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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

(2013) TRANSPLANTATION. 96(3). p.306-315
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Abstract
Background. We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin. Methods. LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells. Results. Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (VA/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-gamma and interleukin (IL)-17, increased intragraft expression of IFN-gamma mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells. Conclusion. High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-gamma and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.
Keywords
MULTIPLE-MYELOMA, CUTTING EDGE, ORGAN-TRANSPLANTATION, HEPATOCELLULAR-CARCINOMA, LYMPHOHEMATOPOIETIC CHIMERISM, KIDNEY-TRANSPLANTATION, OPERATIONAL TOLERANCE, POLYMERASE-CHAIN-REACTION, RENAL-ALLOGRAFT REJECTION, T cells, Memory, Tolerance, Transplantation, Liver, RECIPIENTS

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Chicago
Donckier, Vincent, Ligia Craciun, Patrick Miqueu, Roberto Troisi, Valerio Lucidi, Xavier Rogiers, Nathalie Boon, 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 96 (3): 306–315.
APA
Donckier, V., Craciun, L., Miqueu, P., Troisi, R., Lucidi, V., Rogiers, X., Boon, N., 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, 96(3), 306–315.
Vancouver
1.
Donckier V, Craciun L, Miqueu P, Troisi R, Lucidi V, Rogiers X, et al. 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. 2013;96(3):306–15.
MLA
Donckier, Vincent, Ligia Craciun, Patrick Miqueu, et al. “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 96.3 (2013): 306–315. Print.
@article{4322908,
  abstract     = {Background. We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin.
Methods. LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells.
Results. Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (VA/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-gamma and interleukin (IL)-17, increased intragraft expression of IFN-gamma mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells.
Conclusion. High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-gamma and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.},
  author       = {Donckier, Vincent and Craciun, Ligia and Miqueu, Patrick and Troisi, Roberto and Lucidi, Valerio and Rogiers, Xavier and Boon, Nathalie and Degr{\'e}, Delphine and Buggenhout, Alexis and Moreno, Christophe and Gustot, Thierry and SAINZ-BARRIGA, MAURICIO and Bourgeois, Nadine and Colle, Isabelle and Van Vlierberghe, Hans and Amrani, Mohammed and Remmelink, Myriam and Lemmers, Arnaud and Roelen, Dave L and Claas, Frans H and Reinke, Petra and Sawitzki, Birgit and Volk, Hans Dieter and Le Moine, Alain and de Hemptinne, Bernard and Goldman, Michel},
  issn         = {0041-1337},
  journal      = {TRANSPLANTATION},
  keyword      = {MULTIPLE-MYELOMA,CUTTING EDGE,ORGAN-TRANSPLANTATION,HEPATOCELLULAR-CARCINOMA,LYMPHOHEMATOPOIETIC CHIMERISM,KIDNEY-TRANSPLANTATION,OPERATIONAL TOLERANCE,POLYMERASE-CHAIN-REACTION,RENAL-ALLOGRAFT REJECTION,T cells,Memory,Tolerance,Transplantation,Liver,RECIPIENTS},
  language     = {eng},
  number       = {3},
  pages        = {306--315},
  title        = {Expansion of memory-type CD8\unmatched{207a} T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin},
  url          = {http://dx.doi.org/10.1097/TP.0b013e3182985414},
  volume       = {96},
  year         = {2013},
}

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