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Using the cell model of regenerative cardiomyogenesis (formation of contracting cardiomyocyte colonies from resident stem cells), we found that the addition of cardiomyocyte-derived apoptotic bodies to the culture of neonatal myocardial cells stimulated proliferation and differentiation of cardiomyocyte precursors and the frequency of their contraction was 1.5-fold higher than in the control. Systemic administration of cardiomyocyte-derived apoptotic bodies to Wistar rats with chronic postinfarction heart failure during the early period of myocardial remodeling considerably improved the contractile function of the heart.

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The experimental study of macrophage-activating chemotactic peptide N-f-met-leu-phe-gly (chemotaxic peptide), as well as its liposomal form, on the proliferation and migration of colony-forming precursor cells in mice was carried out. The study revealed that the subcutaneous injection of chemotaxic peptide into mice in a dose of 20 Mg led to a pronounced, but short-term increase in the proliferation of such precursor cells in the marrow: as shown by the hydroxyurea "suicide" method, a day after the injection almost 50% of hematopoietic stem cells entered the S-phase of the cellular cycle; in addition, an increase in the content of colony-forming precursor cells in the peripheral blood and the spleen was observed. The injection of chemotaxic peptide, incapsulated into liposomes, led to a considerable increase in the duration of the stimulating effect, manifested by the maintenance of a stable proliferative state of the pool of hematopoietic stem cells during 4 weeks (the term of observation). This effect could be attributed to the formation of the liposomal "depot" and the gradual liberation of chemotaxic peptide from it.

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The main causes of failures during allogenous bone marrow transplantation is the development of graft versus host reactions. The methods of its prevention and treatment are the use of large doses of human toxic cytostatics and immunosuppressants aimed against donor immunocompetent cells. A way of preventing the adverse effects of cytostatics are targeted transport of long-acting cytostatic dosage forms to an organ or target cell through carriers, such as liposomes, microcapsules, microspheres and their conjugates with monoclonal antibodies. For this purpose, the study used gelatin and gum arabic microspheres containing the immunosuppressive cytostatic adriamycin. To enhance the efficiency of cytostatic depositing at the site of transplantation, the procedure of intraosseous transplantation of allogenous bone marrow transplantation with long-acting adriamycin depositing was developed. With this approach, the authors could not only deposit the agent, but could substantially increase the proportion of donor cells kept at the site of grafting as compared to the intravenous and intraosseous infusion of donor cells. The main advantage of the new technique of allogenous bone marrow transplantation in combination with a long-acting cytostatic dosage form is that acute and chronic graft versus host reactions can be inhibited long by using adriamycin in subtherapeutic dosages.

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A method for the evaluation of bacterial persistence in the bone marrow in association with particular clonogenic target cells was developed. The method was based on the negative selection of cells expressing microbial antigens after treatment with hyperimmune antiserum specific to a given infective agent and the subsequent quantitation of target cells thus eliminated in appropriate assays. Using this approach, we demonstrated that Mycoplasma arthritidis and L-forms of Streptococcus strain L-406 were capable of persisting in murine bone marrow in close association with CFUs-7 (a subpopulation of hematopoietic stem cells) for at least several months after experimental infection. Francisella tularensis was also found to be capable to express on the CFUs-7 membranes. Persisting microorganisms enhanced both proliferation and migration of CFUs-7.

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Purified mouse IL-1 at doses 15-100 mu/ml inhibits the growth of stromal clonogenic cells /CFU-f/ both in full bone marrow cell cultures /F-cultures/ and in adherent bone marrow cell cultures /A-cultures/. Rec. human TNF-alpha inhibits growth of these cells at doses greater than 50 u/ml, but stimulates it /in 1.5 fold increase/at low doses /0.1-20 u/ml/ in cultures of both types. Rec. mouse IL-3 at doses 0.8-50 mu/ml slightly increases/in 1.6 fold increase/the in vitro growth of CFU-f and inhibits it at low doses in F-cultures. In A-cultures this factor stimulates CFU-f growth at all doses tested, but this stimulating effect takes place if only explantation density of mouse bone marrow cells in sufficiently high.

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The experiments carried out on inbred mice have revealed that the level of the immunological memory to staphylococci depends on the intensity of the antigenic stimulation; high priming dose of antigen proving to be the most effective one. The opposite character of immune responsiveness observed during primary antibody response to particulate staphylococcal antigen in C3H and A/Sn mice increased after the second immunization. It is established that immunological memory to staphylococci may be induced in genetically athymic mice. Many antibody-forming cells are found in the bone marrow of the secondary immunized mice. This phenomenon may be due to the repopulation of the bone marrow tissue by recirculating memory cells.

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The basic regularities of the formation and realization of immunological memory to staphylococcal corpuscular antigen were studied in adoptive transfer experiments on CBA mice. The capacity of spleen cells for generating anamnestic response to staphylococci in the body of irradiated syngeneic recipients appeared on day 3 after the immunization of donors. The formation of immunological memory to staphylococci in mice was shown to be directly related to the dose of the antigen. The study also revealed that intact splenocytes did not suppress the realization of immunological memory to staphylococci in the system of adoptive transfer. The conclusion of the absence of the "isogeneic barrier" for memory cells specific to staphylococcal corpuscular antigen was made.

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The mechanism of the increase in immune response to particular staphylococcal antigen was studied in CBA and BALB/c mice injected by primed bone marrow cells (BMC). It was found that immunostimulatory effect of immune BMC is not mediated by macrophages or T cells, but is associated with staphylococcus-specific B memory cells present in the pool of primed BMC. Splenectomy performed in donor animals prior to immunization did not abolish the induction of stimulating BMC activity. It was concluded that primed B lymphocyte migration from spleen into bone marrow is not obligatory for the induction of staphylococcus-specific immunological memory in the bone marrow.

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It was established by previous works that thymocytes treated with antilymphocyte serum secrete soluble factor capable of inhibiting exogenous colony formation in the spleen of lethally irradiated mice injected with bone marrow cells treated with the stem cell inhibition factor (SCIF). The purpose of the present investigation was to explore possible mechanisms of SCIF action. Regeneration of erythropoiesis (measured by 59Fe incorporation) in the spleen and bone marrow of mice injected with SCIF-treated bone marrow cells was inhibited as compared with control, while CFUs started proliferating with a 3-day delay. Two hours after SCIF treatment 60% of CFUs entered S phase as judged by hydroxyurea cell kill. The CFUs fraction treated with the SCIF was found to be diminished 3-4-fold as compared with control. The data obtained suggest that SCIF treatment makes CFUs enter 3 phase, which may account for the reduced capacity of CFUs to populate the spleen and to proliferate with a 3-day delay.

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Thymocytes of mice of different H-2 haplotypes are capable of releasing into culture medium an activity similar to that of stem cell inhibitory factor (SCIF) as regards suppressing action. All the test supernatants caused a decline in the number of hemopoietic colonies in the spleens of lethally irradiated (830 rad) syngeneic recipients. During study of the SCIF effect on bone marrow cells of different H-2 haplotypes, none of the strains appeared to be resistant to its action, which, probably, indicates the absence of genetic restriction of SCIF suppressive activity. Unlike migration inhibitory factor, SCIF does not appear to possess strain specificity.

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The activated T lymphocytes release in the culture medium a factor inhibiting the ability of hemopoietic stem cells to form hemopoietic colonies in the spleens of lethally irradiated recipients. An analysis of the effect of this factor on hemopoietic colonies was carried out. Its inhibiting effect was not related to the process of opsonization and to changes in the migration of spleen cells in the irradiated organism. No marked changes in the ratio of erythroid, myeloid and megakaryocytic foci were found in the spleens of irradiated mice which received the syngeneic bone marrow cells treated in vitro by the factor of stem cell inhibition: all three sources of hemopoiesis suffered under its effect to the same extent and their total number of the spleens was sharply reduced. Some mechanisms of the effect of the factor of stem cell inhibition on the formation of hemopoietic foci are discussed.

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Thymus cells from syngeneic donors treated in vitro with antilymphocyte globulin release into the medium a soluble hemopoietic stem cell inhibitory factor (SCIF). It has been found that SCIF inhibits the immune response to sheep red blood cells in the adoptive immunity system. Primarily affected by SCIF are the mature progenitors of B cells whose ability cooperate with T lymphocytes seems to be impaired. The role of lymphokines in the induction of the immune response is discussed.

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The activated mouse T-cells release in the culture medium a factor suppressing the ability of stem hemopoietic cells to form hemopoietic colonies in the spleens of lethally irradiated recipients. The factor of stem cell inhibition (FISC) obtained from the mouse thymocytes on the 1st, 7th and 10th day of postnatal life does not differ, by its inhibiting activity, from that obtained from the adult thymocytes, whereas the embryonic thymocytes under similar experimental conditions released FISC with a low inhibiting activity. A study of some physical-chemical and biological properties of FISC has shown that the latter is actively synthesized both by cortical and medullary thymocytes, has no (linear) specificity and resembles, by its characteristics, lymphokins of a wide effect, such as MIF and LT, rather than short-distant mediators, such as suppressor and helper factors.

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Pretreatment with crude interferon preparations obtained from suspension cultures of bone marrow, spleen and thymus cells or from mouse L-cell cultures or with mouse serum interferon preparations did not change the colony-forming activity of bone marrow cells on syngeneic transplantation to lethally irradiated mice. Preparations of L-cell culture interferon, dialysed and purified by carboxymethyl-Sephadex (G-25) column chromatography, showed an inhibitory effect on exogenous colony formation by bone marrow cells. The results suggested the presence in crude interferon preparations of a substance either inhibiting the anticellular effect of interferon or stimulating colony formation. The factor produced by thymus cells following their treatment with antilymphocyte serum inhibited colony formation by bone marrow cells and, unlike interferon, possessed no antiviral activity when tested in cell cultures.

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The migration activity of the spleen cells from intact mice is inhibited by the stem cell inhibitory factor (SCIF) released by lymphocytes treated with antilymphocytic globulin. The degree of the migration inhibition is proportional to the activity of SCIF in the colony-formation inhibition. The macrophage-migration inhibitory factor (MIF), obtained in the H-2 system exhibited a stimulating effect on the colony formation in mice when used in vitro for the treatment of bone marrow transplants. This activity of MIF corresponds to its migration-inhibitory effect on the spleen cells. Incubation of the bone marrow cells with MIF for 30 minutes is more effective than the 2-hour treatment. The observed effects are interpreted as an indication of non-identity of SCIF and MIF.

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The in vitro treatment of the mouse spleen cells immunized by the ram erythrocytes with the rabbit and mouse sera against the thermoaggregated mouse immunoglobulins resulted in the inhibition of antigen binding receptors of rosette forming cells. The mouse serum, unlike the rabbit one, induced the inactivation of receptors in rosette forming lymphocytes both in the non-immune and immune mice on the 8th day after the antigenic stimulation. The treatment of bone marrow cells from the intact mice with these sera increased insignificantly the number of hemopoietic colonies in the spleens of lethally irradiated syngenic recipients and stimulated markedly the migration of spleen cells. This may be due both to the direct effect of these sera and to their mediated (through the humoral factor) influence. The inactivation of antigen binding receptors in the spleen rosette forming cells suggests the presence of immunoglobulins on the membrane of B-lymphocytes in the aggregated state or in the form of antigen--antibody complexes.

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