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Unresponsiveness to human leukocytes in immunosuppressed mice by combined donor-derived human transferrin and
W Pierpaoli1, V A Lesnikov, M P Lesnikova
1CELLENA Inc., Zürich, Switzerland.
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.
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.