title: In vivo or in vitro anti-CD3 epsilon chain monoclonal antibody therapy for the prevention of lethal murine graft-versus-host disease across the major histocompatibility barrier in mice.
abstract: We explored the use of a single in vivo dose of an anti-CD3 epsilon mAb for graft-vs-host disease (GVHD) prevention in mice. Anti-CD3 epsilon (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-CD3 epsilon 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-CD3 epsilon 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-CD3 epsilon 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 CD3 epsilon chain modulation and T cell depletion obtained with in vitro vs in vivo anti-CD3 epsilon chain mAb. In mice given syngeneic BM transplants to avoid the confounding effects of GVHD, we found that in vivo anti-CD3 epsilon mAb administration induced a more prolonged period of CD3 epsilon chain modulation and/or T cell depletion than either the in vitro approach or a third approach that involved anti-CD3 epsilon F(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.
authors.affiliation: Department of Pediatrics, University of Minnesota Hospital and Clinic, Minneapolis 55455.
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: P A
authors.initials: PA
authors.lastname: Taylor
authors.forename: D A
authors.initials: DA
authors.lastname: Vallera
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016525:Antigenic Modulation; D016026:Bone Marrow Transplantation / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D066298:In Vitro Techniques; D008212:Lymphocyte Depletion; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex