Expansion of Memory-Type CD8+ T Cells Correlates With the Failure of Early Immunosuppression Withdrawal After Cadaver Liver Transplantation Using High-Dose ATG Induction and Rapamycin

Donckier, Vincent; Craciun, Ligia; Miqueu, Patrick; Troisi, Roberto; Lucidi, Valério; Rogiers, Xavier; Boon, Nathalie; Degré, Delphine; Buggenhout, Alexis; Moreno, Christophe; Gustot, Thierry; Sainz-Barriga, Mauricio; Bourgeois, Nadine; Colle, Isabelle; Vlierberghe, Hans Van; Amrani, M.; Remmelink, Myriam; Lemmers, Arnaud; Roelen, Dave L.; Claas, Frans H.J.; Reinke, Petra; Sawitzki, Birgit; Volk, Hans‐Dieter; Moine, Alaín Le; Hemptinne, Bernard de; Goldman, Michel

doi:10.1097/tp.0b013e3182985414

Cited by 38 publications

(26 citation statements)

References 66 publications

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“…Increasing differentiation in the CD8 + compartment has previously been associated with a reduced incidence of acute rejection postrenal transplant but conversely an increased risk of rejection in liver transplantation. 54,55 A recent 42 Taken together, these studies and our own suggest that further analysis is required in order to understand their role post-transplant.…”

Section: Discussionmentioning

confidence: 75%

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

Bottomley

Harden

Wood

2015

JASN

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Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8 + T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8 + T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8 + T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8 + T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.

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Section: Discussionmentioning

confidence: 75%

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

Bottomley

Harden

Wood

2015

JASN

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“…Furthermore, this cell population is relatively resistant to immunosuppression, such as costimulatory blockade (13,14). Multiple studies have established that early infiltration of CD8 + memory T cells into allografts, such as hearts, kidneys, and livers, facilitates accelerated rejection and presents a barrier to immunosuppression-mediated long-term graft survival (12,(15)(16)(17)(18)(19). Therefore, preclinical studies have focused on targeting this cell population in an effort to improve the survival of solid organ allografts, such as kidneys (17,20,21).…”

Section: Introductionmentioning

confidence: 99%

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

Krupnick¹,

Lin²,

Li³

et al. 2014

J. Clin. Invest.

115

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Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade-mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8 + T cells (CD44 hi CD62L hi CCR7 + ). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts.

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“…In contrast, patients 6-11 years posttransplant experienced a success rate of 38%, and in those >11 years post-transplant, the success rate was 80%, regardless of recipient age [32] . In contrast, a recent trial on early weaning during the 1 st year failed completely despite using a "pro-tolerogenic" protocol [33] . To identify the state of operational tolerance and predict the development of rejection following withdrawal, Sanchez-Fueyo performed several gene expression studies for discovering and validating a biomarker signature [4] .…”

Section: Lift -Molecular Tolerance Signature For Guiding Immunosupprementioning

confidence: 93%

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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Expansion of Memory-Type CD8+ T Cells Correlates With the Failure of Early Immunosuppression Withdrawal After Cadaver Liver Transplantation Using High-Dose ATG Induction and Rapamycin

Cited by 38 publications

References 66 publications

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

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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