| Abstrakt: |
In a mouse model for vascularized heart transplantation, CBA recipients of BALBc hearts were treated with 0.25 mg of antiCD4 GK1.5 given intraperitoneally on the day of grafting and on days 1, 2, and 3 thereafter. This reduced splenic CD4cells to <1 and all grafts survived >100 days, compared with 810 days in untreated recipients. Despite recovery of the CD4cells after day 21, mice did not reject donortype skin grafts at >30 days, but rapidly rejected thirdparty skin, showing alloantigenspecific tolerance. The surviving heart grafts had significant mononuclear cell infiltration at time points from 7 to 100 days after transplantation. In the normal rejection process, where extensive myocyte necrosis was seen at 7 days, graftinfiltrating T cells produced IL2 and IFN. These cells responded in vitro to IL2 and displayed donorspecific CTL activity. In contrast, cells from CD4mAbtreated hearts did not show significant growth in IL2 or kill donor cells in CTL assays. In these nonrejecting hearts, immunohistology showed a diffuse infiltrate of T cells and macrophages by day 3. The allograft infiltrate increased rapidly thereafter in both rejecting and nonrejecting grafts, peaking at day 67 in rejecting grafts, when CD4, CD8, and IL2Rcells were present, with expression of IL2, IFN, and IL4, but only trace levels of IL10. From 14 to 100 days, nonrejecting allografts showed a characteristic cytokine profile of dense IL4 and IL10 expression on intragraft leukocytes and endothelial cells, with low levels of IL2 and IFN. This cytokine profile, characteristic of Th2 responses, was seen in all nonrejecting grafts and was not present in rejecting grafts. Allograft tolerance can studied by examination of the functions and cytokine profile of the cells within the graft, and tolerance develops in the presence of a Th2 response within the graft. |
