title: Harnessing regulatory T cells for transplant tolerance in the clinic through mTOR inhibition:  myth or reality?
abstract: OBJECTIVE
  The inhibition of mTOR promotes immune tolerance in mouse models of transplantation, by favoring the expansion of regulatory T cells over effector T cells. However, attempts at inducing immune tolerance with the mTOR inhibitor (mTOR-I) in humans have so far failed. We herein review the immunological obstacles that need to be overcome in order to translate mTOR-I-related tolerogenic properties into the clinic.
  
  
  RESULTS
  Our knowledge of regulatory T-cell biology has exploded over the past few years, providing clues to explain the complex impact of prolonged mTOR inhibition on the biology of regulatory T cells. Furthermore, recent data have shed light on the unexpected pro-inflammatory burst observed in some transplant recipients treated with mTOR-I. We propose that the exposure of an organism to pathogens determines the immunodominant effect of mTOR-I, altering the immune system from a state of tolerance in inbred animals to a state of infection-triggered enhanced inflammation in humans.
  
  
  CONCLUSIONS
  Recent advances in the understanding of the pleiotropic effects of mTOR-I on the immune system are paving the way to new therapeutic avenues. Future mTOR-I-based tolerogenic protocols should counter the mTOR-I-related inflammation in order to selectively promote expansion of stable regulatory T cells. We herein envisage promising therapeutic perspectives.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France. julien.zuber@nck.aphp.fr
authors.forename: Julien
authors.initials: J
authors.lastname: Zuber
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D058990:Molecular Targeted Therapy; D016377:Organ Transplantation / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases