title: Unresponsiveness to human leukocytes in immunosuppressed mice by combined donor-derived human transferrin and antigens.
abstract: Previous work on the facilitation of xenogeneic and allogeneic bone marrow engraftment in irradiated mice and dogs with transferrins allowed the development of a model for induction of an apparently durable state of immunological unresponsiveness or 'tolerance' in chemically immunosuppressed mice. The system is based on the simultaneous and combined administration of donor-derived cell antigens, namely human leukocytes, and specific donor-derived or plasma pool human transferrin into BALB/c or C57BL/6 mice previously treated with prednisolone and cyclophosphamide on day 0 and day 1 of the experiment. A properly timed presentation of both donor-specific or plasma pool transferrin and leukocyte antigens into the mice on day 3 and day 16 of the experiment, in the course of initial restoration of their lymphohaemopoietic tissues and cells after severe immunosuppression, results 1-3 months later, in their inability to 'recognize' human donor lymphocytes and to mount an immediate or a delayed-type immune response against human antigens. This durable state of unresponsiveness was evaluated by a complement-mediated cytotoxicity assay, with a mixed lymphocyte culture method and confirmed by the abrogation of the humoral (antibody response to human erythrocytes) and of the cell-mediated (popliteal lymph node test) immune responses in vivo. Our findings demonstrate the capacity of human plasma-derived transferrins to induce a state of durable unresponsiveness (xenogeneic tolerance?) in mice when administered with human antigens in the course of regeneration of stem cells in the bone marrow and lymphatic organs.
authors.affiliation: CELLENA Inc., Zürich, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Pierpaoli
authors.forename: V A
authors.initials: VA
authors.lastname: Lesnikov
authors.forename: M P
authors.initials: MP
authors.lastname: Lesnikova
authors.forename: S
authors.initials: S
authors.lastname: Arrighi
authors.forename: A
authors.initials: A
authors.lastname: Bardotti
mesh_terms: D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006084:Graft Rejection / Q000517:prevention & control*; D006680:HLA Antigens / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017708:Leukocyte Transfusion; D007962:Leukocytes / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011239:Prednisolone / Q000494:pharmacology; D014168:Transferrin / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D007166:Immunosuppressive Agents; D014168:Transferrin; D003520:Cyclophosphamide; D011239:Prednisolone