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 In the absence of acute rejection (AR), rapamycin was withdrawn after month 4.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 (Vβ/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)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ 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-γ 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.
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 In the absence of acute rejection (AR), rapamycin was withdrawn after month 4.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 (Vβ/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)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ 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-γ 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.
Authors: Alexander Sasha Krupnick; Xue Lin; Wenjun Li; Ryuiji Higashikubo; Bernd H Zinselmeyer; Hollyce Hartzler; Kelsey Toth; Jon H Ritter; Mikhail Y Berezin; Steven T Wang; Mark J Miller; Andrew E Gelman; Daniel Kreisel Journal: J Clin Invest Date: 2014-02-24 Impact factor: 14.808
Authors: Sulemon Chaudhry; Yojiro Kato; Joshua Weiner; Paula Alonso-Guallart; Sam Baker; David C Woodland; Jay H Lefkowitch; Raimon Duran-Struuck; Hugo P Sondermeijer; Jonah Zitsman; Mallory L Sears; Anette Wu; Brian Karolewski; Philipp J Houck; Mercedes Martinez; Tomoaki Kato; Megan Sykes; Adam D Griesemer Journal: Transplantation Date: 2020-04-06 Impact factor: 4.939
Authors: Jason M Gauthier; Wenjun Li; Hsi-Min Hsiao; Tsuyoshi Takahashi; Saeed Arefanian; Alexander S Krupnick; Andrew E Gelman; Daniel Kreisel Journal: Ann Am Thorac Soc Date: 2017-09
Authors: M B Ezzelarab; H Zhang; H Guo; L Lu; A F Zahorchak; R W Wiseman; M A Nalesnik; J K Bhama; D K C Cooper; A W Thomson Journal: Am J Transplant Date: 2016-03-17 Impact factor: 8.086
Authors: Sulemon Chaudhry; Yojiro Kato; Joshua Weiner; Paula Alonso-Guallart; Sam Baker; David C Woodland; Jay H Lefkowitch; Raimon Duran-Struuck; Hugo P Sondermeijer; Jonah Zitsman; Mallory L Sears; Anette Wu; Brian Karolewski; Philipp J Houck; Mercedes Martinez; Tomoaki Kato; Megan Sykes; Adam D Griesemer Journal: Transplantation Date: 2020-08 Impact factor: 5.385