DOWN-MODULATION OF HOST REACTIVITY BY ANTI-CD44 IN SKIN TRANSPLANTATION1

Abstract

Background. A major goal in transplantation medicine is to achieve donor-specific tolerance while sustaining unaltered immunoreactivity toward donor-independent stimuli. Pretransplant immunization and concomitant blockade of costimulatory molecules may be one way to achieve this goal. We investigated whether transplant acceptance could be achieved by sensitization with semiallogeneic blood and blockade of CD44s (standard isoform) or CD44v6 (variant exon 6), since the adhesion molecule CD44 is known to function as a costimulatory molecule in T-cell activation. Methods. Immunoregulatory regimens were examined in BDX rats that had received full-thickness (DA×BDX)F1 skin grafts by controlling graft acceptance and immunoreactivity. Results. When BDX rats received full-thickness (DA×BDX)F1 skin grafts together with either anti-CD44s or anti-CD44v6, graft rejection was delayed, but none of the animals accepted the graft. An analysis of immunoreactivity revealed reduced numbers of infiltrating lymphocytes in anti-CD44s- as well as anti-CD44v6-treated rats. Expansion of donor-specific helper and cytotoxic T cells was particularly impaired in anti-CD44v6-treated rats. The effect of anti-CD44s could not be intensified by presensitization with donor-derived blood. However, when rats received anti-CD44v6 concomitantly with presensitization, 75% permanently accepted the graft and 50% accepted a second graft provided they were continuously treated with anti-CD44v6 and received a low dose of cyclosporine (CsA) during the first weeks after grafting. The frequency of graft-reactive helper T cells was reduced to less than 10% of the level in controls, and cytotoxic T cells could hardly be detected. Conclusion. According to the in vivo and the vitro analyses of the graft and the draining lymph nodes, anti-CD44s blocked homing of activated lymphocytes into the graft, while anti-CD44v6 inhibited clonal expansion of donor-specific T cells. Suppression by anti-CD44v6 apparently functioned distinctly to cyclosporine and was most effective in combination with presensitization. Since expression of CD44v6 on lymphocytes is restricted to a short period during lymphocyte activation, anti-CD44v6 treatment could lead to a quite specific immunosuppression during a limited time period.