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

Publication ,  Journal Article
Singh, K; Stempora, L; Harvey, RD; Kirk, AD; Larsen, CP; Blazar, BR; Kean, LS
Published in: Am J Transplant
December 2014

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 × 10(6) 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.

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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

December 2014

Volume

14

Issue

12

Start / End Page

2691 / 2703

Location

United States

Related Subject Headings

  • Transplantation, Autologous
  • Tissue Distribution
  • Tacrolimus
  • T-Lymphocytes, Regulatory
  • Surgery
  • Succinimides
  • Sirolimus
  • Phenotype
  • Macaca mulatta
  • Interleukin-2 Receptor alpha Subunit
 

Citation

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Singh, K., Stempora, L., Harvey, R. D., Kirk, A. D., Larsen, C. P., Blazar, B. R., & Kean, L. S. (2014). Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant, 14(12), 2691–2703. https://doi.org/10.1111/ajt.12934
Singh, K., L. Stempora, R. D. Harvey, A. D. Kirk, C. P. Larsen, B. R. Blazar, and L. S. Kean. “Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer.Am J Transplant 14, no. 12 (December 2014): 2691–2703. https://doi.org/10.1111/ajt.12934.
Singh K, Stempora L, Harvey RD, Kirk AD, Larsen CP, Blazar BR, et al. Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant. 2014 Dec;14(12):2691–703.
Singh, K., et al. “Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer.Am J Transplant, vol. 14, no. 12, Dec. 2014, pp. 2691–703. Pubmed, doi:10.1111/ajt.12934.
Singh K, Stempora L, Harvey RD, Kirk AD, Larsen CP, Blazar BR, Kean LS. Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant. 2014 Dec;14(12):2691–2703.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

December 2014

Volume

14

Issue

12

Start / End Page

2691 / 2703

Location

United States

Related Subject Headings

  • Transplantation, Autologous
  • Tissue Distribution
  • Tacrolimus
  • T-Lymphocytes, Regulatory
  • Surgery
  • Succinimides
  • Sirolimus
  • Phenotype
  • Macaca mulatta
  • Interleukin-2 Receptor alpha Subunit