Highly disparate xenogeneic skin graft tolerance induction by fetal pig thymus in thymectomized mice - Conditioning requirements and the role of coimplantation of fetal pig liver

Background. Highly disparate xenogeneic pig ski graft tolerance and efficie nt repopulation. of mouse CD4(+) T cells are achieved in thymectomized (ATX ) B6 mice that receive T cell and natural killer (NK) cell depletion by inj ection of a mixture of monoclonal antibodies (mAbs) (GK1.5, 2.43, 30-H12, a nd PK136) on days -6, -1, +7, and +14 and 3 Gy total body irradiation (TBI) followed by implantation of fetal pig thymus/liver (FP THY/LIV) grafts on day 0. The requirements for each treatment in this model to achieve pig ski n graft tolerance have not previously been defined Therefore, we performed a series of experiments to address the role of each treatment in achieving maxi mal skin graft tolerance. Methods. Peripheral mouse CD4+ T-cell repopulation and pig skin graft survi val were followed in this pig-to-mouse model in which recipient B6 mice wer e treated with modified regimens that omitted thymectomy, 3 Gy TBI, anti-Th y1.2, and anti-NK1.1 mAbs, injection of a mixture of mAbs on day +14, or co implantation of FP LIV, respectively. Results. Prolongation but not permanent survival of donor MHC-matched pig s kin grafts was observed in euthymic B6 mice that received T and NK cell dep letion, 3 Gy TBI, and 7 Gy thymic irradiation and FB THY/LIV in the mediast inum, suggesting that full xenogeneic tolerance was not achieved in euthymi c mice. However, after grafting FP THY alone to ATX B mice treated either w ith the "standard" regimen, or with a conditioning regimen that omitted all components of the conditioning regimen except treatment with anti-CD4 and anti-CD8 mAbs, efficient peripheral repopulation of mouse CD4(+) T cells an d long-term do nor MUC-matched pig skin graft acceptance were observed. Conclusions. Highly disparate xenogeneic pig skin graft tolerance can be ac hieved by grafting FP THY alone in anti-CD4 and anti-CD8 mAb-treated ATX B mice, but not in euthymic B6 mice. Additional treat ment of ATX recipient m ice with anti-Thy1.2 an NK1.1 mAbs and 3 Gy TBI is not essential for donor pig skin graft tolerance induction.