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Permanent tolerance of the entire H-2 complex incompatible B10 skin allografts was induced in adult B10.A mice by post-transplant treatment. Recipient mice were treated with heterologous antithymocyte serum (ATS) and specific tissue extracts or monoclonal antibodies anti-Thy-1.2. Combination of treatments with the specific tissue extracts and monoclonal antibodies leads to a high degree of tolerance in the majority of ATS-treated animals. Results thus show that it is possible to induce long-term tolerance of the entire H-2 complex incompatible skin allografts in mice using specific and non-specific immunosuppression given in the post-transplant period.

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The presence of very high numbers of type C and type A retroviral particles was repeatedly confirmed not only in myeloma cells NSI, Ag 8 and in thymoma cells BW5147, EL 4 but also in B and T cell hybridomas constructed from the myeloma and thymoma cells used. Retroviral particles were demonstrated by current electron-microscopic and physicochemical methods. Biological tests for the induction of possible malignant or any pathological changes in the artificially infected sensitive cells during long-term cultivations in vitro or in vivo gave negative results. Nevertheless, on account of the hitherto unknown action of retroviruses one can suppose that monoclonal products from B and T cell hybridomas, particularly when used for practical purposes, should be purified because of their infectious nature.

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A permanent cell line designated SL4c has been established from a primary culture of murine BALB/c spleen cells regularly stimulated with large doses of irradiated allogeneic cells plus exogenous interleukin-2(IL-2). After 8 months of cultivation, the cells of the SL4c line proliferate spontaneously and do not respond with an increase in proliferation to alloantigenic stimulation. The cells have the Lyt 1.2+, Lyt 2.2-, L3T4a+, Thy 1.2+ phenotype and exert a strong suppressive effect upon stimulation with freshly explanted cells. The SL4c line produces a suppressor factor (SF4c), which inhibits the mitogen-induced proliferation of normal lymphoid cells but does not suppress the proliferation of fibroblasts and sarcoma cells. The suppression is antigen non-specific, is not limited by H-2 restriction nor by interspecies barrier, and is not due to cytotoxic effect. However, the suppression is only detectable if the SF4c is added to the stimulated cells during the early stages of mitogen-induced proliferation. A tentative characterization of the relative molecular weight (MW) of the suppressor molecule based upon fractionation of SF4c supernatant on a Sepharose 6B column shows that the inhibitory activity is confined to the high MW fractions (300,000-350,000). Translation material obtained from Xenopus laevis oocytes, which were injected with RNA preparations isolated from SL4c cells, also shows the suppressive effect.

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The effect of cytotoxic monoclonal antibodies against T lymphocyte subpopulations on skin allograft survival in mice was compared. Antibodies against cytotoxic lymphocytes (anti-Lyt-2.2) suppressed the allotransplantation reaction more effectively than antibodies against helper/inducer T lymphocytes (monoab anti-Lyt-1.2 and GK1.5). The suppressive effect of anti-Lyt-2.2 antibodies was comparable with that of the antibodies against the whole T lymphocyte population (monoab anti-Thy-1.2). Antibodies anti-Lyt-2.2 led up to a permanent survival (in 40% of animals) of H-2 incompatible skin allografts, when administered for long periods since the day of birth. The effect of the different antibodies, however, depends on the timing of application in relation to skin grafting. The results indicate that prolongation of survival and almost permanent tolerance of skin allografts can be obtained by the specific elimination of T lymphocyte subpopulations by the use of monoab and that Lyt-2 positive T lymphocytes play an important role in rejection allotransplantation reaction.

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A permanent T cell line producing an antigen-non-specific suppressor factor was established. This factor inhibits the proliferation of lymphoid cells in vitro and, when injected in vivo, it suppresses the allotransplantation reaction. The line established may represent one of the cell populations playing an active role in the induction and maintenance of immunological tolerance.

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In view of the discrepancy in the results concerning the question of inheritance of immunological tolerance, we tried to enhance the genetic effect of tolerization by tolerizing male mice over three succeeding generations and by testing the ability of their progeny to reject an allogeneic tumour graft. This highly sensitive in vivo test, even of partial tolerance, did not reveal any difference in allogeneic tumour growth between progeny of control and tolerized males. Thus, the results again did not confirm genetic transmission of induced tolerance. The possible causes of the discrepancy between the results reported here and the results obtained by others are considered.

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A continuous macrophage hybrid population, designated MBW-1, was produced by the fusion of peritoneal macrophages from a normal AKR mouse with thymoma cells BW5147. The hybrid cells are resistant to HA selection medium. In their nearly triploid chromosome complement they carry metacentric chromosomes typical of BW5147 cells and express the typical macrophage-like characteristics (morphology of macrophages, adherence properties, phagocytosis, expression of macrophage-specific antigen and receptor for the C3b component of complement). However, they do not express Fc receptors and the receptor for SBA lectin. An interesting property is the high resistance to the toxic action of silica particles. Thanks to the unique properties, which were not observed in other, hitherto described macrophage-like cell lines, the MBW-1 cell population provides a useful material for study of macrophage functions.

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B10.A male mice were grafted with H-2-incompatible murine B10.A(2R) skin allografts and treated with antithymocyte serum on days 2, 4, and 7 after transplantation. Repeated injections of cell-free tissue extracts from livers or spleens of B10.A(2R) mice were given in the standard doses, starting on the day of transplantation or on day 14 or day 28 after transplantation. The standard doses were the equivalents of material extracted from 40 mg or 80 mg of wet weight of liver or spleen tissue. Almost all of the regimens used in which antigen injections were begun on day 14 or day 28 after transplantation were successful and led to a marked prolongation in skin allograft survival. In some experimental groups most of the grafts survived 100 days after grafting and 8--33% grafts showed long-term survival in individual groups. The mechanism of this tolerance is mediated by suppressor cells which were characterized by means of anti-Thy 1.2 antibodies as T lymphocytes. the in vitro experiments have shown that cytotoxic cell precursors may be present in long-term tolerant mice and that they may be reactive to the tolerated antigens after sensitization.

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Peripheral blood leucocytes from normal, non-immunized adult rats recognize syngeneic and allogeneic tissue antigens, and this recognition can be detected by the tube leucocyte adherence inhibition assay. We show that PBL from newborn rats have the same and even a stronger ability for recognition and that the recognition is preserved in rats bearing tolerated skin allografts after neonatal induction of transplantation tolerance. Testing of tissue extracts prepared from the congenic strain of rats suggested that PBL from normal animals recognize histocompatibility antigens.

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Mice of the inbred strains B10.A (H-2a), B10 (H-2b), and BALB/c (H-2d) were immunized with the syngeneic cells, and the sera obtained from individual animals on day 10 after the 8th immunizing injection were assayed for the presence of alloreactive cytotoxic antibodies. Anti-H-2Kk antibodies were present in the sera from 50% of the syngeneically immunized BALB/c mice. The syngeneic-immune B10 sera contained weak anti-H-2Dd antibodies in 14% of the immunized animals. B10.A mice produced no antibodies after syngeneic immunization.

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Transplantation tolerance was induced in A.TL mice to donors having disparity in the Ia antigens and identity at the H-2K, H-2D and non-H-2 antigens. After neonatal injection of 12 X 10(6) semiallogeneic lymphoid cells, permanent survival of A.TH skin allografts was observed in more than 90% of the recipients. Adoptive transfer of 50 X 10(6) lymphoid cells from normal A.TL donors to tolerant mice resulted in rejection of the tolerated grafts only in half of the animals. When cells from tolerant mice were tested in MLC and GVH assays, they reacted positively as did cells from normal mice. After sensitization in vitro, cells from tolerant mice were cytotoxic to A.TH antigens. Serum from tolerant mice did not inhibit cell proliferation in MLC assay nor blocked cytotoxic reaction in vitro and also did not enhance survival of A.TH skin grafts in normal A.TL mice. When the enhancing effect of this serum was tested in the recipients treated with ALS, prolonged survival of allografts was observed. Attempts to prolong survival of A.TH skin allografts by transfer of spleen cells from tolerant donors failed in normal A.TL recipients, while they were successful in the recipients treated with ALS. Long-term tolerated A.TH allografts, when transferred to normal A.TL recipients, were rejected. The findings show that loss of antigenicity of the tolerated skin allografts is not the mechanism of tolerance in this model and that cells capable of recognizing antigens of the tolerated allografts and reacting against them are still present in tolerant animals. Tolerance of skin allografts disparate only in Ia antigens, as has been shown at least for the strain combination tested, is probably mediated by the positive serum and cell suppressor mechanisms that block in vivo the effector phase of allotransplantation reaction.

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Neonatal transplantation tolerance was induced in strain combinations of mice involving differences in the H-2D or H-2K regions, in the K or D ends of H-2, or in the central I region of the H-2 complex. Attempts were made to transfer the tolerance adoptively by suppressor cells to syngeneic non-immunosuppressed recipients. Adoptive transfer of tolerance was successful only in the combination with H-2D region disparity, and significant but short-lasting prolongation of skin allograft survival time was also obtained in the combination disparate at the D end of H-2. Transfers of tolerance were not successful in the combinations involving differences in the K or I regions of the H-2 complex irrespective of whether cells were transferred one day before or four days after skin grafting. The results are discussed with respect to hitherto known antigenic and tolerogenic properties of individual H-2 regions.

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