Details

Autor(en) / Beteiligte

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

Titel

Superiority of Rapamycin Over Tacrolimus in Preserving Nonhuman Primate Treg Half‐Life and Phenotype After Adoptive Transfer

Ist Teil von

• American journal of transplantation, 2014-12, Vol.14 (12), p.2691-2703

Ort / Verlag

Hoboken, NJ: Wiley

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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.