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Results for “IMMUNOSUPPRESSIVE AGENTS”

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PubMed1978

2 [(methylsulfinyl) acetyl] pyridine (Oxisuran): a new immunosuppressive agent in EAE.

The authors discuss the effects of a new immunosuppressive agent on the development of EAE. Animals (albino rabbits) were inoculated with an encephalitogenic emulsion, according to Kies' method, whereas a control group was inoculated by a physiological saline solution. Some animals were treated by Oxisuran in the first day after challenge; some others after initial symptoms (18th day). Thirty days after challenge, the animals were sacrificed. No toxicity was found in thoracic and abdominal structures neither in blood count. Pharmacological effectiveness of Oxisuran is well documented either in pretreatment or in therapy; the course was positively influenced in animals, when treated after the appearance of initial symptoms.

Animals↗

PubMed1990

Effects of a novel immunosuppressive agent, FK506, on human B cell activation.

We examined the effect of new immunosuppressive agent, FK506, on the human B cell function, in comparison with that of cyclosporin A (CyA) and tried to define the discrete activation step(s) which is selectively affected by FK506 and CyA. We used polyclonal B cell activators, Staphylococcus aureus Cowan I (SAC) and pokeweed mitogen (PWM). We found that (i) the initial B cell activation process by PWM, which is on the basis of T cell-dependent manner, is susceptible to the inhibitory effects of FK506 and CyA, while initial B cell activation on the basis of T cell-independent manner by SAC is resistant to these drugs; (ii) they also inhibit helper factor production by T cells; (iii) once they are activated, the B cells become resistant to inhibition by the drugs; and (iv) on an equimolar basis, FK506 exhibits 100-fold greater inhibitory activity than does CyA. Thus FK506 mainly interferes with interactions between T cells and other cells which are essential for B cell activation process, resulting in inhibition of B cell function.

Anti-Bacterial Agents↗

PubMed2001

A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration.

The immunosuppressant agent FK506 (tacrolimus) has proven to be neuroprotective against brain ischemia, but there are no data on potential neuroprotective effects of FK506 in peripheral nerve ischemia. We examined the potential effects of two doses of FK506 in protecting peripheral nerve from ischemic fiber degeneration. Ischemia in the left sciatic nerve of the rat was produced by injecting 2 x 10(6) microspheres (14 microm) into the left femoral, hypogastric, and superior gluteal arteries in proportions of 47%, 37%, and 17%, respectively. After embolization, FK506 was injected into the left femoral, hypogastric, and superior gluteal arteries in doses of 9.4, 7.4, and 3.4 microg, respectively, for the high-dose group and 4.7, 3.7, and 1.7 microg, respectively, for the low-dose group. The control rats were injected with saline. FK506 treatment resulted in dramatic behavioral improvement in nerve function, in the number of functioning nerve fibers, and in the salvage of a majority of nerve fibers from ischemic fiber degeneration in a dose-dependent fashion. These results suggest that a small dose of FK506 protects peripheral nerve from ischemic fiber degeneration and that it may have potential in the treatment of ischemic neuropathy.

Action Potentials↗

PubMed2003

The immunosuppressive agent tacrolimus induces p21WAF/CIP1WAF1/CIP1 via TGF-beta secretion.

Tacrolimus (Tac) is more immunosuppressive drug compared to cyclosporine (CsA). Our previous studies have demonstrated that CsA induces the expression of p21WAF/CIP1 expression. In this study we explored if like CsA, Tac also induces expression of p21WAF/CIP1. We also determined if induction of p21WAF/CIP1 by Tac is dependent on TGF-beta. Using RT-PCR and Western blot analysis, we studied the induction of p21WAF/CIP1 mRNA and protein in human T cells and A-549 cells (human lung adenocarcinoma cells) by Tac. The stimulation of p21WAF/CIP1 promoter activity was studied by luciferase assay using p21WAF/CIP1-luc, chimeric plasmid DNA containing a p21WAF/CIP1 promoter segment and luciferase reporter gene. Using anti-TGF-beta antibody, we studied if induction of p21WAF/CIP1 by tacrolimus is dependent on TGF-beta. The results demonstrate that Tac induced p21WAF/CIP1 mRNA and protein expression as well as stimulated its promoter activity in T cells and A-549 cells. The induction of p21WAF/CIP1 expression by tacrolimus was dependent on TGF-beta since a neutralizing anti-TGF-beta antibody inhibited induction of p21WAF/CIP1in A-549 cells. These data support the hypothesis that cyclin inhibitor p21WAF/CIP1 might represent a unified mediator of the anti-proliferative effects of Tac and other immunosuppressive agents. Strategies involving p21WAF/CIP1 induction should be considered a viable alternative strategy to achieve immunosuppression possibly with reduced toxicity associated with current immunosuppression.

Blotting, Western↗

PubMed1985

Immunosuppressive agents in penetrating keratoplasty.

One of the problems with corneal grafting is the occurrence of rejection. Immune reaction is considered to be an important cause of graft failure. Early recognition of such graft reaction can frequently be treated successfully with intensive topical administration of corticosteroids. Generally, I prefer to add systemic corticosteroids and immunosuppressive agents such as azathioprine. In the present study two cases are described to illustrate the use of azathioprine and demonstrate that even severe and recurrent graft reactions can be successfully treated with immunosuppressive agents.

Adrenal Cortex Hormones↗

PubMed2005

Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy.

Effective immunosuppression is an essential pre-requisite for successful organ transplantation and improvements in outcome after transplantation have to a large extent been dependent on developments in immunosuppressive therapy. Here we provide an overview of the different immunosuppressive agents currently used in solid organ transplantation. A historical perspective on the development of immunosuppression for organ transplantation is followed by a review of the individual agents, with a focus on their mechanism of action and efficacy. Steroids, anti-proliferative agents (azathioprine and mycophenolate), calcineurin inhibitors (cyclosporine and tacrolimus) and TOR inhibitors (sirolimus and everolimus) are discussed along with both polyclonal and monoclonal antibody preparations. Many of the key clinical trials that underpin current clinical usage of these agents are described and side-effects of the different agents are highlighted. Finally, a number of newer agents still in various stages of clinical development are briefly considered.

Animals↗

PubMed1998

Immunosuppressive agents in dermatology. An update.

Azathioprine, cyclophosphamide, methotrexate, and cyclosporine are the immunosuppressive agents most commonly used by dermatologists. Azathioprine has a relatively good safety profile and is therefore often preferred for the treatment of chronic eczematous dermatitides and bullous disorders. Awareness of the role of genetic polymorphisms in its metabolism can increase the efficacy and safety of this drug. Cyclophosphamide is an antimetabolite that has a more rapid onset of immunosuppressive effect than azathioprine, but has significant short-term and long-term toxicity. It is of use in fulminant, life-threatening cutaneous disease. Methotrexate is an antimetabolite that has significant anti-inflammatory activity. Despite its hepatotoxicity, its role in inflammatory dermatoses is broadening. Likewise, the role of cyclosporine is being expanded. This drug has potent T-cell inhibitory effects secondary to interference with intracellular signal transduction. Given the evidence for cumulative renal toxicity, it currently has a role in the short-term treatment of refractory psoriasis and atopic dermatitis, as well as in select inflammatory dermatoses. Familiarity with disease-specific clinical efficacy, side-effect profile, and dosage allows the successful and judicious use of these drugs in dermatologic disorders.

Azathioprine↗

PubMed1986

Inhibition of hepatic microsomal drug metabolism by the immunosuppressive agent cyclosporin A.

Cyclosporin A (CsA), an orally active immunosuppressive agent, was shown to inhibit cytochrome P-450 dependent biotransformation of drugs in the mouse. It competitively inhibited the hydroxylation of benzo[a]pyrene and the N-demethylation of aminopyrine in hepatic microsomes with Ki values of 93 and 1540 microM respectively. This selective inhibition for benzo[a]pyrene hydroxylase by CsA was substantiated in vivo by selective inhibition of total body clearance of theophylline, but not of antipyrine. CsA was itself N-demethylated by hepatic microsomes with a Km of 808 microM. CsA interacted directly with cytochrome P-450, causing a reverse type I spectral change in hepatic microsomes. No metabolic intermediate complexes could be demonstrated. These results suggest that CsA has the potential to cause drug interactions involving inhibition of drug biotransformation, particularly of drugs that are metabolised by the same types of cytochrome P-450 which oxidise benzo[a]pyrene and theophylline.

Aminophylline↗

PubMed1983

Rodent carcinogenesis bioassay with oxisuran, a selective immunosuppressive agent.

The carcinogenic potential of oxisuran, a synthetic immunosuppressive agent, was studied for 80 weeks and 104 weeks in mice and rats, respectively. Groups of 50 mice and 70 rats of each sex received oxisuran at doses of 600, 240, and 40 mg/kg/day as dietary admixtures over the entire experimental period. Adequate survival rates allowed accurate statistical analysis of diagnosed neoplasia. Increased susceptibility to tumor development was not clearly demonstrated. In mice the only statistically significant increase in the incidence of malignancy was lung carcinomas in high dose females (P less than 0.05). However, lung carcinoma incidence was significantly decreased in mid- and low-dose male mice when compared to spontaneous control rates (P less than 0.01). Although not confirmed statistically, there was an increased incidence of lung carcinomas and liver cell adenomas in high dose male mice, and increased lymphoid tumors in all female treated groups. In rats, the incidence of liver cell adenomas in high dose animals of both sexes was increased, although confirmed statistically in males only (P less than 0.01). In high dose females, significantly decreased incidences of mammary fibroadenomas, pituitary chromophobe adenomas, and thyroid parafollicular cell tumors (P less than 0.01) contributed to an overall decrease in both benign tumors and in the combined benign and malignant tumor rates.

Animals↗

PubMed1986

Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent.

We describe the first clinical trial of OKT3, a monoclonal anti-T-cell antibody, for prevention of kidney transplant rejection. 13 patients receiving a first cadaveric kidney transplant were randomly assigned to conventional treatment with azathioprine and high-dose steroids (7 patients) or to treatment with daily injection of OKT3 alone (6 patients). The first OKT3 injection resulted in a dramatic decrease in T3+, T4+, and T8+ cells, while patients simultaneously experienced fever, chills, and diarrhea. These symptoms did not recur with subsequent injections. All six OKT3-treated patients had a rejection necessitating introduction of steroids 12.8 +/- 2.9 days after surgery. Rejection was related to appearance of anti-OKT3 antibodies leading to disappearance of detectable OKT3 in the serum. Modulating (T3-, T4+ or T3-, T8+) cells were observed in all patients but were functionally inactive. As no rejection was observed before day 9 posttransplant, despite the lack of additional immunosuppressive agents, we conclude that OKT3 is a powerful, well-tolerated immunosuppressive agent. However, it is highly immunogenic and anti-OKT3 antibodies lead to loss of clinical effectiveness in this protocol. The use of OKT3 alone for prevention of kidney graft rejection cannot be recommended until a method for reducing the effects of anti-OKT3 immunization is developed.

Acute Disease↗

PubMed1998

Effect of different immunosuppressive agents on acute pancreatitis: a comparative study in an improved animal model.

BACKGROUND: Immunosuppressive drugs have been associated with the development and progression of acute pancreatitis after organ transplantation. Consequently, a reduction or a change in immunosuppressive therapy has been recommended once posttransplantation pancreatitis has been suspected. However, it is not known which of the available immunosuppressive agents is most harmful to the pancreas and which may be used safely in this situation. The objective of this study was to investigate the effect of different immunosuppressive drugs in various dosages on intrapancreatic protease activation, acinar cell necrosis, and mortality in an improved model of acute necrotizing pancreatitis in the rat. The rat model of acute necrotizing pancreatitis, like posttransplantation pancreatitis, is characterized by ischemia and microcirculatory disorders. METHOD: Acute pancreatitis was induced in rats by using a combination of low-dose controlled intraductal glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. Six hours thereafter, animals were randomized to intravenous therapy with 2, 10, or 50 mg/kg/day prednisolone (PRED); 3, 15, or 60 mg/kg/day cyclosporine A (CsA); 10 mg/kg/day azathioprine (AZA); 0.6 mg/kg/day orthoclone OKT3 (OKT3); or saline. After 36 hr, surviving animals were killed to determine acinar cell necrosis and trypsinogen activation peptides levels (TAP) in blood and ascites. RESULTS: Compared with saline-treated control rats, animals treated with 60 mg/kg/day CsA developed significantly more acinar cell necrosis and had increased amounts of TAP in ascites. Likewise, there was more extensive acinar cell necrosis in animals subjected to AZA therapy. However, this was not associated with incremental TAP. Animals treated with 3 or 15 mg/kg/day CsA, OKT3, or PRED showed no significant changes in these target parameters. Animals given 10 or 50 mg/kg/day PRED even had decreased hematocrit values and produced significantly less ascites than animals in the other groups. CONCLUSION: The present results suggest that AZA and high doses of CsA aggravate acute pancreatitis and should, therefore, be avoided once posttransplantation pancreatitis has been suspected, whereas lower doses of CsA, OKT3, and PRED may be used safely. PRED can even be used at higher doses as may be required when graft rejection is suspected.

Acute Disease↗

PubMed1994

Immunosuppressive agents.

The present success of organ transplantation is largely due to advances in immunosuppressive therapy. Progress has been made from a cytotoxic strategy associated with a high morbidity rate to a strategy that seeks to alter the activity of cells that regulate the immune response, in order to selectively dampen antidonor responses. This article presents a comprehensive review of the clinical matrix of immunosuppressive agents, which includes various combinations of pharmacologic agents tailored to minimize toxicity and to enhance efficacy.

Antigen Presentation↗

PubMed1990

Inhibition of leukocyte chemotaxis by immunosuppressive agents. Specific inhibition of lymphocyte chemotaxis by cyclosporine.

Since chemotaxis is an important mechanism by which leukocytes are recruited to allografts during rejection, the effect of immunosuppressant agents on in vitro chemotactic responses of neutrophils, monocytes, and lymphocytes was studied. Cyclosporine caused profound inhibition of lymphocyte chemotaxis to three different chemotactic factors at pharmacologic levels but had no effect on neutrophil or monocyte chemotaxis. Methylprednisolone and azathioprine both inhibited chemotactic responses of neutrophils and monocytes as well as lymphocytes. These data suggest that immunosuppressant agents are potent inhibitors of leukocyte chemotaxis and that drugs differ as to which leukocyte cell type they inhibit. The selective action of cyclosporine might explain why this drug is ineffective in reversing established rejection episodes in which monocytes and neutrophils are also involved. Inhibition of leukocyte chemotaxis may be an important mode of action of immunosuppressant drugs, and drug regimes might be adjusted to cause selective inhibition of particular cell types.

Azathioprine↗

PubMedDate not supplied

15-Deoxyspergualin, an immunosuppressive agent, used in organ transplantation showed suppressive effects on malarial parasites.

Deoxyspergualin (DSG), which was discovered to be an immunosuppressive agent, was examined for its in vivo effect on parasites of rodent malaria. Although the mice that were not treated by DSG had an increased parasite percentage (% parasitemia) until they died, those that were treated with DSG had a decreased parasitemia and finally had 0% parasites. The spleens of infected mice became small by DSG treatment. Parasitemia of mice increased again after DSG treatment was stopped. However, DSG was a polyamine inhibitor. The two other types of polyamine inhibitors used in this study were not effective for decreasing the % parasitemia of Plasmodium berghei. Only DSG was available and the survival time of mice increased. The antiprotozoal effects shown by DSG-even this chemical is an immunosuppressive agent-suggest that there is a relation between the inhibition of the polyamine synthetic pathway or immunosuppression of DSG and the suppressive effect of malarial parasites.

Animals↗

PubMed2003

FR252921, a novel immunosuppressive agent isolated from Pseudomonas fluorescens no. 408813 III. In vivo activities.

A novel immunosuppressive agent, FR252921 was isolated from the cultured broth of a species of Pseudomonas fluorescens. We have shown that FR252921 inhibit activating protein-1 (AP-1) transcription activity and act dominantly against antigen presenting cells comparing to T cell. Possibility of FR252921 as concomitant drug of FK506, T-cell specific inhibitor was evaluated. FR252921 showed synergy with FK506 in immunosuppressive activity both in splenic proliferation and in murine skin transplantation.

Animals↗

PubMed1979

Cyclosporin A: an immunosuppressive agent preferentially active against proliferating T cells.

The in vitro action of the immunosuppressive agent Cyclospirin A has been investigated using porcine cells. Lymphocyte proliferation induced in response to transplantation antigens and phytohaemagglutinin (PHA), was inhibited by this agent at doses that failed to inhibit mitogenisis in response to sheep anti-pig IgM, growth of kidney cell monolayers, and leukocyte migration.

Animals↗

PubMed1987

Modulation by immunosuppressive agents of peripheral blood mononuclear cell responses to influenza A virus.

The response to influenza A virus of peripheral blood mononuclear cells (PBMC) isolated from normal healthy adults was studied by measuring antigen-specific lymphocyte proliferation and interferon and interleukin-2 production by these cells in vitro. Under various experimental conditions, methylprednisolone, doxorubicin, vincristine, and vinblastine each reduced lymphocyte proliferation of the PBMC exposed to influenza A virus antigen. Treatment of cells with these drugs did not reduce expression of influenza A virus antigens by PBMC as detected by flow cytometry and did not reduce cell viability. In vitro treatment of the cells with methylprednisolone and doxorubicin reduced interferon and interleukin-2 yields. Experimental conditions necessary to reduce lymphokine yields varied with the immunosuppressive drug tested. Vincristine and vinblastine treatment of the cells did not reduce interferon or interleukin-2 yields. We conclude that methylprednisolone and doxorubicin at clinically achievable concentrations significantly affected the response of PBMC to influenza A virus in vitro. The effects of these immunosuppressive agents on lymphokine production were different from those reported in previous studies in which mitogens and Newcastle disease virus were used as inducers. The sensitivity of PBMC to these immunosuppressive agents is clearly related to the inducing agent used.

Adult↗

PubMed1996

In vitro effects of immunosuppressive agents on cytokine production by HTLV-I-infected T cell clones derived from the ocular fluid of patients with HTLV-I uveitis.

The present study was designed to investigate the in vitro effects of potential therapeutic agents on cytokine production by five HTVL-I-infected T cell clones (TCC) established from the ocular fluid of patients with HTLV-I uveitis. Each of the five HTLV-I-infected TCC was cultured at 1 x 10(6) cells/ml with or without an immunosuppressive agent (hydrocortisone, FK506, rapamycin, indomethacin, or prostaglandin E2) for 22 hr in humidified 5% CO2 in air at 37 C. The production of various cytokines in the culture supernatant from each TCC was measured by ELISA. The HTLV-I-infected TCC produced high amounts of IL-1 alpha, IL-3, IL-6, IL-8, TNF-alpha, IFN-gamma, and GM-CSF, and low but significant levels of IL-2 and IL-10 without any stimuli. Hydrocortisone severely depressed the production by these TCC of all the cytokines except for IL-2, which was slightly increased. Prostaglandin E2 depressed the production of IL-1 alpha, while it up-regulated the production of IL-6, TNF-alpha, and IFN-gamma. Rapamycin depressed the production of IL-6 and TNF-alpha, and FK506 depressed the production of TNF-alpha. Hydrocortisone also severely depressed the cytokine production by PHA-stimulated peripheral blood mononuclear cells obtained from healthy volunteers. Of the immunosuppressive agents tested, hydrocortisone exhibited the strongest suppression of cytokine production by HTLV-I-infected TCC. This result was in agreement with the in vivo effects of hydrocortisone in patients with HTLV-I uveitis. These TCC will be useful in investigating the effects of potential therapeutic agents for HTLV-I uveitis in vitro.

Body Fluids↗