Superiority of rapamycin over tacrolimus in preserving nonhuman primate treg half-life and phenotype after adoptive transfer

K. Singh, L. Stempora, R. D. Harvey, A. D. Kirk, C. P. Larsen, B. R. Blazar, L. S. Kean

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Many critical issues remain concerning how best to deploy adoptive regulatory T cell (Treg) immunotherapy to the clinic. These include a determination of their pharmacokinetic characteristics, their optimal dose, their phenotypic stability and the best therapies with which to pair Tregs. By performing a CFSE-labeled autologous Treg pulse experiment, we determined that the accessible peripheral blood Treg pool in rhesus macaques is quite large (75-±-11-×-106-Tregs/kg). Pharmacokinetic analysis revealed that Tregs have two phases of elimination: an α phase, with a T1/2 in the peripheral blood of 32.4-±-11.3-h and a β phase with a T1/2 of 120.4-±-19.7-h. In addition to their short initial half-life, Tregs underwent rapid phenotypic shifts after infusion, with significant loss of both CD25 and FoxP3 by day +6. While tacrolimus stabilized CD25 expression, it did not improve T1/2, nor mitigate the loss of FoxP3. In contrast, rapamycin significantly stabilized both CD25 and FoxP3, and supported an increased half-life, with an α phase of 67.7-±-6.9-h and a β phase of 252.1-±-54.9-h. These results suggest that rapamycin may be a necessary addition to Treg immunotherapy, and that tacrolimus may be deleterious to Treg integrity posttransfer. Adoptively transferred Tregs exhibit two-phase elimination kinetics after transfer and demonstrate a loss of phenotypic integrity, both of which are unchanged with concomitant tacrolimus therapy but improved with rapamycin. See editorial by Tang on page 2679.

Original languageEnglish (US)
Pages (from-to)2691-2703
Number of pages13
JournalAmerican Journal of Transplantation
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2014

Bibliographical note

Publisher Copyright:
Copyright © 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Keywords

  • Basic (laboratory) research/science
  • T cell biology
  • immunobiology
  • immunosuppression/immune modulation
  • lymphocyte biology: trafficking
  • tolerance: experimental
  • translational research/science

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