Journal of immunopharmacology最新文献

In vitro culture of normal BALB/c spleen cells with staphylococcal enterotoxin B (SEB) activates antigen non-specific suppressor T cells (Ts) which can be assayed by their ability to suppress antibody production in a plaque assay. Addition of the experimental immunomodulatory drug Wy-18,251 (10-100 microM) to cultures of spleen cells plus SEB significantly increased Ts activity relative to cultures without the drug. Similar results were obtained with levamisole, but, in contrast, indomethacin (0.1-10 microM) inhibited SEB-induced suppressor cell activity. The ability of Wy-18,251 to augment Ts activity could be therapeutically useful in the treatment of those autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, in which hyperactive B cell function is a characteristic feature.

We have used a murine renal adenocarcinoma of spontaneous origin (Renca) inplanted in the peritoneal cavity to study the therapeutic potential of biological response modifiers (BRMs) used alone or in conjunction with chemotherapy. This tumor model is therapeutically challenging since following intraperitoneal (i.p.) injection, the tumor grows progressively with hemorrhagic ascites, abdominal metastases to lymph nodes, liver, spleen, most serous membranes, and, in some animals, metastases to extra-abdominal sites (lungs). In the absence of therapy, death invariably occurs within 36 +/- 2 days. The tumor is efficiently lysed in 4 hours by peritoneal cells isolated from mice treated with BRMs. Both MVE-2 and rIL-2 significantly increased the survival time of tumor-bearing mice, but only treatment with MVE-2 led to definite cures of i.p. Renca. A single i.p. injection of MVE-2 cured 20% of the tumor-bearing mice, while repeated i.p. administration of this drug at 12 day intervals cured 70% of i.p. Renca-bearing mice. Combined therapy with doxorubicin hydrochloride and a single dose of MVE-2 cured 90% of tumor-bearing animals. The superior therapeutic efficiency of MVE-2 compared to that of the rIL-2 may be due to its ability, after i.p. inoculation, to generate and maintain high levels of cytotoxic effector cell activity for an elevated period of time within the peritoneal cell population. Additionally, MVE-2 augments effector cell activity in the liver, lungs, spleen, and blood and may therefore more efficiently interfere with metastasis formation in those compartments. The additive effects of MVE-2 and the chemotherapeutic agent suggest that more effective therapy may be achieved by the combination of immunotherapy with BRMs with chemotherapeutic drugs.

We have studied the mechanism by which cyclosporin A (CsA), dexamethasone (DEX), and ouabain (OUA) inhibit T cell proliferation by measuring the effects of these agents on 1) interleukin-2 (IL-2) production, 2) acquisition of IL-2 responsiveness, 3) the induction of IL-2 receptor expression, and 4) the specific interaction of IL-2 with its receptor. DEX primarily inhibited IL-2 production and did not block acquisition of responsiveness to IL-2 or interaction of IL-2 with its receptor. OUA mainly interfered with the mitogenic activity of IL-2 on IL-2 dependent cells and showed a modest inhibitory effect on IL-2 production. In contrast, CsA blocked acquisition of responsiveness of resting T cells to IL-2, inhibited IL-2 production, and also inhibited IL-2 receptor expression at 48 hrs but not at 24 hrs following mitogen stimulation. The protocol described in these studies should prove to be useful in dissecting the mechanisms responsible for the depressed lymphoproliferative responses in different autoimmune and immunodeficiency disease states.

Azimexone causes in mice the formation of unstable haemoglobins after a single dose of 20 mg/kg. BM 41.332, another immunomodulating drug of the 2-cyanaziridine class, induces these unstable haemoglobins only after a single oral administration of 500 mg/kg. Subsequently to the formation of unstable haemoglobins we observed a development of Heinz bodies. These effects of the 2-cyanaziridines were elicited neither by methaemoglobin formation nor by an impairment of the components protecting haemoglobin against oxidation (G6PD, catalase, glutathione). The elimination of the altered haemoglobin in the spleen could be followed by measurement of the rise in the iron content of the spleen.

Death most often results from human acute poisonings due to paraquat, a widely used herbicide. It causes a quick and insidious accumulation in lungs. It was proposed to study the effects of the administration of antiparaquat F(ab')2 fragments in mice intoxicated with paraquat. Antisera against a paraquat acid derivative coupled to bovine serum albumin were prepared in rabbits, then purified using immunoaffinity chromatography columns and fragmented by pepsin. Antiparaquat F(ab')2 antibodies obtained were preventively injected to mice. After intravenous paraquat injection of 8 mg/kg, plasma paraquat levels were measured from 0.25 to 48 hours. Plasma from antiparaquat F(ab')2 pretreated mice as compared with non-specific immunoglobulin pretreated control mice showed a significant increase (p less than 0.001) of the paraquat concentrations from the 4th (1.17 +/- 0.06 versus 0.20 +/- 0.01 microgram/ml) to the 48th hour (0.47 +/- 0.08 versus 0.02 +/- 0.01 microgram/ml). Although pulmonary paraquat concentrations presented no modification, it could be considered that these preliminary results would have to be studied thoroughly with a view to finding an efficient treatment in human acute poisoning with paraquat.

Pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase, was administered therapeutically to rats with type II collagen-induced arthritis and the effects on hindpaw swelling, serum haptoglobin concentration, and anticollagen antibody titer determined. Daily intraperitoneal administration of pentostatin at 10.0 or 1.0 mg/kg/day for three weeks produced significant enhancement of hind-paw swelling and elevation of serum haptoglobin. Continuous subcutaneous infusion of pentostatin at 1.0 or 0.1 mg/kg/day had the same effects. None of the dosing regimens had any effect on anticollagen antibody titer.

This study investigated the effect of various clinically used chemotherapeutic agents on non-modulated and human alpha Interferon (IFN) modulated natural killer cell (NK) activity. The inhibitors of DNA synthesis, Adriamycin, Cis-Platinum, 5-Fluorouracil and Methotrexate, did not alter NK cell activity at comparable clinically used doses. Similarly, Vincristine and Vinblastine, which are antimitotic agents, did not affect the NK activity. Only inhibitors of RNA synthesis L-Asparaginase and Actinomycin D reduced non-modulated and IFN modulated NK cell activity.

The effects of inactivated streptococci (OK-432) on murine macrophage functions were investigated. In vivo treatment of peritoneal macrophages with OK-432 augmented the direct cytotoxic activity against TU5 tumor cells in a 48 h tritiated thymidine release assay. OK-432 also stimulated the rapid (6 h, 51Cr release) macrophage-mediated killing of Actinomycin D-sensitized WEHI 164 sarcoma cells. Moreover, the expression of la antigens on peritoneal macrophages was found to be greatly enhanced after in vivo treatment with OK-432. The immunomodulatory effects of OK-432 on macrophages functions may contribute to the antitumor activity of inactivated streptococci.

We have compared the effects on number and function of bone marrow progenitors and peripheral effector cells of the myelomonocytic lineage of treatment with the 2-cyanaziridine compounds Azimexone and BM 41.332 to those of maleic anhydride divinyl ether copolymer (MVE-2) or granulocyte-macrophage colony stimulation factor (GM-CSF). Within a few hours after i.p. injection of either Azimexone or BM 41.332, there was a dose-dependent increase in serum CSF levels, CSF secretion by mononuclear bone marrow cells (BMC) and macrophages (M phi), which was followed by an increase in granulocyte-M phi committed stem cells (GM-CFU-C), nucleated BMC, and peripheral blood leukocytes. Optimal effects occurred 3 days after 50 mg/kg Azimexone or 25 mg/kg BM 41.332. Three i.p. injections of 50 mg/kg Azimexone into mice pretreated with cyclophosphamide (CY) (150 mg/kg) were able to significantly restore suppressed bone marrow cellularity (GM-CFU-C and nucleated BMC). Azimexone also increased the number of peripheral M phi in normal or CY-treated mice, without inducing detectable tumoricidal activity. These M phi, however, retained their capacity to become fully activated (cytotoxic) by appropriate activation signals such as IFN or LPS. Analogous to the 2-cyanaziridines. MVE-2 (at 25 mg/kg) had similar stimulatory effects on myeloid functions in normal mice. MVE-2 induced, in addition, a significant augmentation of cytoxicity by both M phi and NK cells. In contrast, single or multiple injections of semipurified GM-CSF into normal mice (1000 U or 5000 U per mouse) failed to detectably stimulate myelopoietic growth and differentiation. 2-cyanaziridine compounds thus offer the potential of selectively augmenting growth and differentiation of myelomonocytic cells in normal and bone marrow-depressed mice without appreciably affecting their immunological status.

A potent antischistosomal drug, Amoscanate, was found to induce vigorous serum antibody responses when either fed or administered parenterally as a drug-protein conjugate. Because of preliminary evidence that the drug could bind covalently to proteins in vivo, we decided to investigate the possibility that the drug could act as a contact sensitizing agent like DNCB. It was found that Amoscanate could induce a delayed-type hypersensitivity (DTH) response when painted on the shaved skin of guinea pigs. Moreover, the type of DTH response elicited was found to be cutaneous basophilic hypersensitivity (CBH). The significance of these findings are discussed.