title: IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice.
abstract: To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5x10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.
authors.affiliation: Department of Surgery, Hallym University College of Medicine, Chuncheon, Korea.
authors.forename: Jeong-hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.forename: Shi-hwa
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D023201:CD40 Ligand / Q000276:immunology*; D004338:Drug Combinations; D006085:Graft Survival / Q000276:immunology*; D018796:Immunoconjugates / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods
chemical_list: D000906:Antibodies; D004338:Drug Combinations; D018796:Immunoconjugates; D007376:Interleukin-2; D023201:CD40 Ligand; D000069594:Abatacept