APMAdvances in Precision Medicine2424-85922424-9106Bio-Byword Scientific Publishing Pty. Ltd.10.18063/APM.2016.01.001Perspective ArticleStrategy to achieve biomarker-driven immunosup-pression after solid organ transplantation by an aca-demic-industry partnership within the European  BIO-DrIM consortiumhttps://artdesignp.com/journal/APM/1/1/10.18063/APM.2016.01.001VolkHans-Dieter,BanasBernhard,BemelmanFrederike,BestardOriol,BrouardSophie,CuturiCristina,GrinyóJosep M,Hernandez-FuentesMaria,KochMartina,NashanBjörn,Rebollo-MesaIrene,Sanchez-FueyoAlberto,SawitzkiBirgit,BergeIneke J M ten,ViklickyOndrej,Wood KKathryn,ReinkePetra2016112016-03-18Solid 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 un-changed 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 re-sult 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. BIO-DrIM, personalized immunosuppression, biomarker, solid organ transplantation, stratification into high/low responder patients, Elispot, multiparameter flow cytometry, urinary IP-10, health-economic analyses

1. Casey M J and Meier-Kriesche H U, 2011, Calcineurin inhibitors in kidney transplantation - friend or foe? Current Opinion in Nephrology Hypertens, vol.20(6): 610-615.2. Rostning L and Karnar, 2010, mTOR inhibitor/proliferation signal inhibitors: entering or leaving the filed? Journal of Nephrology, vol.2: 133-142.3. Martinez-Llordella M, Lozano J J, Puig-Pey I, et al. 2009, Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. Journal of Clinical Investigation, vol.118: 2845-2857.4. Sanchez-Fueyo A, 2011, Hot debate on tolerance: immunosuppression withdrawal. Liver Transplantation, vol.17: S69-S73.5. Brouard S, Mansfield E, Braud C, et al. 2007, Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proceedings of the National Academy of Sciences of the United States of America, vol.104: 15448-15453.6. Pallier A, Hillion S, Danger R, et al. 2010, Patients with drug free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney International, vol.78(5): 503-513.7. Sagoo P, Perucha E, Sawitzki B, et al. 2011, Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. Journal of Clinical Investigation, vol.120: 1848-1861.8. Hernandez-Fuentes M P and Lechler R A, 2010, 'Biomarker signature' for tolerance in transplantation. Nature Reviews Nephrology, vol.6: 606-613.9. Lozano J J, Pallier A, Martinez-Llordella M, et al. 2011, Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. American Journal of Transplantation, vol.11: 1916-1926.10. Brouard S, Giral M, Souillou J P, et al. 2011, Elaboration of gene expression-based clinical decision aids for kidney transplantation: where do we stand? Transplantation, vol.91: 691-69.11. Nickel P, Bestard O, Volk H D, et al. 2009, Diagnostic value of T-cell monitoring assays in kidney transplantation. Current Opinion in Organ Transplantation, vol.14: 426-431.12. Andree H, Nickel P, Nasiadko C, et al. 2006, Identification of dialysis patients with panel-reactive memory T cells before transplantation using an allogeneic cell bank Journal of the American Society of Nephrology, vol.17: 573-580.13. Sawitzki B, Reinke P, Pascher A, et al. 2010, State of the art on the research for biomarkers allowing individual, tailor-made minimization of immunosuppression. Current Opinion in Organ Transplantation, vol.15: 691-696.14. Sawitzki B, Bushell A, Steger U, et al. 2007, Identification of gene markers for the prediction of allograft rejection or permanent acceptance. American Journal of Transplantation, vol.7: 1091-1102.15. Bestard O, Nickel P, Cruzado J M, et al. 2008, Circulating alloreactive T cells correlate with graft function in longstanding renal transplant recipients. Journal of the American Society of Nephrology, vol.19: 1419-1429.16. Nadig S N, Wieckiewicz J, Wu D C, et al. 2010, In vivo prevention of transplant arteriosclerosis by ex vivo expanded human regulatory T cells. Nature Medicine, vol.16: 809-813.17. Hricik D E, Rodriguez V, Riley J, et al. 2013, Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. American Journal of Transplantation, vol.3: 878-884.18. Sanchez-Fueyo A, 2013, Tolerance profiles and immunosuppression. Liver Transplantation, vol.19(Suppl 2): S44-S48.19. Viklicky O, Krystufkova E, Brabcova I, et al. 2013, B-cell-related biomarkers of tolerance are up-regulated in rejection-free kidney transplant recipients. Transplantation, vol.95: 148-154.20. Streitz M, Miloud T, Kapinsky M, et al. 2013, Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study. Transplantation Research, vol.2: 17-23.21. Gerlach U A, Vogt K, Schlickeiser S, et al. 2013, Elevation of CD4+ differentiated memory T cells is associated with acute cellular and antibody-mediated rejection after liver transplantation. Transplantation, vol.95: 1512-1520.22. Sawitzki B, Schlickeiser S, Reinke P, et al. 2009, Pre-transplant immune risk assessment. Current Opinion in Organ Transplantation, vol.14: 650-655.23. Hu H, Aizenstein B D, Puchalski A, et al. 2004, Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction. American Journal of Transplantation, vol.4: 432-437.24. Matz M, Beyer J, Wunsch D, et al. 2006, Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function. Kidney International, vol.69: 1683-1690.25. Dziubianau M, Hecht J, Kuchenbecker L, et al. 2013, TCR repertoire analysis by next generation sequencing allows complex differential diagnosis of T cell-related pathology. American Journal of Transplantation, vol.13: 2842-2854.26. Lei H, Kuchenbecker L, Streitz M, et al. 2015, Human CD45RA(low) FoxP3(high) memory-type regulatory T cells show distinct TCR repertoires with conventional T cells and play an important role in controlling early immune activation. American Journal of Transplantation, vol.15: 2625-2635.27. Wieczorek G, Asemissen A, Model F, et al. 2009, Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Research, vol.69: 599-608.28. Krepsova E, Tycova I, Sekerkova A, et al. 2015, Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance. BMC Nephrology, vol.16: 146-151.29. Sawitzki B, Brunstein C, Meisel C, et al. 2014, Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood toll-like receptor 5 mRNA expression. Biology of Blood and Marrow Transplantation, vol.20: 173-182.30. Hutchinson J A, Riquelme P, Sawitzki B, et al. 2011, Cutting edge: immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. Journal of Immunology, vol.187: 2072-2078.31. Keeren K, Friedrich M, Gebuhr I, et al. 2009, Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies. Journal of Immunology, vol.183: 4077-4087.32. Benitez C, Londono M C, Miquel R, et al. 2013, Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients. Hepatology, vol.58: 1824-1835.33. Donckier V, Craciun L, Miqueu P, et al. 2013, 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. Transplantation, vol.96: 306-315.34. Bohne F, Martinez-Llordella M, Lozano J J, et al. 2012, Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation. Journal of Clinical Investigation, vol.122: 368-382.35. Bonaccorsi-Riani E, Danger R, Lozano J J, et al. 2015, Iron deficiency impairs intra-hepatic lymphocyte mediated immune response. PLoS One, vol.10: e0136106.36. Siepert A, Ahriich S, Vogt K, et al. 2012, Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. American Journal of Transplantation, vol.12: 2384-2394.37. Bestard O, Cruzado J M, Lucia M, et al. 2013, Prospective assessment of antidonor cellular alloreactivity is a tool for guidance of immunosuppression in kidney transplantation. Kidney International, vol.84: 1226-1236.38. Bestard O, Crespo E, Stein M, et al. 2013, Cross-validation of IFN-γ Elispot assay for measuring alloreactive memory/effector T cell responses in renal transplant recipients. American Journal of Transplantation, vol.13: 1880-1890.