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 Aug 15;96(3):306-15. doi: 10.1097/TP.0b013e3182985414.

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 In the absence of acute rejection (AR), rapamycin was withdrawn after month 4.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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antilymphocyte Serum / administration & dosage*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cadaver
  • Cytomegalovirus / immunology
  • Graft Rejection / immunology
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunologic Memory*
  • Immunosuppression*
  • Immunosuppressive Agents / administration & dosage*
  • Interleukin-7 / blood
  • Isoantibodies / blood
  • Liver Transplantation*
  • Lymphocyte Depletion
  • Sirolimus / administration & dosage*

Substances

  • Antilymphocyte Serum
  • Immunosuppressive Agents
  • Interleukin-7
  • Isoantibodies
  • Sirolimus