title: Anti-third-party veto CTLs overcome rejection of hematopoietic allografts: synergism with rapamycin and BM cell dose.
abstract: Several bone marrow cells and lymphocyte subpopulations, known as "veto cells," were shown to induce transplantation tolerance across major histocompatibility antigens. Some of the most potent veto cells are of T-cell origin, and in particular a very strong veto activity was documented for cytotoxic T-lymphocyte (CTL) lines or clones. However, these cells also possess marked graft-versus-host (GVH) reactivity. In the present study we evaluated a new approach to deplete CTLs of antihost clones by stimulating the donor T cells against third-party stimulators in the absence of exogenous interleukin 2 (IL-2). We demonstrate that such CTLs are depleted of GVH reactivity while maintaining marked veto activity in vitro. Furthermore, marked synergism was exhibited between the veto CTLs and rapamycin when tested in a murine model, which measures T-cell-mediated bone marrow allograft rejection, or in sublethally irradiated allogeneic hosts. Our results suggest that engraftment of early progenitors could be enhanced by using host-nonreactive anti-third-party CTLs, in conjunction with nonmyeloablative rapamycin-based conditioning protocols, thereby significantly reducing the toxicity of allogeneic transplantation.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Bachar-Lustig
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007167:Immunotherapy; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D020123:Sirolimus