THE OPPORTUNITIES OF NON-INVASIVE LIVER GRAFT REJECTION DIAGNOSTICS BY USING TERMINALLY DIFFERENTIATED EFFECTOR CD8+ T-LYMPHOCYTES
Abstract
Background. Immune-mediated graft dysfunction with the prevalence of 40% is one of the main problems of modern transplantology. Although percutaneous liver graft biopsy is associated with the development of different complications occurring in 2,2% of cases and can also lead to fatal outcome Objective – to develop a noninvasive method of graft dysfunction diagnostics in the late post-transplant period using terminally differentiated effector CD8+ T-lymphocytes. Material and methods. There was carried out a single center observational retrospective case-control pilot study, including 45 recipients after orthotopic liver transplantation. According to the postoperative clinical course the patients were stratified into 2 groups depending on the presence of graft rejection episodes. All patients got immunosuppressive therapy after liver transplantation. Immunophenotypes of the recipients were determined by flow cytometry method. Percutaneous liver graft biopsy was performed in all patients, the results of histological examination were evaluated according to the international Banff schema for grading liver allograft rejection. Results. The results of liver biopsies showed that 14 (31%) out of 45 patients had morphological signs of rejection. The patients with rejection had a reliably higher level of CD8+ Temra cells absolute number (0,23 (0,14;0,38) x 109/l) in comparison to those without rejection (0,09 (0,034;0,16) x 109/l (p=0,034)). The results of ROC-analysis have shown that the most optimal cut-off threshold of CD8+ T-lymphocytes level in immune-mediated graft dysfunction diagnostics in the late post-transplant period is 0,1882x109/l; sensitivity and specificity in this case being 73,33 (95%; 44,9-92,0) and 96,55 (95%; 82,2-99,4) respectively. Conclusions. The increase of terminally differentiated effector CD8+ T-lymphocytes absolute number has diagnostic importance in patients with immune-mediated graft dysfunction in the late post-transplant period. High sensitivity and specificity of cut-off threshold of CD8+ Temra lymphocytes absolute number in patients after liver transplantation as well as reliable difference between cell number in patients with normal postoperative period and in patients with immune-mediated graft dysfunction allow considering T-lymphocyte subpopulation as a rejection predictor in the late post-transplant period. The correlation between CD8+ T-lymphocyte absolute number and the results of histological examination makes the former an alternative and, what is more, safe noninvasive method in early diagnostics of liver graft rejection.References
Gonzalez MG, Madrazo CP, Rodriguez AB, Gutiérrez MG, Herrero JI, Pallardó JM, Ortiz de Urbina J, Paricio PP. An open, randomized, multicenter clinical trial of oral tacrolimus in liver allograft transplantation: a comparison of dual vs. triple drug therapy. Liver Transpl. 2005;11(5):515-524. https://doi.org/10.1002/lt.20382.
Piccinino F, Sagnelli E, Pasquale G, Giusti G, Battocchia A, Bernardi M, Bertolazzi R, Bianchi FB, Brunelli E, Budillon G, Buscarini L, Cargnel A, Carrara G, Carulli N, Caruso L, Cataldi V, Celle G, Chiandussi L, Chiesa L, Colombo M, Coltorti M, De Bac C, Del Vecchio Blanco C, Di Marco G, Fiaccadori F, et al. Complications following percutaneous liver biopsy: A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2(2):165-173. https://doi.org/10.1016/s0168-8278(86)80075-7.
Benichou G, Gonzalez B, Marino J, Ayasoufi K, Valujskikh A. Role of Memory T Cells in Allograft Rejection and Tolerance. Front Immunol. 2017;8:170. https://doi.org/10.3389/fimmu.2017.00170.
Tilly G, Yap M, Brouard S, Degauque N. TEMRA CD8 T-Cells Are Highly Cytopathic Cells That Escape From Costimulatory Based-Therapy. Transplantation. 2015;98:318-319. https://doi.org/10.1097/00007890-201407151-01012.
Yap M, Boeffard F, Clave E, Pallier A, Danger R, Giral M, Dantal J, Foucher Y, Guillot-Gueguen C, Toubert A, Soulillou JP, Brouard S, Degauque N. Expansion of Highly Differentiated Cytotoxic Terminally Differentiated Effector Memory CD8+ T Cells in a Subset of Clinically Stable Kidney Transplant Recipients. J Am Soc Nephrol. 2014;25(8):1856-1868. https://doi.org/10.1681/ASN.2013080848.
Irure J, Ballesteros M, Iturbe D, Merino D, Mora V, Mons R, Fernández-Rozas S, Asensio E, Gómez-Román J, Cifrián J, López-Hoyos M, Segundo DS. CD8 T Effector Memory T Cells as Predictive Biomarker of Severe Acute Rejection in Lung Transplantation. Transplantation. 2013;102:S682. https://doi.org/10.1097/01.tp.0000543627.01804.d6.
Yap M, Boeffard F, Pallier A, Danger R, Giral M, Dantal J, Foucher Y, Guillot-Gueguen C, Soulilou J, Brouard S, Degauque N. A Subset of Patients Accumulated Highly Differentiated CD4 and CD8 T Memory Cells Despite Having Long-Term Stable Graft Function. Transplantation. 2014;98:877. https://doi.org/10.1097/00007890-201407151-02992.
Sarwal MM, Jani A, Chang S, Huie P, Wang Z, Salvatierra OJr, Clayberger C, Sibley R, Krensky AM, Pavlakis M. Granulysin expression is a marker for acute rejection and steroid resistance in human renal transplantation. Human Immunol. 2001;62(1):21-31. https://doi.org/10.1016/s0198-8859(00)00228-7.
Tilly G, Doan-Ngoc T-M, Yap M, Caristan A, Jacquemont L, Danger R, Cadoux M, Bruneau S, Giral M, Guerif P, Nicol B, Garcia A, Laplaud DA, Brouard S, Pecqueur Hellman C, Degauque N. IL-15 Harnesses Pro-inflammatory Function of TEMRA CD8 in Kidney-Transplant Recipients. Front Immunol. 2017;8:778. https://doi.org/10.3389/fimmu.2017.00778.
Akoglu B, Lafferton B, Kalb S, Yosuf SE, Herrmann E, Zeuzem S, Goßmann J, Kachel HG, Scheuermann EH, Faust D. Rejection quantity in kidney transplant recipients is associated with increasing intracellular interleukin-2 in CD8+ T-cells. Transpl Immunol. 2014;31(1):17-21. https://doi.org/10.1016/j.trim.2014.05.004.
Cossarizza A, Chang HD, Radbruch A, Acs A, Adam A, Adam-Klages S, Agace WW, Aghaeepour N, Akdis M, Allez M, Nogueira Almeida L, Alvisi G, Anderson G, Andrä I, Annunziato F, Anselmo A, Bacher P, Baldari CT, Bari S, Barnaba V, Barros-Martins J, Battistini L, Bauer W, Baumgart S, Baumgarth N, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (2nd edition). Eur J Immunol. 2019;49(10):1457-1973. https://doi.org/10.1002/eji.201970107.
Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997;25(3):658-663. https://doi.org/10.1002/hep.510250328.
Halamay KE, Kirkman RL, Sun L, Yamada A, Fragoso RC, Shimizu K, Mitchell RN, McKay DB. CD8 T cells are sufficient to mediate allorecognition and allograft rejection. Cell Immunol. 2002;216(1-2):6-14. https://doi.org/10.1016/s0008-8749(02)00530-0.
Gerlach UA, Vogt K, Schlickeiser S, Meisel C, Streitz M, Kunkel D, Appelt C, Ahrlich S, Lachmann N, Neuhaus P, Pascher A, Sawitzki B. Elevation of CD4+ Differentiated Memory T Cells Is Associated With Acute Cellular and Antibody-Mediated Rejection After Liver Transplantation. Transplantation. 2013;95(12):1512-1520. https://doi.org/10.1097/TP.0b013e318290de18.
Delfs MW, FurukawaY, Mitchell RN, Lichtman AH. CD8+ Tcell subsets TC1 and TC2 cause different histopathologic forms of murine cardiac allograft rejection. Transplantation. 2001;71(5):606-610. https://doi.org/10.1097/00007890-200103150-00005.
1.png)
