Journal of immunopharmacology最新文献

Sinomenine, an epimorphinan alkaloid, was tested for the immunosuppressive effect in mice. This compound produced a decrease of plaque-forming cells (PFC) to a T cell-dependent antigen, sheep red blood cells, in vivo. The depression of the PFC response induced with sinomenine was dose and time dependent. On the other hand, it failed to suppress the PFC response to a T cell-independent antigen, lipopolysaccharide. The immunosuppressive dose of sinomenine did not alter the cellularity of spleen, thymus, bone marrow and peripheral blood leucocytes, the DNA synthesis activity of bone marrow cells nor the proliferative responses of spleen cells induced by T cell and B cell mitogens in unprimed mice. These data suggest a selective effect of sinomenine on lymphoid cells. This compound has a potential for use in studies of immuno-deficiencies or clarifying some aspect of immunity.

Experiments were designed to demonstrate the synergism of low dose cyclophosphamide (CY), (15 mg/kg or 45 mg/M2) in combination with 5-aza-2'deoxycytidine (DAC). This dose of CY increased the cytotoxic response to DAC on L1210 tumor in mice by an additional 4 logs of L1210 cell kill or an approximate doubling of the response to DAC alone. These data support the hypothesis that CY at this low dose selectively inhibits suppressor t-cells which normally function to prevent the full cytotoxic potential of DAC from being realized.

Delayed hypersensitivity (DTH) to sheep erythrocytes (SRBC) in mice is a simple model of cellular immunity mediated primarily by Ly 1+ T-cells. Because little is known about the pharmacology of this model, the therapeutic effects of a variety of antiarthritic agents were tested. Swelling was determined using mercury plethysmography and used to determine drug activity. Two immunosuppressive agents (cyclophosphamide and azathioprine) and two steroids (dexamethasone and hydrocortisone) significantly reduced swelling. Only one of six nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, reduced swelling. Indomethacin, phenylbutazone, and benoxaprofen augmented swelling and ibuprofen and isoxicam were inactive. Four disease-modifying antirheumatic drugs (DMARDs), D-penicillamine, levamisole, chloroquine, and aurothioglucose, were tested and none inhibited swelling. Aurothioglucose significantly augmented swelling. In conclusion, only steroids and immunosuppressive agents had consistent effects on DTH to SRBC. In general, NSAIDs and DMARDs were either inactive or augmented swelling. These results suggest that this model may be of use as a routine screen for immunomodulatory agents.

Adenosine is able to in vitro inhibit FMLP-dependent activation of polymorphonuclear leukocytes as evaluated by enzyme release, superoxide anion generation and chemiluminescence production. The inhibiting effect is more relevant when A23187 is employed as stimulating agent. In this case the effect is significantly reversed by increasing concentrations of extracellular calcium. Since A23187-dependent activation is strictly dependent on Ca++ influx into the cell, the hypothesis is suggested that adenosine could act by regulatory mechanisms involving membrane calcium transport.

The compensatory effect of a bacterial lysate, Broncho-Vaxom (BV) on the immunosuppressive action of cyclophosphamide (CY) was investigated. In CY immunosuppressed mice, BV treated animals recovered to normal levels of IgM and IgG in serum as well of IgA and IgG in gut secretions significantly earlier than controls. Furthermore, normal cell proliferation in thymus, as estimated by measuring the relative size of this organ was achieved earlier in BV treated mice than in control mice. Oral treatment with BV restores the number of IgM anti SRBC producing cells in spleen, in CY immunosuppressed mice. Since immunosuppression induced by CY increases the susceptibility to various infections, we tested in immunosuppressed animals the protective effect of BV towards IP challenge infections with Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae var ozaenae, Pseudomonas aeruginosa and Candida albicans. BV led to an enhanced resistance towards both pneumococci and staphylococci challenge infections but not to the other challenge microorganisms.

The antimicrobial and antitumor effects of CP-20,961, a synthetic lipoid amine with immunomodulating properties, were investigated. Mice given CP-20,961 ip seven or three days before challenge with ip Listeria monocytogenes had a lower mortality than control mice. By contrast, CP-20,961 did not protect against lethal challenges of either Salmonella typhimurium or Toxoplasma gondii. In parallel with the in vivo studies, peritoneal macrophages from CP-20,961-injected mice inhibited multiplication of L. monocytogenes but not T. gondii. Further studies demonstrated that CP-20,961 protected mice against an ip challenge of P815 tumor cells as measured by survival time. This correlated with the ability of stimulated peritoneal macrophages to inhibit (3H-TdR uptake inhibition) and kill (Cr51 release) P815 cells in vitro. These data indicate that CP-20,961 affords protection against an ascitic mastocytoma tumor line and at least one, but not all, intracellular pathogens. The dissociation of the immunomodulating effect, which was reflected in peritoneal macrophage function, may be characteristic of this new class of immunomodulators.

Macrophages treated with various compounds that enhance host antitumor resistance exhibit measurable changes in metabolism, function, and surface antigens. In this study, murine peptone-induced peritoneal macrophages were stimulated in vitro by bacterial lipopolysaccharide (LPS), muramyl dipeptide (MDP), and poly I.poly C. They were subsequently compared in their ability to release superoxide and act as tumoristatic and tumoricidal effector cells. Superoxide generation was assayed by the reduction of ferricytochrome C. All three compounds failed to induce significant O2- release, unless the cells were also treated with phorbol myristate acetate (PMA). MDP was most active in potentiating the PMA response. In the tumor growth inhibition assay, cytostatic activity was comparable for all three compounds and did not exceed 32 percent. The combination of subthreshold levels of these compounds and hybridoma-derived MAF acted synergistically to induce potent cytostatic activity. In the chromium release assay, LPS and poly I.poly C rendered macrophages cytolytic for P815 target cells at concentrations greater than or equal to 1 microgram/ml. In contrast, significant cytolysis was observed with MDP only at 100 micrograms/ml. Defining precisely the effect of various biological response modifiers on several parameters of macrophage function may facilitate use of these agents in cancer therapy.

A patient is presented with a clinical syndrome of erythroderma, fever, liver function abnormalities, eosinophilia and atypical lymphocytosis due to carbamazepine hypersensitivity. Immunological analysis of peripheral blood mononuclear cells was performed using mouse monoclonal antibodies against T-cell and Ia antigens. A 12-fold increase in the absolute numbers of suppressor-cytotoxic T-cells was found, resulting in a reversed helper/suppressor ratio. Also the number of Ia-positive cells was greatly increased. Carbamazepine may induce a reversible proliferation and activation of the suppressor-cytotoxic subset of T-cells. Implications and pathogenetic possibilities are briefly discussed.

L-alanosine is an antitumor compound which has recently entered clinical trials. Single i.p. doses of this drug inhibit antibody production to thymus-dependent and thymus-independent antigens as well as delayed hypersensitivity to SRBC in mice. Moreover, the in vitro lymphoproliferative responses of splenocytes to Concanavalin A and bacterial Lipopolysaccharides are also affected when the drug is added upon setting up the cultures. On the other hand, in vivo treatment with L-alanosine does not impair spleen natural killer (NK) activity. The results are discussed in an effort to characterize the immuno-suppressive activity of L-alanosine.