE2 gene-modified human amniotic mesenchymal stem cells (hAD-MSCs) on immune tolerance. In this study, the TIPE2 over-expressed and the non-transfected hAD-MSCs were severally co-cultured with injured cardiomyocytes. Cell cycle and apoptosis were detected by flow cytometry. Cell viability was measured by MTT, and expressions of immune-related factors were detected by qRT-PCR and western blot. When compared with the empty vector-transfected hAD-MSCs, the TIPE2-overexpression hAD-MSCs co-cultured with injured cardiomyocytes show accelerated cell viability and declined apoptosis. After TIPE2 over-expression, the mRNA and protein levels of p38, extracellular signalregulated kinases (ERK) and interferon-γ (INF-γ) notably decreased, whereas those of transforming growth factor-β (TGF-β) and interleukin-10 (IL-10) increased in a converse trend. This study suggested that TIPE2 may enhance the cellular immune tolerance in co-culture systems of hAD-MSCs and injured cardiomyocyte, providing a theoretical basis for the allogeneic heart transplantation.

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Identification of the immunological profile in rejection-free heart transplantation

Cited by 8 publications

References 33 publications

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation

Immune Monitoring Assay for Extracorporeal Photopheresis Treatment Optimization After Heart Transplantation

TIPE2 Improves the immune tolerance of human amniotic mesenchymal stem cells

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