title: Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer.
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 × 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.
authors.affiliation: Department of Surgery, The Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: K
authors.initials: K
authors.lastname: Singh
authors.forename: L
authors.initials: L
authors.lastname: Stempora
authors.forename: R D
authors.initials: RD
authors.lastname: Harvey
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: L S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005452:Fluoresceins; D005456:Fluorescent Dyes; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006207:Half-Life; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008253:Macaca mulatta; D010641:Phenotype; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D013388:Succinimides; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014182:Transplantation, Autologous
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D005456:Fluorescent Dyes; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D013388:Succinimides; D020123:Sirolimus; D016559:Tacrolimus
keywords: Basic (laboratory) research/science; T cell biology; immunobiology; immunosuppression/immune modulation; lymphocyte biology: trafficking; tolerance: experimental; translational research/science