title: Use of mixed lymphocyte reaction to identify subimmunosuppressive FK-506 levels in mice.
abstract: The immunosuppressive agent FK-506 has a well-described neuroregenerative effect that is mediated by a mechanism independent of calcineurin inhibition. FK-506 levels that fall below the threshold for immunosuppression could therefore potentially enhance nerve regeneration while minimizing toxicity. The purpose of this study was to characterize the dose-dependent effects of FK506 on T-cell proliferation, and establish a subimmunosuppressive dosing regimen for FK-506 in mice. Forty BALB/cJ mice were randomized to four groups corresponding to 0, 0.25, 0.5, or 1.0 mg/kg/day doses of FK-506. Ten days postoperatively, animals were sacrificed, and mixed lymphocyte reaction assays were performed to quantify the immune response to nerve allografts. Mice receiving 0.25 and 0.5 mg/kg/day of FK-506 exhibited a robust T-cell proliferation response, with stimulation indices approaching those of untreated animals. Mice treated with 1.0 mg/kg/day of FK-506 demonstrated significantly decreased T-cell proliferation. These results establish 0.5 mg/kg/day as an upper limit for subimmunosuppressive FK-506 administration.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Ramsay A
authors.initials: RA
authors.lastname: Ellis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brenner
authors.forename: Susan E
authors.initials: SE
authors.lastname: Mackinnon
authors.forename: Terence M
authors.initials: TM
authors.lastname: Myckatyn
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010525:Peripheral Nerves / Q000187:drug effects / Q000637:transplantation*; D011897:Random Allocation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*; D016378:Tissue Transplantation / Q000379:methods*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus