Journal of immunopharmacology最新文献

Five multiple sclerosis patients were treated weekly with cytosine arabinoside (araC) on an escalating dose schedule. The dose was initiated at 50 mg/M2 and then increased once each week by 50 mg/M2 (unless toxicity caused delay). Dosage decisions were based on whether or not the antibody-dependent cellular-cytotoxicity (ADCC) or natural killer (NK) cytotoxicity levels had been reduced to a level more than 2 standard deviations below the control range. Cytosine arabinoside treatment was discontinued in 2 of 5 subjects at doses of 500 mg/M2 due to toxicity. The 3 remaining patients demonstrated sustained reductions in the percentage of FcR+ cells in their peripheral blood. The maximum percentage reductions from the baseline values ranged from 50% to 76%. Concomitant reductions in the NK activity at the same doses ranged from 65% to 83%. ADCC activity in all 3 patients, however, was relatively resistant to suppression. The nadirs for the ADCC activity were only 16% to 44% below the baseline minimum. AraC was shown to reduce the proportion of FcR+ cells and NK cytotoxic activity in preference to ADCC activity.

Oral administration of diazepam at doses of 5-10 mg/kg to restraint-stressed mice resulted in almost complete recovery in the stress-induced suppression of the antibody response to sheep red blood cell (SRBC). Moreover, this compound restored the suppression of antibody response to SRBC in cyclophosphamide-treated mice. Diazepam treatment also enhanced the antibody response against SRBC in normal mice only when the animals were immunized with the reduced amount of antigen. It was demonstrated that antigen specific helper T cell activity was promoted by diazepam administration in mice. Addition of diazepam augmented the in vitro anti-SRBC hemolytic plaque-forming cell (PFC) response in mouse splenocytes without altering kinetics of the response. However, the enhancing effect was observed only when the drug was added to the medium at the culture initiation. On the other hand, antibody response to T cell-independent antigens such as trinitrophenylated (TNP)-Ficoll and TNP-lipopolysaccharide were not enhanced by diazepam. Concanavalin A or LPS-induced 3H-thymidine uptake into splenocytes were not stimulated by diazepam. These results suggest that diazepam promotes the antibody response through stimulating helper T cell functions.

The in vivo administration of tumor necrosis factor (TNF) provides a new approach to the immunotherapeutic treatment of tumors. We evaluated the pharmacokinetics of murine tumor necrosis factor in mice as a model for application in the human system. TNF had a clearance of 0.013 ml/min/g and a serum half life of 10.5 minutes. Its volume of distribution was consistent with the extracellular space. This information can provide parameters by which to select optimal modes of treatment for eradication of in vivo neoplasms.

Indomethacin (IN) was administered to untreated or to cyclophosphamide (CY) treated C57B1/6 mice to study the roles of prostaglandins in regulating hematopoiesis. The following hematopoietic parameters were quantitated: peripheral blood leukocyte (PBL) count; total nucleated cells per spleen; total nucleated cells per femur; and spleen weight. Assays were performed in vitro to measure the number of colony forming units (CFU) present in the bone marrow and spleen. Untreated mice administered IN had a transient rise in their PBL count. These animals also developed splenomegaly and had an increased number of nucleated cells in their spleen. All CY treated mice had a marked decrease in PBL count, spleen cellularity, bone marrow cellularity, and spleen size during the first 5 days after CY treatment. These observations were followed by hematopoietic recovery over the next 10 days. Cyclophosphamide treated mice exhibited a more rapid hematopoietic recovery when treated with IN than without IN treatment. Analysis of the CFU capacity of bone marrow and spleen cells in soft agar showed a larger number of CFU in the bone marrow and spleen of IN treated mice or of CY/IN treated mice than in animals not receiving IN. These results indicate that prostaglandins are involved in the regulation of hematopoiesis in untreated mice and that prostaglandins may limit the hematopoietic recovery of CY treated mice.

By altering the receptor binding specificity of the highly potent natural toxin ricin, a macrophage specific immunotoxin was developed. Ricin ordinarily does not demonstrate cell type specificity and is capable of binding and entering cells through galactose containing receptors resulting in rapid cell death. A murine anti-rat peritoneal macrophage IgGl monoclonal antibody, B-6, was developed to serve as a target specific carrier for ricin. By covalently binding monoclonal antibody B-6 and reversibly binding lactose to ricin, a new biologically active hybrid toxin possessing macrophage specificity was developed. When P3X63-Ag8.653 myeloma cells, which served as an nonspecific target cell type, and macrophages were treated with the ricin conjugate over a broad range of concentrations and various time periods, the conjugate demonstrated substantially greater toxicity toward macrophages than myeloma cells even though both cell types responded similarly to treatments with unconjugated ricin. It was also observed that ricin was considerably more toxic to macrophages when conjugated to monoclonal antibody B-6 than unconjugated ricin. Through ricin-antibody conjugation a high degree of specificity and toxicity can be attained potentially suitable for anti-tumor reagents and immuno-modulators.

The effect of benzo(a)pyrene (BaP) at different molar (M) concentrations on the in vitro anti-sheep red blood cell (SRBC) plaque (antibody) forming cell (PFC) response and the one-way mixed lymphocyte response (MLR) was tested. Inhibition of the PFC response and the MLR occurred when spleen cells were exposed to a wide range of BaP concentrations from 10(-4) M to 10(-8) M. Maximum depression of the responses occurred at 10(-5) M for PFC production (47% of controls) and for the MLR (19% of controls) as measured by a stimulation index. No significant loss in cell viability was observed at this or lower molar concentrations of BaP. The non-carcinogenic analog of BaP, benzo(e)pyrene, did not suppress PFC responses at comparable concentrations. This in vitro system will facilitate manipulations of T and B lymphocytes and macrophages (adherent cells) in a controlled culture environment for precisely characterizing the sensitivity of these cells and their subpopulations on exposure to BaP.

Resident peritoneal macrophages can be activated to develop cytotoxicity against P815 mastocytoma target cells following incubation in vitro with either D-lactoyl-L-alanyl-gamma-D-glutamyl-(L)-meso-diaminopimelyl-(L)-gl ycine (FK-156), heptanoyl-gamma-D-glutamyl-(L)-meso-diaminopimelyl-(D)-alani ne (FK-565), or bacterial lipopolysaccharide (LPS) at a minimum concentration of 10 micrograms/ml. Subthreshold levels of hybridoma-derived macrophage activating factor (MAF) markedly potentiated this activity. In an experimental metastasis model, subcutaneous or intraperitoneal treatment with FK-565 (1 to 10 mg/kg) markedly inhibited lung metastasis formation when administered 2-4 days prior to i.v. tumor inoculation. Moreover, this protective activity could be abrogated by the selective macrophage inhibitor, 2-chloroadenosine, suggesting that activated macrophage were responsible for the antimetastatic activity of FK-565.

The immunomodulatory effects of Wy-41,770 (5H-dibenzo[a,d]cyclohepten-5-ylidene) acetic acid, were compared to levamisole and indomethacin in several in vivo models. In the Jerne plaque assay, Wy-41,770 (1 and 100 mg/kg, p.o.) administered on day 1 after sensitization suppressed IgM plaque forming cells (PFC) while levamisole was active when given on days 1 and 2 after sensitization. In contrast, indomethacin administered on days 2 and 3 after sensitization increased PFC. In the rat experimental allergic encephalomyelitis (EAE) model, Wy-41,770 reduced limb paralysis at 10 and 100 mg/kg, p.o. when dosed before sensitization. Indomethacin was active too when predosed in the rat EAE model. In the methylated bovine serum albumin model (MBSA) delayed hypersensitivity (DH) model in mouse, Wy-41,770 (10 mg/kg, p.o.) given on day 1 prior to sensitization and day 2 after sensitization in subliminally sensitized animals augmented the DH response while inhibiting the subliminal DH response when administered at 6 hr after challenge. Levamisole showed similar activity in this subliminal model while indomethacin given 6 hr post challenge was inhibitory. All three drugs were inactive in mice normally sensitized to MBSA at the same drug regimens. In guinea pigs, subliminally sensitized to tuberculin, Wy-41,770 (10 and 100 mg/kg, p.o.) and levamisole augmented the DH response. No changes in DH response were observed for both drugs in normally sensitized guinea pigs. In the rat adjuvant arthritic model, Wy-41,770 (5 and 15 mg/kg, p.o.) inhibited day 16 uninjected paw edema and restored significantly the depressed proliferative responses to mitogen by spleen cells taken from the same arthritic rats at day 16. The moderate immunomodulatory activity of Wy-41,770 may contribute along with its antiinflammatory activity, towards the treatment of arthritic diseases.