Nonmitogenic anti-CD3F(ab')₂ fragments inhibit lethal murine graft- versus-host disease induced across the major histocompatibility barrier

We have investigated the in vivo administration of nonmitogenic anti- CD3F(ab')₂ fragments for the prevention of lethal graft-vs-host disease (GVHD) in irradiated recipients of fully allogeneic bone marrow cells plus splenocyte (BMS) inocula. Recipients of anti-CD3F(ab')₂ fragments administered for 1 mo post-bone marrow transplantation (BMT) had 100% survival without clinical or histopathological evidence of GVHD. Controls given saline injections succumbed by 39 days post-BMT. Similar results were obtained in groups of recipient mice given BMS in which T cells were depleted by in vitro anti-Thy-1.2 plus C' treatment. Further studies were undertaken to define mechanistic differences in the two approaches. Using Ly-5 congenic sources of donor bone marrow and spleen, we determined that anti-CD3F(ab')₂ fragments induced TCR modulation and T cell depletion. Mature splenic- derived CD4⁺ cells were depleted to a greater extent than CD8⁺ cells. Early post-BMT, recipients receiving injections with control saline had the highest number of CD4⁺ and CD8⁺ cells (which may cause GVHD) followed by recipients of anti-CD3F(ab')₂ fragments, with the fewest CD8⁺ cells observed in the anti-Thy-1.2 + C' treated group. CD3⁺CD4^-CD8^- cells (which may suppress GVHD generation) were present in higher numbers early post-BMT in recipients given anti-CD3F(ab')₂ fragments as compared to recipients given anti-Thy- 1.2 + C'-treated BMS. In long term survivors, a mononuclear T cell containing infiltrate without evidence of destruction was observed in sites of GVHD (lung and liver), consistent with a 'Quilty' effect, which was not observed in either of the other two groups. Although survivors were tolerant of donor skin grafts and rejected third party grafts, recipients given anti- CD3F(ab')₂ fragments but not anti-Thy-1.2 + C'-treated BMS had vigorous anti-host proliferative responses. These results demonstrate that although in vitro anti-Thy-1.2 + C' treatment of BMS (which is highly depletionary) and in vivo administration of anti-CD3F(ab')₂ fragments (which is modulatory and less depletionary) are both effective strategies for GVHD, the cellular events involved in achieving GVHD prevention are indeed different.