We explored the use of a single in vivo dose of an anti-CD3ε mAb for graft-vs-host disease (GVHD) prevention in mice. Anti-CD3ε (145-2C11) given on the day of bone marrow (BM) transplant was highly effective in preventing GVHD in a dose-dependent manner. However, mice experienced acute toxicity as measured by early post-BM transplantation mortality, severe weight loss, and cachexia, which is likely due to T cell-dependent lymphokine production. Donor T cells were partly responsible because toxicity still occurred in mice injected with an allelic specific anti-CD3ε mAb that only reacted with the donor strain. Toxicity was also dependent on the number of radioresistant host T cells present at the time of transplant, because toxicity still occurred when recipients were depleted of mature T cells in vivo with anti- CD4 + anti-CD8 mAbs, and were given T cell-depleted BM from SCID mice. Toxicity was eliminated by treating BM with anti-CD3ε mAb in vitro before BM transplant instead of administering the mAb in vivo. However, GVHD protection was not complete. Direct comparison of the in vivo and in vitro approaches revealed that the in vivo administration of anti-CD3ε mAb was more effective for GVHD protection and that a combination of the approaches was not beneficial. Flow cytometry studies were performed to assess the degree of CD3ε chain modulation and T cell depletion obtained with in vitro vs in vivo anti-CD3ε chain mAb. In mice given syngeneic BM transplants to avoid the confounding effects of GVHD, we found that in vivo anti-CD3ε mAb administration induced a more prolonged period of CD3ε chain modulation and/or T cell depletion than either the in vitro approach or a third approach that involved anti-CD3εF(ab')2 fragments administered in vivo. These data indicate that targeting the Ag-specific TCR, especially in such a way as to avoid toxicity associated with T cell activation, may provide an important key for developing future GVHD therapies.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of Immunology|
|State||Published - 1994|