title: Conventional immunosuppression is compatible with costimulation blockade-based, mixed chimerism tolerance induction.
abstract: T-cell costimulatory blockade has emerged as an effective strategy to prevent allograft rejection in experimental models. We and others have reported that the beneficial effects of costimulation blockade can be negated when combined with certain immunosuppressants. The current study evaluates the compatibility of various immunosuppressive agents in a costimulation blockade-based, mixed chimerism tolerance protocol. The addition of conventional agents, including calcineurin inhibitors, did not interfere with tolerance induction. All mice developed multilineage macrochimerism and accepted donor allografts. Analysis of specific T-cell receptor utilization demonstrated selective deletion of donor-reactive T cells. Challenge with donor and third-party allografts confirmed donor-specific tolerance. Clinical introduction of costimulation blockade-based strategies will likely incorporate currently approved immunosuppressive agents. While it has been reported that certain conventional agents are detrimental to costimulation blockade-based strategies, our results suggest that these agents could safely be combined in clinical trials when used as part of a nonmyelosuppressive, mixed chimerism-based tolerance strategy.
authors.affiliation: The Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Nozomu
authors.initials: N
authors.lastname: Shirasugi
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jones
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Williams
authors.forename: Megan M
authors.initials: MM
authors.lastname: Durham
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guo
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Newell
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Pearson
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007116:Immunization, Passive / Q000379:methods*; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology
chemical_list: D000906:Antibodies; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2