Abstract
In organ transplantation, achieving an operational tolerance is the ultimate goal. However, inducing this tolerance with a minimal dose of anti-rejection drugs can only be safely achieved when guided by biomarkers reflecting the immune reactivity in patients. We review recently described biomarkers and assays for the identification of patients for their risk of organ rejection and their suitability for drug weaning. The clinical assessment of tolerance has been attempted with immunological tools, including the analysis of immune cell subsets, regulatory T cells, ELISPOT, and trans-vivo delayed-type hypersensitivity assays. These methods are promising tools for diagnosis; however, their ability to determine the presence and persistence of responsiveness to their transplant is not available. As the "omics" technologies advance, comprehensive and high-throughput biomarker studies have become more accessible, more affordable, and more customizable. Validating the use of microarray analysis has important implications for monitoring patients for the development of tolerance following transplantation as well as for determining the mechanisms by which tolerance is induced and maintained. Finally, collaborative efforts are needed to design and perform prospective multicenter trials to validate the identified biomarkers across different laboratories.
References
1. Truong DQ, Bourdeaux C, Wieërs G, Saussoy P, Latinne D, Reding R. The immunological monitoring of kidney and liver transplants in adult and pediatric recipients. Transpl Immunol. 2009. 22:18–27.
2. Londoño MC, Danger R, Giral M, Soulillou JP, Sánchez-Fueyo A, Brouard S. A need for biomarkers of operational tolerance in liver and kidney transplantation. Am J Transplant. 2012. 12:1370–1377.
3. Sánchez-Fueyo A, Strom TB. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology. 2011. 140:51–64.
4. Bishop GA, Ierino FL, Sharland AF, Hall BM, Alexander SI, Sandrin MS, et al. Approaching the promise of operational tolerance in clinical transplantation. Transplantation. 2011. 91:1065–1074.
5. Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol. 2012. 12:417–430.
6. Sawitzki B, Schlickeiser S, Reinke P, Volk HD. Monitoring tolerance and rejection in organ transplant recipients. Biomarkers. 2011. 16:Suppl 1. S42–S50.
7. Cox JH, Ferrari G, Janetzki S. Measurement of cytokine release at the single cell level using the ELISPOT assay. Methods. 2006. 38:274–282.
8. Warnecke G, Chapman SJ, Bushell A, Hernandez-Fuentes M, Wood KJ. Dependency of the trans vivo delayed type hypersensitivity response on the action of regulatory T cells: implications for monitoring transplant tolerance. Transplantation. 2007. 84:392–399.
9. Louis S, Braudeau C, Giral M, Dupont A, Moizant F, Robillard N, et al. Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation. 2006. 81:398–407.
10. Pacheco-Silva A. Immune function, as assessed by the ImmuKnow assay, correlates with clinical outcomes in transplant recipients. Nat Clin Pract Nephrol. 2007. 3:196–197.
11. Roedder S, Gao X, Sarwal MM. The pits and pearls in translating operational tolerance biomarkers into clinical practice. Curr Opin Organ Transplant. 2012. 17:655–662.
13. Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med. 2003. 349:125–138.
14. Patel JK, Kobashigawa JA. Should we be doing routine biopsy after heart transplantation in a new era of anti-rejection? Curr Opin Cardiol. 2006. 21:127–131.
15. Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A. 2007. 104:15448–15453.
16. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010. 120:1836–1847.
17. Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010. 120:1848–1861.
18. Martínez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J, et al. Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest. 2008. 118:2845–2857.
19. Lozano JJ, Pallier A, Martinez-Llordella M, Danger R, López M, Giral M, et al. Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. Am J Transplant. 2011. 11:1916–1926.