title: 4-1BB promotes long-term survival in skin allografts treated with anti-CD45RB and anti-CD40L monoclonal antibodies.
abstract: 4-1BB (CD137) is a T-cell co-stimulatory molecule that promotes T cell activation. Using a skin transplantation model, we observed that simultaneous administration of monoclonal antibodies (mAb) targeting CD45RB and CD40L prolonged skin allograft in co-stimulation blockade (CTLA4-Ig and anti-CD40L mAb)-resistant mice, because of reducing CD8(+) T cells and CD4(+) CD45RB(high) T cells. Anti-CD45RB mAb (45RB) blocks the activation of T helper 1 (Th1) cells and generates regulatory T cells (T(reg)). The experimental design included five groups: group 1, control; group 2, 45RB-MR1; group 3, 45B-MR1 + 4-IBBL; group 4, anti-CD4 mAb plus group 3 treatment; group 5, anti-CD8 mAb plus group 3 treatment. In this study we highlight the involvement of 4-1BB/4-1BBL in the development of T-cell responses. C57BL/6 recipients of BALB/c skin grafts were treated with 45RB, anti-CD40L mAb (MR1), and antagonistic anti-4-1BBL mAb (4-1BBL) on days 0, 2, 4, 6, and 8 posttransplantation. Additional 4-1BBL further prolonged skin graft survival, although the percentage of splenocyte-derived CD8(+) T cells was reduced similarly in both groups. Use of 4-1BBL seems to have additive effects on T(reg) cells, which play a major role in the maintenance of tolerance. Even after immunosuppressive therapy in combination with CD4(+) T-cell depletion, we did not achieve prolonged graft survival, possibly because of the absense of T(reg) cells, which require CD4-independent CD8(+) T cells, based on the observation of increasing proportion of CD8(+) T cells in similar degree as the control group.
authors.affiliation: Transplantation Research Center, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 135-710.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: E N
authors.initials: EN
authors.lastname: Lee
authors.forename: E Y
authors.initials: EY
authors.lastname: Kim
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.forename: C L
authors.initials: CL
authors.lastname: Sun
authors.forename: S K
authors.initials: SK
authors.lastname: Lee
authors.forename: J W
authors.initials: JW
authors.lastname: Joh
authors.forename: K W
authors.initials: KW
authors.lastname: Lee
authors.forename: G Y
authors.initials: GY
authors.lastname: Kwon
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D016516:CD4-CD8 Ratio; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens