A potential mechanism of action of an antibody (HIS45) which has been shown to induce prolonged graft survival

Animals treated with the antibody HIS45 According to a regimen known to prolong the survival of allogeneic skin grafts (1), show no significant decrease in αβ⁺ T cells from their lymph nodes and no dramatic change in the levels of either αβ⁺CD4⁺ or αβ⁺CD8⁺ cells compared with untreated controls. However, the T cells of treated animals showed reduced expression of the αβ form of the T cell receptor. Although treatment did not lead to an upregulation of the CD25 molecule on the rat cells, treatment does lead to a reduction at the cell surface in the amount of the determinant recognized by HIS45. In vitro analysis revealed that the HIS45 determinant was lost from T cells following their activation but re-expressed later. The T cells in treated animals may be partially activated. This ability of HIS45 to partially activate cells was supported by experiments which revealed that the antibody HIS45 was only weakly mitogenic in vitro, but when present in conjunction with another stimulus such as anti-Vβ cell receptor antibody or a mitogen or a superantigen, the HIS45 antibody was shown to produce significantly increased proliferation. Functional analysis of cells from treated animals showed they respond significantly less well in vitro to either superantigen (TSST-1) or alloantigen, compared to cells from age and sex marched untreated controls. Since no T cell depletion occurred following treatment the reduced functional ability of these cells must have been due to a functional defect in their ability to respond. The results suggest that HIS45 was having its immunosuppresive effect by delivering an incomplete activation signal to T cells leading to a state of anergy.