IMMUNOSUPPRESSION BY INHIBITION OF CELLULAR ADHESION MEDIATED BY LEUKOCYTE FUNCTION-ASSOCIATED ANTIGEN-1 INTERCELLULAR-ADHESION MOLECULE-1 IN MURINE CARDIAC TRANSPLANTATION

Background. Donor alloantigen-specific tolerance to vascularized allog rafts can be induced by several treatments, but the immunological mech anism(s) of these effects remain unclear. One hypothesis is that allog raft unresponsiveness is correlated with a shift in the pattern of exp ression of the T helper 1 versus T helper 2 T-cell cytokines. We repor t here an extensive analysis of murine cardiac allografts, during norm al first set rejection and in mice treated with anti-adhesion molecule monoclonal antibodies (mAbs), a regimen that results in prolonged unr esponsiveness. Methods. A combination of immunohistochemical staining with a panel of mAbs, and in situ hybridization with a panel of digoxi genin-labeled riboprobes, was performed on frozen-tissue sections of c ardiac allografts. Results, In several strain combinations, injection of anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1, from day 0 to day 6 after transplantation, resul ts in significant long-term survival, Examination of tolerated cardiac allografts by in situ hybridization and immunohistochemical staining shows an altered cytokine expression pattern, although the frequency o f CD3 and CD4 cells is not dramatically reduced, These allografts show a decreased frequency of interferon-gamma and interleukin (IL)a-expre ssing cells and a slightly increased frequency of cells expressing IL- 4 and IL-10, compared with unmodified acute rejection, A direct role o f these changes in T-cell. cytokine expression is demonstrated by reve rsal of tolerance induction and rejection of the allograft by in vivo injection of either anti-IL-10 or anti-IL-4 mAb. Conclusions. Although there are significant differences in the frequency of different cellu lar subsets and patterns of cytokine gene expression, these difference s are quantitatively subtle, suggesting a delicately balanced immune r esponse that can develop a pattern of specific unresponsiveness, with relatively minor alterations in the specific T-cell response.