Approach to withdrawal from tacrolimus in a fully allogeneic murine skin graft model

With few exceptions, transplant patients must take immunosuppressants throu ghout their lives. In this study, we used anti-T-cell receptor (TCR/CD3) mo noclonal antibodies (mAbs) to induce immunological tolerance to alloantigen s after withdrawal from tacrolimus in a fully allogeneic murine skin graft model. Skin grafts from AKR donor mice were maintained in C57BL/6 recipient s by administering tacrolimus for one month. Anti-T-cell receptor (TCR) alp ha beta mAb was administered to recipient mice on the day of withdrawal fro m tacrolimus administration. Seven days after mAb administration, the recip ient mice were treated with various combinations of the following treatment s: low-dose whole body irradiation, AKR bone marrow transfer (BMT), and ant i-CD3 mAb administration. The control recipient mice did not receive treatm ent with either mAb, nor any other treatment. All the control recipient mic e showed rejection of AKR skin grafts 42 days after tacrolimus withdrawal ( mean skin graft survival: 77 days). Mice treated with a combination of anti -TCR alpha beta antibody, low-dose irradiation and AKR BMT showed stable ch imerism in their peripheral blood lymphocytes and significantly prolonged s kin graft survival (mean skin graft survival: >151.2 +/- 15.3 days). Mice g iven the combination of anti-TCR alpha beta mAb, anti-CD3 mAb, low-dose irr adiation, and AKR BMT exhibited more stable chimerism but had earlier skin graft rejection (mean skin graft survival: 116.7 +/- 17.6 days) than the mi ce that did not receive anti-CD3 mAb. These results suggest that anti-TCR a lpha beta mAb, but not anti-CD3 mAb, in combination with low-dose irradiati on and BMT, is useful for long-lasting allograft survival after withdrawal from tacrolimus in mice with fully allogeneic skin grafts.