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Results for “immunomodulation”

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PubMed1992

Effects of the immunomodulator diacetyl-splenopentin on antigen-induced arthritis in rabbits.

Long-term treatment with the immunomodulator diacetyl-splenopentin reduces the severity of chronic joint inflammation and cartilage destruction in rabbits with antigen-induced arthritis. The level of specific antibodies as well as specific and non-specific cell-mediated immune reactivities including the proliferative response of spleen lymphocytes to cartilage proteoglycans in treated animals are lower than in untreated arthritic rabbits. Moreover, suppressor cell activity, which normally decreases during the early phase of inflammation, is enhanced and hyperreactive helper cell potential is reduced. These findings suggest that treatment with diacetyl-splenopentin normalizes the immune regulation, which is disturbed in the early phase of inflammation. This might result in a depression of the hyperreactive immune system including the autoimmunity developed against cartilage. Lowered immune reactivity in the joint in turn reduces the severity of chronic joint inflammation.

Adjuvants, Immunologic↗

PubMed1990

Effects of immunomodulating therapy in systemic sclerosis.

We reviewed studies concerning immunomodulating therapy in systemic sclerosis. These comprise mostly uncontrolled trials and case reports. Some of these studies hint at a possible beneficial effect of antimetabolites (azathioprine, 5-fluoro-uracil and methotrexate), cyclosporine and interferon-gamma. However, to give a clearcut answer on the efficacy of these drugs in systemic sclerosis, controlled studies are urgently needed.

Adjuvants, Immunologic↗

PubMed1985

Antibiotics and immunomodulation: effects of cefotaxime, amikacin, mezlocillin, piperacillin and clindamycin.

The effects of 7 days' chemotherapy on the humoral and cellular parameters of the host immune system are described. In Balb/c mice the effects of cefotaxime, amikacin, mezlocillin, piperacillin and clindamycin were examined. The delayed-type hypersensitivity reaction, as well as the IgM and IgG responses, were suppressed by four of the five drugs tested: cefotaxime, amikacin, mezlocillin and piperacillin. One to two weeks after completion of chemotherapy with cefotaxime and amikacin, these parameters returned to normal values, whereas the mezlocillin- or piperacillin-modified reactions were still suppressed after 20 days. The concanavalin A and lipopolysaccharide-induced proliferative activities of mouse spleen cells were suppressed, especially by mezlocillin. The possible consequences of the immunomodulating effects of antibiotics for antimicrobial chemotherapy are discussed.

Amikacin↗

PubMed1995

FK-506 and cyclosporine A (CsA) immunomodulation of the human gut mucosal immune system.

FK-506 and cyclosporine A (CsA) are two immunosuppressive drugs used in the treatment of patients after liver and small intestine transplantation. A clinical advantage of FK-506 over CsA has been observed in these patients. Although the immunomodulation of both drugs has been well documented in the circulatory immune system, their effect on the mucosal immune system is not well established. In this study, the effect of FK-506 on the human gut mucosal immune system was compared to CsA. Proliferation of human colonic lamina propria lymphocytes (LPL) was measured by DNA synthesis and ornithine decarboxylase (ODC) activity. Results show that FK-506 and CsA suppress LPL DNA proliferation in a dose-dependent manner. FK-506 had a stronger antiproliferative effect compared to CsA. Moreover, the antiproliferative effect of both drugs was not dependent on monocytes or monocyte-associated factors (IL-1 beta, IL-6). In addition, exogenous addition of IL-2 did not restore the suppressive effect of either drug on LPL DNA synthesis. We conclude that: (1) both drugs have an antiproliferative effect on the human mucosal immune system; and (2) the stronger effect of FK-506 on human LPL compared to CsA may explain its superior clinical response observed in patients after liver/small intestine transplantation.

Cell Division↗

PubMed1993

Immunomodulating effects of levamisole in chicks immunocompromised by infectious bursal disease virus.

Immunomodulating effects of levamisole in experimentally IBD induced immunosuppressed 7-days old White Leghorn chicks have been observed. For this, infectious bursal disease (IBD) virus (Poona strain) was used. All the chicks were immunised with sheep red blood cells to monitor antibody responses. A group of chicks each from infected (PS-L) and uninfected (PBS-L) groups were given 4 injections of levamisole hydrochloride at the daily dose of 1.5 mg per 100 g body weight starting from the second day post inoculation with IBD virus. Serum samples were collected and the haemagglutination titre against sheep red blood cells was determined. IBDV infected chicks showed a significant decrease in HA titre compared with uninfected control chicks. In levamisole treated IBDV infected birds the HA titres were comparable to those of uninfected controls. However, uninfected chicks treated with levamisole showed no significant increase in HA titre to SRBC compared with uninfected untreated control chicks.

Animals↗

PubMed1996

Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A.

The effects of the new immunomodulating isoxazol derivative leflunomide, in comparison with cyclosporin A, on established antigen-induced arthritis in rats as well as serum antibody levels were determined. When treatment with leflunomide, at concentrations from 2.5 to 10 mg/kg/d, was started on day 3 of arthritis, the acute and chronic phases of arthritis were effectively inhibited. This was demonstrated by decreased joint swelling and reduced histopathological arthritis score at the end of experiment (day 26). Furthermore, the treatment resulted in a significantly reduced level of serum antibodies to the matrix components collagen type I, type II and proteoglycans. Neither leflunomide nor cyclosporin A, at doses of 1 mg/kg/d, had an effect on the severity of arthritis and antibody levels. However, when both drugs were used together, at these non-effective doses, the histopathological score of chronic arthritis was significantly reduced. The results of our experiments demonstrate that leflunomide has a strong suppressive effect on both acute and chronic phases of antigen-induced arthritis and formation of autoantibodies in rats. Furthermore, orally administered doses of leflunomide were as effective as doses of cyclosporin A given intraperitoneally. The combination of sub-effective doses of leflunomide and cyclosporin A resulted in significant inhibition of chronic arthritis.

Animals↗

PubMed1996

Leflunomide, a novel immunomodulating drug, inhibits homotypic adhesion of peripheral blood and synovial fluid mononuclear cells in rheumatoid arthritis.

OBJECTIVE AND DESIGN: A novel immunomodulating drug, leflunomide has been shown recently to be effective and well tolerated in patients suffering from rheumatoid arthritis (RA). The present study evaluated the effect of the drug on cell adhesion in RA. MATERIAL AND TREATMENT: Peripheral blood and synovial fluid mononuclear cells were obtained from a clinical trial, undertaken primarily to evaluate the efficacy and pharmacokinetic profile of multiple-dose pulsing leflunomide therapy in RA patients. PB MNC and corresponding synovial fluid (SF) MNC for in vitro homotypic aggregation (HA) assay were obtained from healthy volunteers and RA patients with active disease not treated with leflunomide in vivo. METHODS: Expression of activation antigens (CD25, CD54, CD69, CD71, HLA-DR) on peripheral blood mononuclear cells (PB MNC), as well as ex vivo ability of cells to aggregate spontaneously were determined in patients before entering into the clinical trial and at the end of 6 months treatment. HA was measured by aggregation in vitro. Data were compared by Student's t-test. RESULTS: There was a decreased expression of activation antigens and decreased spontaneous MNC clustering after leflunomide therapy. We found in the in vitro study that HA of PB and SF MNC was mainly mediated through beta 2-integrin molecules. The active metabolite of leflunomide, A77 1726, effectively suppressed both spontaneous and phorbol-ester (PMA)-induced HA. Disruption of cell aggregates by A77 1726 was dose-dependent and, most likely, unrelated to the quantitative modulation of integrin receptors. CONCLUSIONS: Results from this study support the idea that leflunomide elicits its immunomodulatory action, at least partially, by modulating the adhesion process.

Adjuvants, Immunologic↗

PubMed1990

Biological activity of bacterial surface components: bacterial extracts and defined bacterial cell wall components as immunomodulators.

Bacterial extracts obtained from pathogenic strains occurring in lung infections (Broncho Vaxom) or urogenital infections (Urovaxom) as well as defined surface components of Gram-negative bacteria purified from bacteria or obtained by chemical synthesis were tested for their immunomodulatory properties in a murine system. The bacterial extracts were able to act as immunogens inducing an antigen-specific response. Both the bacterial extracts and the purified bacterial cell wall components constituted polyclonal activators of murine splenic B cells, as demonstrated by proliferation assays measuring the incorporation of [3H]thymidine into DNA. They were also able to act as immunoadjuvants increasing the SRBC and the BSA-TNP specific immune response, and could induce tumor cytotoxicity in bone marrow-derived macrophages. The results show that bacterial extracts and defined bacterial surface components constitute immunogens as well as immunomodulators in vitro and in vivo.

Animals↗

PubMed1998

Thymopentin and splenopentin as immunomodulators. Current status.

Splenopentin (SP-5, Arg-Lys-Glu-Val-Tyr) and thymopentin (TP-5, Arg-Lys-Asp-Val-Tyr) are synthetic immunomodulating peptides corresponding to the region 32-34 of a splenic product called splenin (SP) and the thymic hormone thymopoietin (TP), respectively. TP was originally isolated as a 5-kDa (49-amino acids) protein from bovine thymus while studying effects of the thymic extracts on neuromuscular transmission and was subsequently observed to affect T cell differentiation and function. TP I and II are two closely related polypeptides isolated from bovine thymus. A radioimmunoassay for TP revealed a crossreaction with a product found in spleen and lymph node. This product, named splenin, differs from TP only in position 34, aspartic acid for bovine TP and glutamic acid for bovine splenin and it was called TP III as well. Synthetic pentapeptides (TP-5) and (SP-5), reproduce the biological activities of TP and SP, respectively. It is now evident that various forms of TPs were created by proteolytic cleavage of larger proteins during isolation. cDNA clones have been isolated for three alternatively spliced mRNAs that encodes three distinct human T cell TPs. The immunomodulatory properties of TP, SP, TP-5, SP-5 and some of their synthetic analogs reported in the literature have been briefly reviewed.

Adjuvants, Immunologic↗

PubMed1998

Inhibition of lymphoproliferative response and its restoration with a glucan immunomodulator in mice with experimental larval toxocarosis.

A high infective dose of Taxocara canis eggs (2,500 eggs per mouse) induced a partial immunosuppression in mice, manifested by inhibition of the proliferative response of splenic T and B cells to polyclonal activators. A glucan immunomodulator given to infected animals at the beginning of the experiment showed a marked stimulative and restorative effect on the parasite-suppressed lymphoproliferative response. The ability of T. canis to migrate in the host was reduced in glucan-treated animals by 27%.

Adjuvants, Immunologic↗

PubMed1999

Lymphocyte subsets as prognostic markers for cancer patients receiving immunomodulative therapy.

Immunogenic features of some malignancies have aroused interest in immunotherapy of cancer. Immunotherapy seems most effective in patients with a small tumour burden, and the focus of immunotherapy trials has, thus, lately been on adjuvant treatment. To enable further development of immunotherapy we need to know more about the mechanisms involved in host defence, especially when the system is influenced by extrinsic factors, that is, immunomodulative agents. T lymphocytes play an important role in the host defence against tumour cells trying to escape from immune surveillance. The mechanisms that regulate the host defence systems are complex, and the influence of extrinsic factors such as immunotherapeutic agents is poorly understood. Most data on lymphocyte subsets in malignant disease originate from melanoma or renal cell carcinoma (RCC) studies, although there are scattered data on lymphocyte subsets also in other malignancies. There are several studies implying that the relative amount of CD4+, CD8+, and natural killer (NK) cells may be important and that, by reducing the tumour burden or by using different therapeutic agents, we can stimulate the host defence. However, only some of these studies imply that these changes can have an impact on clinical outcome and prognosis. The findings of the studies reviewed in this paper are mostly encouraging, but whether the lymphocyte subsets have any value as prognostic markers in patients with malignancies receiving immunotherapy is still unclear. Large randomized immunotherapy trials including an observation arm give an ideal opportunity to recognize those immunological changes that are due to therapy, related to the natural host defence, or whether they have any prognostic value.

Antineoplastic Agents↗

PubMed1998

Immunomodulating activity of DW-116, a new quinolone antibiotic.

DW-116, (1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride), is a new quinolone antibiotic with a broad antibacterial spectrum against G(+) and G(-) bacteria. DW-116 was evaluated for the immunomodulating activities, which is one of the efforts to investigate the mechanism of action related to the good in vivo antibacterial efficacy. The results of in vitro studies revealed there was no statistically significant increase in B and T lymphocyte proliferation. But the results of in vivo studies showed that the number of plaque forming cells (PFC), the amount of polyclonal antibodies and delayed-type hypersensitivity (DTH) were significantly increased after the repeat administration with 12 and 60 mg/kg of DW-116. Taken together, these results proposed that immunostimulating effect of DW-116 could be one of the action mechanisms for demonstrating in vivo antibacterial activities under these experimental conditions.

Adjuvants, Immunologic↗

PubMed1989

Effect of the immunomodulator LF 1695 on T-lymphocytes and macrophages. Activity in HIV infection.

LF 1695, a synthetic immunomodulator with a low mol. wt, has been shown to exert its activity on T-lymphocytes and macrophages. It induced T-cell differentiation of bone marrow precursor cells which acquired the expression of CD3, CD4 and/or CD8. It increased lymphocyte proliferative responses to mitogens, antigens and allogeneic cells. IL-2 production was increased in Con A-activated but not in resting lymphocytes. Added to macrophages, LF 1695 augmented IL-1 production and LTB4 synthesis but it decreased PGE2 secretion. Hematological reconstitution of animals, following bone marrow alteration by irradiation or chemotherapy, was accelerated. Many of the effects of this compound may result from the enhancement of interleukin production, by macrophages especially. After investigations of LF 1695 effect on HIV-infected cells, clinical trials have been initiated in AIDS and ARC patients.

Acquired Immunodeficiency Syndrome↗

PubMed2003

[Topical immunomodulators in dermatology].

Immunomodulators include both immunostimulatory and immunosuppressive agents. Obligate contact sensitizers such as diphencyprone or dinitrochlorobenzene have been used against viral and autoimmune diseases. Newer agents such as the toll-like receptor agonists imiquimod and resiquimod have been clinically used to treat viral infections and skin cancers in immunocompetent and immunosuppressed patients. On the other hand, the topical immunosuppressive agents tacrolimus and pimecrolimus have been used with great success in the treatment of chronic inflammatory diseases in children and adults. The introduction of this new class of drugs (i.e. Calcineurin inhibitors) marked the beginning of the post-cortisone era in clinical dermatology. Toll-like receptor agonists and calcineurin antagonists will supplement corticosteroids to improve specific dermatological therapy. Topical immunotherapy with both immunostimulatory and immunosuppressive agents show potential for effective and patient-friendly treatment of inflammatory, infectious and neoplastic skin diseases. Long-term evaluation will define the tolerability and the safety profile.

Adjuvants, Immunologic↗

PubMed2003

[Cholesterol-reducing medications-a new therapeutic option for multiple sclerosis? Statins as immunomodulators].

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is crucial for cholesterol biosynthesis, and are widely used as lipid-lowering agents. These drugs greatly reduce atherosclerosis and cardiovascular morbidity, which in the past was mainly attributed to their cholesterol-lowering properties. However, recent evidence suggests that statins are also potent immunomodulators. They exerted beneficial effects on animal models of experimental autoimmune encephalomyelitis and thus have therapeutic potential for multiple sclerosis. Their exact mechanism of action is still unclear. HMG-CoA-dependent effects and a direct effect on immune receptors are conceivable and are reviewed here.

Adjuvants, Immunologic↗

PubMed1996

Monocyte activation by an oral immunomodulator (bestatin) in lymphoma patients following autologous bone marrow transplantation.

Bestatin (ubenimex), an inhibitor of aminopeptidase, is an oral immunomodulator that binds to CD13 (aminopeptidase N) on macrophages/monocytes. To examine its immunomodulatory effect after high-dose therapy and autologous bone marrow transplantation (BMT), a dose-finding phase Ib trial was conducted with 30 Hodgkin's disease and non-Hodgkin's lymphoma patients who received no drug (control), 10 and 30 mg (low dose), or 90 and 180 mg (high dose) of bestatin daily for 60 days following autologous BMT. Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on 2 consecutive days. The serum neopterin levels, an indicator of monocyte/macrophage activation, increased in the high-dose group compared to the control group (not significantly) and the low-dose group (significantly). Similarly, the colony-stimulating activity in the sera was significantly increased in the high-dose group compared to the control and low-dose groups. We also examined the expression of cell-surface markers on monocytes in these patients by fluorescent cytometry analysis. There was no significant difference either in the frequency or absolute number of monocytes (CD14+) among the three groups at any time. However, a significant increase in the frequency of CD16(FcgRIII)-positive monocytes (a marker of activation) was observed in the high-dose group compared to controls from day 14 to day 60 after the start of bestatin administration. Further, the frequency of HLA-DR+ monocytes (another marker of activation) was significantly increased in the high-dose group. These results indicate that bestatin at higher doses (90 and 180 mg daily), but not lower doses, activates macrophages/monocytes, as demonstrated by phenotypic marker (HLA-DR and CD16) up-regulation, and this provides augmentation of neopterin and colony-stimulating activity in the serum of patients following autologous BMT.

Adjuvants, Immunologic↗

PubMed1997

Phase IB trial of picibanil (OK-432) as an immunomodulator in patients with resected high-risk melanoma.

The microbial immunostimulant OK-432 has been studied intensively in preclinical systems and has shown promise as an anticancer agent in trials that have been conducted over the past 20 years in Japan. To date, no systematic dose response evaluation of this agent has defined its dose-limiting toxicity or immunobiological activity. A phase IA study has been conducted in 25 patients with metastatic cancer at the University of Pittsburgh Cancer Institute Melanoma Center, establishing 30 KE as the maximal tolerable dosage, on the basis of cutaneous reactions. Subsequently, 48 patients with resected high-risk melanoma participated in a phase IB study of OK-432. This study has evaluated the immunomodulatory activity of OK-432 at five dosages ranging from 1 KE to 20 KE, administered ID twice weekly for 3 months. A formal analysis of the treated population in comparison to the randomized control group has been conducted, and profound immunological effects have been defined in the group of patients treated with OK-432. Patients who participated in this trial had a significant depression of OK-432-inducible cytokine production (interleukin-1 beta, interferon gamma, and tumor necrosis factor alpha) at baseline. Treatment with OK-432 reversed this deficit for interferon gamma (IFN gamma) production in a dose-dependent manner, and mitigated the inhibition for interleukin-1 (IL-1) across all dosage groups. The impact of OK-432 upon other immunological functions of the treated cohorts is more variable, with durable suppression of mononuclear cell superoxide production, and in vitro cytotoxicity to tumor. Immunological characteristics of the entire cohort demonstrate a strong and significant correlation of elevated blood CD16+ cell counts and natural killer activity with early tumor progression and death due to melanoma. Favorable prognosis is associated with monocyte capacity to produce tumor necrosis factor (TNF), and polymorphonuclear leukocyte formylmethionyl-leucylphenylalanine-inducible superoxide release. This study reveals several new immunological correlates of tumor progression and lethal outcome in resected high-risk melanoma. It demonstrates that the depressed IL-1, TNF, and IFN gamma release associated with melanoma may be mitigated by treatment with OK-432. This study has defined treatment and dose response patterns of immunomodulation associated with one of the most complex immunological agents yet evaluated in phase IB trials, in a well-defined population of high-risk patients with resected melanoma.

Adjuvants, Immunologic↗

PubMed2003

[Immunomodulation in penetrating keratoplasty. Current status and perspectives].

The immune privileged nature of the cornea contributes to the favourable outcome in corneal grafts. However, preventive measures are necessary to reduce allograft rejection particular in "high-risk" cases. Although corticosteroids are still a major component of our immunopharmacological armentarium, they might be supplemented by other more specific immunomodulating agents. The spectrum includes agents such as azathioprin, methotrexate or more specific calcineurin inhibitors affecting T-cells (cyclosporin A, FK506) and highly selective monoclonal antibodies directed against T-cell subpopulations and other targets. In order to better evaluate the risks and benefit of these agents, the properties of established and forthcoming agents are presented. In addition, this review attempts to address some new concepts of tolerance induction following penetrating keratoplasty.

Adjuvants, Immunologic↗