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PubMed1992

[Neurectodermal malignant tumor of the soft tissues after treatment with immunosuppressive agents of lipoid nephrosis].

Immunosuppressive drugs are known to increase the risk of inducing neoplasia, especially acute leukaemia when high doses are used. A case of nephrosis in a 10 year-old boy treated with chlormethine (cumulative dose: 0.8 mg/kg) and chlorambucil (cumulative dose: 10 mg/kg) is reported. Four years after the beginning of the treatment an extraskeletal Ewing's sarcoma occurred. Since the review of literature failed to find any malignancy induced by such an immunosuppressive treatment for nephrosis, the question whether or not this extraskeletal Ewing's sarcoma was attributable to this treatment remains unanswered.

Adrenal Cortex Hormones↗

PubMed1996

Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro.

Leflunomide and its active metabolite, A771726, are structurally unrelated to immunosuppressive agents currently under investigation. Previous in vitro studies have revealed that leflunomide primarily inhibits interleukin-2-stimulated T cell proliferation. In the current study, we have extended our previous work and demonstrate that leflunomide prevents T cell progression induced by phytohemagglutinin into the S phase of the cell cycle. To discriminate further the action on T cells of leflunomide from other immunosuppressive agents, we performed kinetic studies where leflunomide was added either after the initiation of mixed lymphocyte cultures (MLC) or after interleukin-2 stimulation of CTLL-4 cell proliferation. These studies revealed that leflunomide acted comparably to rapamycin, but was distinct from brequinar sodium in the MLC, and from cyclosporine and mycophenolic acid in both MLC and CTLL-4. Although previous biochemical studies indicated that leflunomide can inhibit src-family tyrosine kinase activity, more recent studies have suggested that leflunomide can also inhibit pyrimidine synthesis. Our data demonstrate that the ability of leflunomide (25-100 microM) to inhibit MLC and CTLL-4 cell proliferation is partially antagonized by uridine (25-100 microM), and support the hypothesis that leflunomide inhibits pyrimidine synthesis in T cells. Unique molecular mechanisms of immunosuppression suggest that drug combinations may result in synergistic immunosuppression. Our in vitro studies revealed synergistic inhibition of T cell proliferation with the combinations of leflunomide with cyclosporine or with rapamycin. We have extended those studies to quantitate inhibition of MLC by the combinations of leflunomide and brequinar sodium or mycophenolic acid.

Cell Division↗

PubMed2004

Posttransplant diabetes mellitus after kidney transplantation with different immunosuppressive agents.

Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 +/- 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 +/- 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P =.003) among TAC (2.1 +/- 1.7 months posttransplantation) versus CSA (27.8 +/- 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.

Administration, Oral↗

PubMed2004

New immunosuppressive agents in chronic progressive glomerulopathies: an update.

The etiology of chronic glomerulopathies is not yet clear, however the impairment of immune system is supposed to play a decisive role. Thus, immunosuppressants are often used to slow the activity and/or progression of the disease. Usually the patients are treated either by corticosteroids alone or by the combination of corticosteroids with other immunosuppressive agents. Recently, immunosuppressants successfully applied in the transplantation medicine have been also tested in the therapy of chronic glomerulopathies. Cyclosporine A, a potent calcineurin inhibitor, has been used as a second line therapy. The place of CsA in lupus nephritis and especially in IgA nephropathy is not defined so well as it is in idiopathic nephrotic syndrome. The newer calcineurin inhibitor tacrolimus is already widely used in the transplantation medicine while its effectiveness in clinical nephrology has to be tested. Mycophenolate mofetil in monotherapy or with concomitant low-dose steroids can be regarded as an alternative therapeutical approach in case of standard regimens' failure. Sirolimus just entered clinical transplant medicine and its role in slowing the progression of chronic glomerulopathies is not yet clear.

Animals↗

PubMed2000

Applications of immunohistochemistry in the evaluation of immunosuppressive agents.

Immunohistochemistry (IHC) can be a valuable endpoint to evaluate lymphocyte subpopulations in tissues following exposure to presumptive immunosuppressive agents. IHC is more sensitive than conventional histology in detecting subtle differences in lymphocyte numbers and distribution in tissue. In combination with flow cytometric analysis of peripheral lymphocyte subpopulations, IHC can determine if alterations detected in the peripheral blood are a result of trafficking or reflective of changes in tissue distribution. These techniques can be used to evaluate adult animals as well as to evaluate the effects of immunosuppressive agents on fetal tissues in reproductive toxicology studies. While IHC can enhance the detection of subtle changes in lymphocyte subpopulations in tissue, the evaluation of additional endpoints of immune function must be done to further assess the biological or clinical significance of these changes.

Animals↗

PubMedDate not supplied

Mechanism of tolerance to DNCB-contact sensitivity induced by immunosuppressive agents.

Specific unresponsiveness to DNCB contact sensitivity has been induced in guinea pigs by a combined application of two immunosuppressive agents, cyclophosphamide and antithymocyte serum, to guinea pigs during the period of sensitization with DNCB. This tolerance was specific since the reactivity to an unrelated hapten (oxazolon) was not impaired by the previous immunosuppressive treatment. The unresponsiveness induced by immunosuppressive treatment has not been reversed by an additional treatment with the high dose of cyclophosphamide known to reverse hapten-induced tolerance, and has not been transferred by parabiosis from tolerant to normal partners. From these results it is concluded that specific unresponsiveness induced by immunosuppressive agents is not mediated by suppressor cells but is rather based on clonal deletion. The relative in unstability of this tolerance may be due to formation of new antigen-reactive cells from undeleted precursors.

Animals↗

PubMedDate not supplied

[Critical opinions on the treatment of multiple sclerosis with immunosuppressive agents].

The author reviews some important publications dealing with treatment of multiple sclerosis (m.s.) with the most commonly used immunosuppressive agents i.e. steroids and cyclophosphamide. He emphasises the methodology referring to group selection as well as placebo group and the way of the therapy results verification. The author concludes that many studies on the effective treatment with immunosuppressive agents are not sufficiently proved from the methodological point of view as well as the evaluation of the therapeutical effects in comparison with the placebo group is not convincing. The author appreciates the use of MRI in evaluation of the treatment effects. In the authors opinion the effectiveness of immunosuppressive therapy has not been so far sufficiently proved.

Adrenocorticotropic Hormone↗

PubMed1995

Deoxyspergualin is a unique immunosuppressive agent with selective utility in inducing tolerance to pancreas islet xenografts.

Recent studies of DSG have demonstrated that this agent has a unique ability among immunosuppressive drugs to induce long-term survival and functional tolerance of discordant islet xenografts from pig to the Lewis rat. In addition, DSG was found to be nontoxic to islet cells in culture and without any inhibitory effect upon insulin secretion in contrast to azathioprine, FK 506, and CyA. The long-term functional tolerance seen with these islets appears to involve a stable block of antidonor humoral immunity, although more testing is necessary to characterize the precise state producing functional tolerance in this model. Other studies presented at this meeting demonstrate the ability of DSG and RATG immunosuppression to produce long-term discordant islet survival in the NOD mouse, which suffers from a virulent autoimmune condition that destroys transplanted islets in most NOD models shortly after transplantation, even when the islets are microencapsulated. The functional tolerance is especially difficult to achieve with a discordant xenograft and thus the ability of RATG and DSG to achieve this impressive. Long-term studies using DSG and total lymphoid irradiation suggest that RATG is not essential to long-term survival but clearly it is quite synergistic with DSG and also has the advantage of being nontoxic. In fact, all animals receiving the DSG/RATG therapy were essentially free of toxicity and no deaths were observed that could be attributed to the drug therapy. This short-term course of administration of the drugs helped achieve this lack of toxicity. The high levels of synergism of ATG in this model could be related to the numerous monoclonal reactivities seen in polyclonal ATG with demonstrated titers of 1 to 4000 or greater for a number of specificities associated with B cells and macrophages, which could well be contributing to the block of humoral antibody previously demonstrated in DSG/RATG treated animals. The DSG, however, is especially effective in synergizing an antihumoral antibody response and can be shown to result in a striking decrease in early humoral antibody production following transplantation. Overall, these studies demonstrate a high potential of this immunosuppressive therapy to promote long-term discordant islet xenograft survival and functional tolerance without chronic rejection or the islet toxicity common to the currently used immunosuppressive agent. DSG may have a wide potential utility in islet transplantation but it appears to have its strongest effect in islet xenografting.

Animals↗

PubMed1999

Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide.

BACKGROUND: Despite progress in antiviral chemotherapy, cytomegalovirus (CMV) remains a major cause of morbidity and mortality among pharmacologically immunosuppressed organ transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide, an inhibitor of protein kinase activity and pyrimidine synthesis, is an experimental immunosuppressive agent effective against acute and chronic allograft rejection in animal models. Because a number of CMV proteins are known to be phosphorylated, we tested the hypothesis that this agent might exert inhibitory activity against CMV. METHODS AND RESULTS: Plaque assays demonstrated dramatic dose-dependent attenuation of production of multiple clinical CMV isolates in leflunomide-treated human fibroblasts and endothelial cells, common targets for CMV infection in vivo. As shown by Northern blot analysis and immunohistochemical staining, leflunomide neither interferes with transcription of immediate early or late viral genes, nor with expression of corresponding proteins. CMV-specific DNA dot blots and biochemical enzyme assays indicated that, in contrast to currently approved anti-CMV drugs, leflunomide exerts no inhibitory effect on the accumulation of viral DNA in infected cells, or on viral DNA polymerase activity. Rather, as visualized by transmission electron microscopy, this agent appears to act at a late stage in virion assembly by preventing tegument acquisition by viral nucleocapsids. Finally we have demonstrated equivalent inhibitory activity of leflunomide against multi-drug-resistant CMV isolates. CONCLUSIONS: These findings imply that leflunomide, an effective immunosuppressive agent, shows potential to concurrently attenuate a major complication of immunosuppression, CMV disease, by a novel mechanism of antiviral activity.

Antiviral Agents↗

PubMed2004

Effect of immunosuppressive agents on long-term survival of renal transplant recipients: focus on the cardiovascular risk.

In the control of acute rejection, attention is being focused more and more on the long-term adverse effects of the immunosuppressive agents used. Since cardiovascular disease is the main cause of death in renal transplant recipients, optimal control of cardiovascular risk factors is essential in the long-term management of these patients. Unfortunately, several commonly used immunosuppressive drugs interfere with the cardiovascular system. In this review, the cardiovascular adverse effects of the immunosuppressive agents currently used for maintenance immunosuppression are thoroughly discussed. Optimising immunosuppression means finding a balance between efficacy and safety. Corticosteroids induce endothelial dysfunction, hypertension, hyperlipidaemia and diabetes mellitus, and impair fibrinolysis. The use of corticosteroids in transplant recipients is undesirable, not only because of their cardiovascular effects, but also because they induce such adverse effects as osteoporosis, obesity, and atrophy of the skin and vessel wall. Calcineurin inhibitors are the most powerful agents for maintenance immunosuppression. The calcineurin inhibitor ciclosporin (cyclosporine) not only induces these same adverse effects as corticosteroids but is also nephrotoxic. Tacrolimus has a more favourable cardiovascular risk profile than ciclosporin and is also less nephrotoxic. It has little or no effect on blood pressure and serum lipids; however, its diabetogenic effect is more prominent in the period immediately following transplantation, although at maintenance dosages, the diabetogenic effect appears to be comparable to that of ciclosporin. The diabetogenic effect of tacrolimus can be managed by reducing the dose of tacrolimus and early corticosteroid withdrawal. The effect of tacrolimus on endothelial function has not been completely elucidated. The proliferation inhibitors azathioprine and mycophenolate mofetil (MMF) have little effect on the cardiovascular system. Yet, indirectly, by inducing anaemia, they may lead to left ventricular hypertrophy. MMF is an attractive alternative to azathioprine because of its higher potency and possibly lower risk of malignancies. Sirolimus also induces anaemia, but may be promising because of its antiproliferative features. Whether the hyperlipidaemia induced by sirolimus counteracts its beneficial effects is, as yet, unknown. It may be combined with MMF, however, initial attempts resulted in severe mouth ulcers.

Cardiovascular Diseases↗

PubMed1979

Cyclosporins: immunosuppressive agents with antitumor activity.

Initial screening of the 2 recently developed immunosuppressive agents, cyclosporin A and cyclosporin C, in 11 murine transplantable neoplasms revealed significant increase of lifespan with long-term survivors after i.p. injection to the ascites tumors, Taper liver, Sarcoma 180J and Ehrlich.

Animals↗

PubMed1999

Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication in vitro.

Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is currently used as an immunosuppressive agent in kidney transplant recipients. After oral administration, MMF is hydrolysed to MPA, the active compound, which is a potent inhibitor of inosine monophosphate dehydrogenase (IMP-DH). Inhibition of this enzyme results in a depletion of the intracellular GTP and dGTP pools. MPA has been shown to inhibit the replication of a number of viruses, including arena viruses (Junin and Tacaribe), yellow fever virus, reovirus-1, parainfluenza-3 virus, Coxsackie B4 virus, Epstein-Barr virus and human immunodeficiency virus. To examine whether MPA also has an inhibitory effect on HBV replication, experiments were performed using cultures of primary human hepatocytes and HBV-transfected, HepG2 2.2.15 cells. After in vitro infection with HBV in human hepatocytes, HBV covalently-closed-circular (ccc) DNA and HBV mRNAs were detectable in the cells during the 10 days following infection. HBV DNA and hepatitis B surface antigen (HBsAg) were also secreted into the culture medium. In the presence of 10 microg ml-1 MPA (the therapeutic serum level of MPA as an immunosuppressive agent) in culture medium, HBV ccc DNA and HBV mRNAs became undetectable 5 days after treatment was started. The secretion of HBV DNA and HBsAg into the medium was also markedly reduced. No cytotoxic effect of the drug was noted during the experiments. The effect of MPA on HBV replication was abolished by the presence of guanosine (50 microg ml-1). In HepG2 2.2.15 cells (which contain an integrated tandem dimer of the HBV genome), MPA treatment had no significant inhibitory effect on the secretion of HBV DNA and HBsAg into the culture medium. HBV ccc DNA and HBV mRNAs in HepG2 2.2.15 cells were also not affected. The observed effect of MPA on HBV replication in primary human hepatocyte cultures may involve only episomal replication and may have clinical implications, especially before integration of HBV DNA into the host genome.

Antiviral Agents↗

PubMed2001

Immunologic targets for currently available immunosuppressive agents: what is the optimal approach for children?

In this review, the authors discuss immunologic targets and events in T cells that are dysregulated by commonly used immunosuppressive agents. These include a description of glucocortcoid receptors as well as targets of glucocorticoids, targets of cyclosporine and FK506, and the mammalian target of rapamycin. In addition, novel antibody-based targets on T cells and antigen-presenting cells including the IL-2 receptor and costimulatory molecules are described. Finally, the authors provide a rationale for an optimal approach to immunosuppression in pediatrics. Because many of the newer immunosuppressive agents are currently in clinical trials, the "optimal" immunosuppressive strategy for the next decade is forthcoming.

Child↗

PubMed2003

Immunosuppressive agents and cytomegalovirus infection.

Cytomegalovirus (CMV) infection is the major infectious complication observed after organ transplantation. As rejection episodes always occur in allograft-transplanted recipients, various kinds of immunosuppressive agents are used to control such rejection episodes. Among the commonly used immunosuppressive agents, anti-pan-T cell polyclonal and monoclonal antibody are known to increase the risk of viral infections. New immunological techniques have recently been developed to measure CMV-specific CD4 and CD8 cells by flow cytometry. Using the techniques, high frequencies of specific CD4 and CD8 T cells have been shown to be required to survey the CMV (re)activation in the persistent/latent phase of CMV infection. An excessive T cell depletion by OKT3 would deplete such surveying T cells, thus resulting in the occurrence of CMV-associated diseases.

Animals↗

PubMed2001

Immunosuppressive agents in childhood nephrotic syndrome: a meta-analysis of randomized controlled trials.

BACKGROUND: Many children with steroid-sensitive nephrotic syndrome (SSNS) relapse frequently and receive immunosuppressive agents. In this systematic review of randomized controlled trials (RCTs), the benefits and harms of these immunosuppressive agents are evaluated. METHODS: RCTs with outcome data at six months or more that evaluated noncorticosteroid agents in relapsing SSNS were included. A summary relative risk for relapse at 6 to 12 months was calculated using a random effects model. RESULTS: Seventeen trials involving 631 children were identified. Cyclophosphamide [3 trials; relative risk (RR) 0.44, 95% confidence interval (CI), 0.26 to 0.73] and chlorambucil (2 trials; RR 0.13, 95% CI, 0.03 to 0.57) significantly reduced the relapse risk at 6 to 12 months compared with prednisone alone. In the single chlorambucil versus cyclophosphamide trial, there was no observed difference in relapse risk at two years (RR 1.31, 95% CI, 0.80 to 2.13). Cyclosporine was as effective as cyclophosphamide (1 trial; RR 1.07, 95% CI, 0.48 to 2.35) and chlorambucil (1 trial; RR 0.82, 95% CI, 0.44 to 1.53), but the effect was not sustained when cyclosporine was ceased. During treatment, levamisole (3 trials; RR 0.60, 95% CI, 0.45 to 0.79) was more effective than steroids alone, but the effect was not sustained. CONCLUSIONS: Cyclophosphamide, chorambucil, cyclosporine, and levamisole reduce the risk of relapse in children with relapsing SSNS compared with prednisone alone. Clinically important differences in efficacy among these agents are possible, and further comparative trials are still needed. Meanwhile, the choice between these agents depends on physician and patient preferences related to therapy duration and complication type and frequency.

Adolescent↗

PubMed1983

Cyclosporine: a new and promising immunosuppressive agent.

Cyclosporine is an exciting new agent that has been heralded as a major advance in chemical immunosuppression for organ transplantation. The drug is a potent, reversible suppressant of both humoral and cellular immunity and does not cause myelosuppression. Its mechanism of action appears to be selective for lymphocytes and may interrupt the necessary cellular signals required for proliferation of alloreactive T-cells. In early clinical trials cyclosporine has been shown to ameliorate renal allograft survival. A major concern about its widespread clinical use has been the observed nephrotoxicity and possible development of lymphomas in treated patients. Adverse side effects may be minimized by pharmacologic monitoring of drug levels. Future questions include the ideal dosage schedule, necessity for additional immunosuppressive agents, distinction between nephrotoxicity and rejection, and the precise mode of absorption, accumulation, and metabolism of the drug. Cyclosporine may be considered the prototype of a new generation of immunosuppressive agents that open up new perspectives in the field of immunoregulation. The ability to synthesize the compound may permit future biochemical manipulations to increase the immunobiologic specificity and decrease the toxicity of the drug.

Adult↗

PubMed1991

Corticosteroids and immunosuppressive agents in rabbit heterolamellar corneal transplant model.

Bovine cornea (epithelium and stroma) was transplanted on to the rabbit cornea from which the epithelium and stroma had been removed. Conjuntival hyperemia and edema occurred from day 1-5 post-operation, followed by neovascularization and graft rejection within 7-10 days. Topical dexamethasone (0.1%) and prenisolone (1%) t.i.d. inhibited post-surgical hyperemia, edema, delayed hypersensitivity and neovascularization. These agents and the immunosuppressants (cyclosporin A and rapamycin) inhibited graft rejection observed up to 20 days. After cessation of treatment on the 20th day, grafts remained viable up to 35 days with dexamethasone, 10 days with prednisolone and rapamycin, and 5 days with cyclosporin A.

Adrenal Cortex Hormones↗

PubMed2003

Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a world-wide disease and the cause of end-stage renal failure (ESRF) in 15 to 20% of patients within 10 years and in 30 to 40% of individuals within 20 years from the apparent onset of disease. No specific treatment has yet been established but many approaches have been investigated. OBJECTIVES: To assess the benefits and harms of immunosuppressive treatment for IgAN. SEARCH STRATEGY: We searched The Cochrane Renal Group's specialized register (May 2003), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2002) MEDLINE (1966 - September 2002), EMBASE (1988 - September 2002) and handsearched reference lists of retrieved articles and conference proceedings. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs comparing treatment of IgAN with immunosuppressive agents against placebo, no treatment, other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, with 95% confidence intervals (CI). MAIN RESULTS: Thirteen eligible RCTs involving 623 patients were identified. All identified RCTs had a placebo, no treatment or warfarin/dipyridamole control group. Seven trials used steroids, three used alkylating agents/cyclosporin and three used combinations of steroids and alkylating agents/cyclosporin. No trial directly compared steroids versus alkylating agents/cyclosporin. Quality was sub-optimal. Steroids were associated with a lower risk of progression to ESRF (RR 0.44, 95% CI 0.25 to 0.80) and lower urinary protein excretion (WMD -0.49 g/24h, 95% CI -0.72 to -0.12). Urinary protein excretion was lower for patients treated with alkylating agents/cyclosporin compared to placebo/no treatment (WMD -0.94 g/24h, 95% CI -1.43 to -0.46). There was no significant reduction of urinary protein excretion with combination treatment of steroids and alkylating agents compared with placebo/no treatment. REVIEWER'S CONCLUSIONS: The optimal management of IgAN remains uncertain. The RCTs identified were small, of sub-optimal methodological quality and tended to only report favorable and surrogate outcomes without a thorough reporting of treatment harms. All outcomes favor the use of immunosuppressive interventions, with steroids appearing to be the most promising. Further study, in the form of RCTs, is necessary to ascertain which patients would benefit from these interventions, whether they are the ones with early signs of renal dysfunction or those with more advanced renal impairment.

Glomerulonephritis, IGA↗