Effect of a bone marrow stimulator of antibody producers on virus-specific antibody formation in animals infected with flaviviruses

The injection of the marrow stimulator of antibody-producing cells (SAPC) into animals infected with Japanese encephalitis and tick-borne encephalitis viruses stimulated the formation of virus-specific antibodies in the infected animals, increasing antibody production 8- to 16-fold. Such SAPC-induced stimulation of the formation of virus-specific antibodies is observed in cases of both acute and chronic virus infection. The prospects of using the preparation of SAPC are discussed.     

Regulation of DNA synthesis and antibody production by soluble factors released by bone marrow cells

Bone marrow cells (BMC) suppressed the antibody response of spleen cells across a cell impermeable membrane. Fractionation of BMC supernatants by column chromatography and ultrafiltration revealed the presence of a suppressor factor and an enhancing factor which acted antagonistically. Bone marrow enhancing factor (B-EF) had a molecular weight greater than 20,000, enhanced antibody synthesis, and stimulated DNA synthesis in thymocytes but not BMC. Bone marrow suppressor factor (B-SF) was produced by non-adherent BMC, had a molecular weight 1000 to 10,000, suppressed the antibody response in vivo and in vitro, and stimulated DNA synthesis in BMC but not thymocytes. The possible role of these factors in homeostasis and regulation is discussed.     

The mechanism of thymus-dependent antibody formation in bone marrow

During the primary immune response of mice to i.v. administered thymus-dependent antigens the spleen is the major site of localization of antibody-producing plaque-forming cells (PFC). During the secondary response, on the other hand, large numbers of PFC not only appear in the spleen, but also in the bone marrow. By inducing B memory cells with a DNP-carrier complex and activating the DNP-specific B memory cells with the same hapten conjugated to a heterologous carrier, we show in this paper that B memory cells, but not necessarily T memory cells, must be present before booster immunization for PFC to appear in the bone marrow. The origin of the PFC that appear in the bone marrow during secondary type immune response was studied in parabiotic mice consisting of members congenic for the Igh-1 locus. From analysis of the allotype of antibodies produced by PFC in the marrow of such pairs of parabionts it appeared that antibody formation in bone marrow is dependent on the immigration into the marrow of B memory cells activated in peripheral lymphoid organs. Consistent with such a migration of activated cells, radioautographic studies in guinea pigs demonstrated an influx of newly formed mononuclear cells into the bone marrow via the blood stream during the first 3 days after intravascular antigen administration.     

Regulatory role of bone marrow in immunogenesis. III. Humoral factors stimulating and suppressing antibody formation produced by bone marrow cells in in vitro cultures

As revealed by the method of cultivation of bone marrow and spleen cells, separated by nucleopore membrane, in two-chamber bottles, the bone marrow cells were capable of producing humoral factor stimulating antibody genesis by the spleen cells. A direct contact of the bone marrow cells with the actively proliferating antigen-stimulated cells of the spleen led to production of a spleen humoral factor suppressing the antibody genesis by the spleen cells. The suppressive action of the bone marrow cells on the antibody genesis in the culture of the spleen cells was mediated through the suppression of the spleen cells proliferation; proliferation of the bone marrow cells is enhanced.     

Antibody formation in mouse bone marrow. IX. Peripheral lymphoid organs are involved in the initiation of bone marrow antibody formation.

Mouse bone marrow is barely capable of plaque-forming cell (PFC) activity during the primary response to sheep red blood cells (SRBC). However, during secondary-type responses, it becomes the major organ, containing IgM, IgG, and IgA PFC. In the present paper, the influence of splenectomy (Sx) upon the secondary bone marrow PFC response to SRBC was investigated. When previously primed mice were splenectomized just before the second intravenous (iv) injection of SRBC, the effect of Sx upon the height of the bone marrow PFC response was dependent on the booster dose. Sx just before a booster of 10⁶ SRBC iv almost completely prevented bone marrow PFC activity, whereas an iv booster dose of 4 × 10⁸ SRBC evoked a normal IgM, IgG, and IgA PFC response in Sx mice. Apparently low doses of iv administered antigen require the spleen in order to evoke antibody formation in the bone marrow. Experiments with parabiotic mice, consisting of Sx and sham-Sx mice, showed that this facilitating influence of the spleen upon bone marrow antibody formation occurs via the blood stream. In a subsequent study, it was investigated whether the spleen is required throughout the bone marrow PFC response or only during the few days of the initiation phase. Therefore, mice were splenectomized at different intervals after a booster injection of 10⁶ SRBC iv. It appeared that Sx 2 days after the booster injection could still prevent the normal bone marrow PFC activity, whereas Sx at Day 4 could no longer do so. Apparently, after an iv booster injection, the spleen is only required for initiation of the bone marrow PFC response and not for the maintenance of this PFC activity thereafter.     

Experimental model for studying the participation of bone marrow cells in antibody formation

Participation of bone marrow cells in the production of IgM antibody forming cells (AFC) in the primary immune response to sheep red blood cells (SRBC) in C57Bl/6 and BDA/2 mice was studied. The animals of this line differed in sensitivity to preoral benz(a)pyren (BP) injection. After BP injection a toxical injury of bone marrow cells was observed for two days in DBA 2 mice but was not marked in C57Bl/6 mice. In the former it was followed by a 10-fold decrease of IgMAFC, while no profound changes were noticed in the immune response of the latter. A new model is offered for the evaluation of bone marrow cell participation. A suggestion is made concerning some connection of immunodepression in the bone marrow with the change of the stem hemopoietic precursor differentiation.     

The capacity and mechanism of bone marrow antibody formation by thymus-independent antigens

Primary immunization of mice with certain thymus-independent (TI) antigens (i.e., TNP-LPS and DNP-Ficoll) leads to antibody formation in the bone marrow (BM). TNP-Brucella abortus, Pneumococcus pneumoniae organisms, and alpha-(1,6) dextran, on the other hand, do not induce a BM antibody-producing plaque-forming cell (PFC) response. This paper deals with the mechanism underlying antibody formation in the BM to TNP-LPS and DNP-Ficoll. The majority of the BM-localizing PFC induced by TNP-LPS are formed within the BM from the proliferating lymphocyte pool, because this response was found to be resistant to splenectomy and sensitive to treatment with hydroxyurea (HU) before immunization. This local activation of newly formed B cells requires in addition to the antigenic signal of TNP-LPS the mitogenic signal from the lipid A component of LPS. In contrast, the BM PFC response to DNP-ficoll was reduced in splenectomized mice and resistant to HU treatment before the primary immunization. Thus, antibody formation in the BM to DNP-Ficoll is mainly dependent on long-lived B cells that migrate from the peripheral lymphoid organs into the BM.     

Effect of bone marrow opioid peptides on antibody formation in the productive phase of the immune response

The cells of intact spinal cord produce a group of biologically active peptides--myelopeptides (MP) stimulating antibody formation at peak of immune response and exerting an analgesic endorphin-like effect. The experiments on comparative studies of antibody-stimulating effect of synthetic opioid peptides and MP have shown that the mixture of opioid substances composed in aliquots corresponding to their content in MP has an antibody-stimulating effect similar to that of MP. Synthetic beta-endorphin also enhances the antibody formation during the productive phase of immune response at doses 1000-fold lower than its MP level. Leu- and met-enkephalins have no antibody-stimulating effect. An antagonist opiate, naloxone, blocks the antibody-stimulating activity of both opiates and MP. A close correlation between antibody-stimulating and analgetic endorphin-like MP activity has been established.     

Effect of stimulating antibody formation under the influence of bone marrow cells in vivo]

Injection of intact bone marrow cells to mice at the peak of the secondary immune response results in a 2.4-fold increase of the number of antibody-forming cells in the regional lymph node. Preliminary injection of bone marrow cells to donors of the immune lymph node cells decreases the stimulation effect of antibody formation when the lymph node cells are subsequently cultivated with the intact bone marrow cells. The data obtained demonstrate the cell interaction at the level of mature antibody producers in vivo.     

Histology of the bone marrow antibody response

The histology of the specific and non-specific antibody response in mouse and rat bone marrow was studied after subcutaneous priming and intravenous boosting with horseradish peroxidase (HRP). Cells producing specific antibody against HRP were found only occasionally in the bone marrow after subcutaneous priming. After the intravenous boost injection their number gradually increased. These anti-HRP forming cells were found as single cells, randomly dispersed throughout the bone marrow. Such a random distribution was also found for cytoplasmic (non-specific) immunoglobulin containing cells. At no time point after immunization could lymphoid aggregates or trapping of immune complexes be observed in the bone marrow of either species. On the basis of these observations it is concluded that the bone marrow forms a suitable microenvironment for immigrating antibody-forming cells but does not contribute actively to the induction of the immune response.     

Effects of growth factors on multipotent bone marrow mesenchymal stromal cells

Multipotent bone marrow mesenchymal stromal cells are progenitors of various cell types capable of long-term self-renewal. These cells are an adequate model for studying the most important problems in cell biology, such as self-renewal of stem cells and regulation of their differentiation. Moreover, these cells are a promising resource for regenerative medicine. In this context, isolation of the earliest multipotent mesenchymal stromal cells, their in vitro maintenance in an undifferentiated state, and stimulation of their differentiation in a desired direction appear to be most important. To successfully use the multipotent mesenchymal stromal cells both in fundamental studies and in therapy, it is necessary to modify and standardize the composition of culture medium, replacing blood serum with certain growth factors. These factors have influence on the proliferation and differentiation of most cell types, including multipotent mesenchymal stromal cells. This paper is a review of available data concerning the effects of some growth factors on the multipotent mesenchymal stromal cells of the bone marrow.     

The effect of myelopid on antibody formation in gamma-irradiated animals

The effect of a new immunocorrecting preparation, Myelopid, on the antibody-forming cell content of mouse spleen after gamma-irradiation (1-3 Gy) has been investigated. The preparation administered after immunization of mice with sheep erythrocytes increases the number of antibody-forming cells in the spleen, the effect being a function of radiation dose and time interval between the exposure and immunization. The preparation is ineffective when delivered after irradiation, but prior to immunization.