B-Cell-Related Biomarkers of Tolerance are Up-Regulated in Rejection-Free Kidney Transplant Recipients

Viklický, Ondřej; Krystufkova, E.; Brabcova, Irena; Sekerkova, Alena; Wohlfahrt, Peter; Hřibová, Petra; Wohlfahrtová, Mariana; Sawitzki, Birgit; Slatinska, Janka; Striz, Ilja; Volk, Hans‐Dieter; Reinke, Petra

doi:10.1097/tp.0b013e3182789a24

Cited by 72 publications

(53 citation statements)

References 25 publications

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“…Previously it was thought that B cells were primarily associated with development of antibodymediated immune response, and B cell clusters in kidney graft tissue were shown to be associated with poor prognosis [25]. More recently, and contrary to this observation, several groups including ours have found immature B cells signatures to be associated with better early rejection outcomes [26][27][28].…”

Section: B Cells and Related Transcriptsmentioning

confidence: 77%

“…In this study, patients with combined T cell-and antibody mediated rejections had the lowest immature B cell related transcripts in the peripheral blood. Moreover, higher expression levels of tolerance associated gene-1 (TOAG-1), a mitochondrial protein involved in the suppression of T cell activation [36], were observed in kidney graft tissue in rejection free patients [26].…”

Section: B Cells and Related Transcriptsmentioning

confidence: 99%

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Circulating biomarkers of tolerance

Girmanova

Hrubá

Viklický

2015

Transplantation Reviews

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Section: B Cells and Related Transcriptsmentioning

confidence: 77%

Section: B Cells and Related Transcriptsmentioning

confidence: 99%

Circulating biomarkers of tolerance

Girmanova

Hrubá

Viklický

2015

Transplantation Reviews

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“…The incidence of BL histopathology in renal grafts is approximately 20%. [1][2][3][4] Treatment in response to BL findings is still debated, as some studies suggest that BL infiltrates are benign and occur in patients with stable graft function. 5,6 while others suggest that persistence of BL infiltrates may negatively influence graft outcome.…”

mentioning

confidence: 97%

Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes

Hrubá

Brabcova

Gueler

et al. 2015

Kidney International

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The significance of borderline changes in kidney allograft biopsies is widely debated. To help resolve this, we studied differences in intrarenal gene expression patterns between early clinical and 3-month protocol biopsies, all of which had borderline histologic changes. The gene expression profiles in training set of patients by microarray analysis and data were validated in a larger cohort using RT-qPCR. There was greater expression of immunity- and inflammation-related genes in the early clinical biopsies compared to the 3-month protocol biopsies with borderline changes. In early clinically manifested borderline changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes. Regression modeling identified higher donor age and expression of macrophage receptor CLEC5A as risk factors for progression. In the 3-month protocol biopsies with borderline changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. The discrimination power of fibrinogen was confirmed by cross-validation on two independent cohorts. Thus, our study highlights variations in gene expression between clinical and subclinical borderline changes despite similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those with borderline changes who received grafts from older donors.

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“…Therefore, increasing the pool of low-responders by specifically targeting donor-reactive effector/memory T cells would have a big advantage. In a pilot trial (Viklicky O et al, submitted [19] ) we demonstrated that a novel induction protocol based on the combination of clonal size reduction (by low-dose alemtuzumab) and selective targeting of very recently (re)activated (allospecific) effector/memory T cells (expressing temporarily mTNF) as well as acute inflammation by the anti-TNF monoclonal antibody, infliximab, allows safe monotherapy (low-dose tacrolimus) as early as after day 3 post-transplantation in all kidney transplant patients, even in patients with high frequencies of donor-specific IFN-gamma Elispot + cells before transplantation. The 5-year data revealed excellent graft function and histology (almost no signs of chronic rejection).…”

Section: Remini -A Multicenter Open-label Single-arm Simon's Two-stagmentioning

confidence: 99%

“…(ii) Real-time RT-PCR platform: Gene panel expression analysis to identify molecular tolerance (and rejection) signatures [4][5][6][7][8][9][10]18,19]  Decision-making parameter (candidate for companion diagnostics) (iii) Multiparameter flowcytometry platform: Several 10-color panels for the characterization of circulating immune cell subsets [20][21][22]  Exploratory test to detect patients at risk (highresponder) and to monitor therapy response (iv) Ligand assay platform: Multiplex and Singleplex Elisa-based tests for quantification of cytokines in blood and urine [23,24]  Exploratory test to detect graft injury and to monitor minimization strategies…”

Section: Biomarker Testsmentioning

confidence: 99%

Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

et al. 2016

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Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium. © 2016 Hans-Dieter Volk, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 34 PERSPECTIVEStrategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium Abstract: Solid organ transplantation has emerged as the "gold standard" therapy for end-stage organ failure as it improves both quality of life and survival. Despite the progress in short-term graft survival, that is closely associated with the impressive reduction of acute rejections within the first year, long-term graft and patient survival remain almost unchanged and unsatisfactory. Incomplete control of chronic allograft injury but particularly the adverse effects of long-term immunosuppression, such as graft toxicity, diabetes, cardiovascular events, infections, and tumours continue to challenge the long-term success. In general, immunosuppression is applied as one-size-fits-all strategy. This can result in over-and under-immunosuppression of patients with low and high allo-responsiveness, respectively. Trial-and -error strategies to minimize or even completely wean of immunosuppression have a high failure rate. Consequently, there is an unmet medical need to develop biomarkers allowing objective risk stratification of transplant patients. To achieve this goal, we engaged in an academic-industrial partnership. The central focus of the European-wide BIO-DrIM consortium (BIOmarker-Driven IMmmunosuppression) is the implementation of biomarker-guided strategies for personalizing immunosuppress-ion to improve the long-term outcome and to decrease the adverse effects and costs of chronic immunosuppression in solid organ transplant patients. The concept includes four innovative investigator-driven clinical trials designed by the consortium. Hans-Dieter Volk, Bernhard Banas, Frederike Bemelman, et al.

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B-Cell-Related Biomarkers of Tolerance are Up-Regulated in Rejection-Free Kidney Transplant Recipients

Abstract: These observations suggest an association of B-cell signatures, seen also in drug-free tolerant patients, with controlled alloimmune response.

Cited by 72 publications

References 25 publications

Circulating biomarkers of tolerance

Circulating biomarkers of tolerance

Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes

Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

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