4-1BB promotes long-term survival in skin allografts treated with anti-CD45RB and anti-CD40L monoclonal antibodies.

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.