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PubMed2002

Histological and electrophysiological analysis of the peripheral nerve allografts using an immunosuppressive agent.

In peripheral nerve allografts, use of an immunosuppressive agent is one of the ways of reducing nerve rejection. FK506 is a newly discovered substance, extracted from Streptomyces tsukubaensis, and has strong immunosuppressive effects. In the present study, immunosuppressive effects of FK 506 were examined using allografts of rat sciatic nerves. Good nerve regeneration was demonstrated through 12 weeks in this model. The immunosuppressed group gained weight over the course of the experiment. Another study was performed to observe the histological changes caused by ceasing the administration of FK506. Administration of FK506 was terminated 12 weeks after grafting. At 8 weeks after cessation, cellular infiltration and large unmyelinated axons were observed in the extended subperineurial space of grafts. At 12 weeks, histological characteristics of rejection were not observed. In the electrophysiological study, the temporal dispersions were recorded at 4 and 8 weeks. However, the normal electrophysiological waves were recorded at 12 weeks after cessation. It was concluded that FK506 is effective for preventing rejection of nerve allografts without any serious side effects on rats, and findings of total rejection of grafts were not recognized after ceasing the administration of FK 506. In peripheral nerve allografts, short-term administration of an immunosuppressive agent is sufficient to lead to good nerve regeneration.

Action Potentials↗

PubMed2002

[Treatment of patients with Graves' ophthalmopathy by immunosuppressive agent and 99Tc-MDP].

The purpose of this study was to evaluate the efficacy of immunosuppressive agents, 99Tc-MDP and both of them in treating patients with Graves' ophthalmopathy(GO). The efficacy was evaluated by randomized controlled trial involving a total of 66 patients. In 22 patients treated with immunosuppressive agents, the general efficacy rate was 19/22, the incidence rate of serious side-effect was 8/22. In 20 patients treated with 99Tc-MDP, the general efficacy rate was 17/20, the incidence rate of serious side-effect was 2/20. In 24 patients treated with immunosuppressive agents and 99Tc-MDP, the general efficacy rate was 22/24, the incidence rate of serious side-effect was 2/24. The results suggested that in the treatment of Graves' ophthalmopathy, when satisfactory efficacy was obtained, the serious side-effect and 'rebound' of symptom could be avoided by using immunosuppressive agents in combination with 99Tc-MDP.

Graves Ophthalmopathy↗

PubMed1999

[Immunosuppressive agents in organ transplantation].

Initial use of intensive immunosuppressive therapy is mandatory after organ transplantation; during the following months treatment is tapered to the lowest effective and tolerable maintenance level. Immunosuppressants with different mechanisms of action are combined in order to obtain additive or synergistic effects, and to reduce the incidence of adverse effects. Traditional immunosuppressive agents like azathioprine, steroids, cyclosporine and polyclonal and monoclonal antibodies against T-cell antigens are challenged by new drugs like mycophenolate mofetil, tacrolimus, sirolimus and interleukin-2 receptor monoclonal antibodies. A combination of the most potent drugs could induce nearly complete immunosuppression. Such treatment, however, is a delicate balance between rejection due to poor immunosuppression on one side and, on the other, infections and malignancies induced by overtreatment. According to current protocols, therapeutic drug monitoring is used to individualize the dosage of immunosuppressants and as a means to control the tapering of these drugs. Validation of new immunosuppressive agents should be based on data from long-term studies including patient survival and graft function and survival as endpoints. Among the most recent achievements, inhibitors of costimulatory signaling in T-cells are of clinical interest since they may induce donorspecific tolerance and thereby alleviate the need for life-long maintenance immunosuppressive therapy.

Graft Rejection↗

PubMed1993

Immunosuppressive agents in dermatology.

Azathioprine, cyclophosphamide, and cyclosporine are immunosuppressive agents commonly used by dermatologists. Azathioprine has a good safety profile and is preferred by most dermatologists for the treatment of bullous pemphigoid, cutaneous vasculitides, chronic eczematous dermatitides, and cutaneous manifestations of connective tissue diseases. For more fulminant diseases such as Wegener's granulomatosis, lymphomatoid granulomatosis, severe cases of systemic lupus erythematosus, or pemphigus, cyclophosphamide is more effective and its use is justified even though it is more toxic. Cyclosporine has been shown to be effective in a variety of dermatoses; the most promising results are seen in psoriasis, lichen planus, pyoderma gangrenosum, and chronic eczematous dermatitides. The long-term safety of cyclosporine remains to be determined, and it should be used judiciously with careful evaluation of the risk-benefit ratio in each case. Dermatologists who use immunosuppressive agents should be familiar with their indications, side effects, dosage, and monitoring.

Azathioprine↗

PubMed1986

Treatment of aplastic anemia with immunosuppressive agents.

184 cases of aplastic anemia were treated by various immunosuppressive agents. 25.1% of the 35 patients with moderately severe aplastic anemia showed a hematological response to bolus methylprednisolone m PSL treatment. 9.6% of 73, 16.9% of 65 and 42.9% of 14 cases with severe aplastic anemia responded to m PSL, anti-lymphocyte globulin and anti-thymocyte globulin treatment, respectively. There was no difference in the survival of these severe aplastic anemia patients, however, which were prolonged invariably by treatment with each of these immunosuppressive agents. No correlation was observed between the in vitro increase of hematopoietic cell colony growth of the patient's bone marrow and clinical response to the immunosuppressive agents.

Adolescent↗

PubMed2001

Identification of novel targets of immunosuppressive agents by cDNA-based microarray analysis.

The immunosuppressive agents cyclosporin A (CsA) and tacrolimus (FK506) bind to unrelated intracellular immunophilin receptors, cyclophilin (CyP) and FK506-binding protein (FKBP), respectively. The complexes of CsA-CyP and of FK506-FKBP both bind to and inhibit the activity of the calcium/calmodulin-dependent serine/threonine phosphatase calcineurin. We used cDNA microarray analysis to characterize early human peripheral blood T cell transcriptional responses following antigen receptor stimulation in the absence or presence of CsA or FK506, hoping to identify novel targets dependent upon calcineurin or immunophilins or, perhaps, specific targets of either CyP or FKBP inhibitable by one drug alone. The array data failed to identify genes uniquely sensitive to only one drug, suggesting that transcriptionally regulated, immunophilin-dependent but calcineurin-independent targets fell below the limits of detection in this system. In contrast, transcript profiling identified and mRNA and protein analysis confirmed novel as well as known genes reproducibly induced or inhibited by both immunosuppressive agents. In this context, we show that transcriptional activation of Stat5a and repression of the cytokine interleukin-16 are regulated by T cell receptor engagement and dependent upon drug-immunophilin complexes and, presumably, calcineurin activity.

Base Sequence↗

PubMed2003

Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia.

Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.

Angioplasty, Balloon↗

PubMed2003

Peripapillary choroidal atrophy in sympathetic ophthalmia and management with triple-agent immunosuppression.

PURPOSE: To describe the occurrence of peripapillary choroidal atrophy and experience with triple-agent immunosuppression in three cases of sympathetic ophthalmia. MATERIALS AND METHODS: Retrospective chart review of three cases of sympathetic ophthalmia with peripapillary choroidal atrophy. RESULTS: Three patients with sympathetic ophthalmia were managed with steroid pulse therapy and triple-agent immunosuppression. All three patients subsequently developed peripapillary choroidal atrophy. CONCLUSIONS: Peripapillary choroidal atrophy can occur in sympathetic ophthalmia and may indicate a severe form of inflammation which would benefit from triple-agent immunosuppression.

Adult↗

PubMed2006

Triple agent immunosuppressive therapy in Vogt-Koyanagi-Harada syndrome.

PURPOSE: To describe the role of triple agent immunosuppression in severe recalcitrant cases of Vogt-Koyanagi-Harada syndrome. MATERIALS AND METHODS: Retrospective chart review of five cases of Vogt-Koyanagi-Harada syndrome. RESULTS: All cases were treated with oral prednisolone, azathioprine, and cyclosporine in combination, and rapid remission was observed in all patients. The synergistic effect of the triple agent immunosuppressives helped in preventing recurrences. Prolonged treatment with steroid sparing immunosuppressives in severe and recalcitrant cases of Vogt-Koyanagi-Harada syndrome maintained disease remission. CONCLUSION: Severe cases of Vogt-Koyanagi-Harada syndrome can be treated with early use of high-dose triple agent immunosuppressives.

Adult↗

PubMed2002

Small molecule immunosuppressive agents in experimental and clinical transplantation.

Immunosuppression is currently the major approach used for the prevention and management of transplant rejection. In this overview, preclinical and clinical studies of the small molecule immunosuppressive agents are reviewed from the discovery of cyclosporine. More recently it was demonstrated that certain agents, namely tacrolimus (FK506), sirolimus (rapamycin), and mycophenolate mofetil (CellCept, MMF), act selectively on adaptive host responses at different stages of T- and B-cell cycles and spare nonspecific host resistance. Because each agent has its specific and significant toxic effects, it has been difficult to optimize the use of individual agents in monotherapy. Therefore, drug combination therapy has been of great interest in addition to the introduction of new small molecule agents, such as malononitrilamides [MNAs (leflunomide, FK778, FK779)], 15-deoxyspergualin (DSG) and its analogues, FTY720 and inhibitors of signal transduction, which offer promising modes of immunosuppression.

Animals↗

PubMed1976

[Immunosuppressive agents and infection (author's transl)].

Immunosuppressive agents often cause severe infection sometimes due to organisms rarely encountered in other circumstances. Virus and parasitic infections, together with tuberculosis and salmonella may be particularly frequent during treatments which depress. T lymphocytes. Gram positive bacterial infections are mainly caused by substances inducing cell B immune deficeincy. In the light of this data, verified both by animal experiments and clinical experience, it is important to determine the target cell of the main immunodepressive agents used in clinical medicine. Azathioprine and antilymphocyte serum act mainly on T lymphocytes whereas alkylating agent are at least as active on B lymphocytes as on T lymphocytes. The mode of action of corticosteroids is particularly obscure. T cells appear, on the whole, to be resistant to corticosteroids, whereas monocytes and macrophages are very sensitive.

Animals↗

PubMedDate not supplied

Effects of steroids in combination with other pharmacologic immunosuppressive agents.

Steroids are commonly employed as immunosuppressive agents following organ transplantation. They may be given in large doses at the time of transplantation and also at times of rejection. At lower doses they are commonly used as maintenance therapy. The justification for these forms of treatments has been critically examined, and the author refers to his own experimental studies and clinical trials of steroids following kidney transplantation. The conclusion reached is that steroids are usually effective in reversing rejection, but there is no good evidence that they are required at the moment of transplantation or for long-term administration afterward if patients are already receiving cyclosporine.

Adolescent↗

PubMed1997

In vivo and in vitro inhibition of the L-type calcium current in isolated guinea-pig cardiomyocytes by the immunosuppressive agent cyclosporin A.

Cyclosporin A (CsA), an immunosuppressive agent used to reduce rejection after organ transplantation, induces secondary effects in heart tissue. We have studied the effects in vivo and in vitro of CsA on L-type Ca2+ current (ICa) and the associated gating currents of isolated guinea-pig ventricular myocytes using the whole-cell patch-clamp technique. For in vivo experiments, a group of animals (n=28) was treated for 21 days by subcutaneous injection of CsA (15 mg/kg/day). Blood level of CsA was 1191+/-221 ng/ml (n=9). In cells from these animals (n=65, 19 animals), ICa was reduced to about 75% of that recorded from control cells (n=32, six animals). CsA decreased the availability of Ca2+ channels at potentials more positive than +30 mV. Isoproterenol (100 nM) was still able to increase ICa but only by 30+/-6% (n=9), whereas in control it increased ICa by 290+/-22% (n=5). Gating currents related to L-type Ca2+ channels were not altered in cells from CsA-treated animals. In in vitro experiments, CsA reduced ICa when applied directly to cardiomyocytes. CsA affected the kinetics of ICa inactivation, slowing down the rapid phase and accelerating the slow phase (n=4). The steady-state inactivation curve of ICa was shifted to more negative voltages and the degree of availability at -80 mV decreased by in vitro application of CsA. The half inactivation potential (V1/2) changed from -23+/-0.6 mV in control to -31+/-2 mV, -48+/-0.6 mV and -49+/-0.6 mV, in 1, 50 and 80 microM CsA, respectively. In these cells, the gating currents related to L-type Ca2+ channels were also not altered by CsA. CsA does not modify the Ca2+ channel density, although it induces a decrease in the beta1-adrenergic stimulation of ICa. The results are explained by a direct effect on the calcium channel inactivation of CsA and a non specific indirect effect.

Adrenergic beta-Agonists↗

PubMed1986

The application, mechanism of action and side-effects of immunosuppressive agents in clinical transplantation.

The conventional agents (azathioprine and steroids) have been the mainstay or organ allograft immunosuppression for the past 20 years. The main drawback of the immunosuppressive agents at present in use is that they act nonspecifically with sequential general depression of the immune system. The introduction of cyclosporin, an undecapeptide of fungal origin, which selectively inhibits T-cell-dependent immuno-reaction has made a significant impact on organ allograft survival rates. Clinical application has been complicated because of renal or hepatotoxicity. Thoracic duct drainage is of historical interest but the use of antilymphocyte serum, despite its chequered history, has recently been shown to be safe and effective in cadaver kidney transplant recipients. There has also been a resurgence of interest in the use of total lymphoid irradiation as an immunosuppressive agent. The introduction of xenogenic monoclonal antibodies with anti-T-cell specificity opened a new era in clinical immunology and OKT3-PAN has emerged as a powerful major immunosuppressive agent with low toxicity.

Graft Rejection↗

PubMed2005

[Therapeutic use of glucocorticoids and immunosuppressive agents].

Pharmacotherapy of autoimmune thyroid disease (AITD) is complex. Apart from the replacement hormone therapy, antithyroid agents, beta adrenoceptor blockers and other drugs, in regard to the present symptoms, it also includes the administration of glucocorticoids and immunosuppressive agents. Physiological actions of glucocorticoids are significant in number, well known and described in details. The most prominent pharmacological properties of glucocorticoids, that are important fortheir clinical use, are antiinflammatory and immunosuppressive actions. In this article, the most notable clinical pharmacology aspects of glucocorticoids have been presented, including the basic principles of their therapeutic use, as well as the most important indications with the examples of dosing regiments (rheumatic disorders, renal diseases, allergic reactions, bronchial asthma, gastrointestinal inflammatory diseases, thrombocytopenia, organ transplantation, and Graves' ophthalmopathy). In addition, adverse and toxic effects of glucocorticoids as well as their interactions with other drugs have been described. Immunosuppressive agents have important role in treatment of immune disorders, including the reduction of immune response in autoimmune diseases and organ transplantation. Apart from glucocorticoids, immunosuppressive agents consist of calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative and antimetabolic agents (sirolimus, azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide), monoclonal antibodies: anti-CD3 antibody (muromonab-CD3), anti-CD25 antibody (daclizumab), anti-TNF-alpha antibody (infliximab). In this part, the most updated facts about mechanism of action, rational therapeutic use, as well as adverse and toxic effects of immunosuppressive agents have been reviewed.

Autoimmune Diseases↗

PubMed2004

Antifungal attributes of immunosuppressive agents: new paradigms in management and elucidating the pathophysiologic basis of opportunistic mycoses in organ transplant recipients.

The currently available immunosuppressive agents cyclosporine A, tacrolimus, and rapamycin have potent antifungal activity against a number of opportunistic fungi in organ transplant recipients, most notably, C. neoformans, Candida, and Aspergillus species. The targets of their antifungal activity are fungal homologs of the signaling molecules that mediate their immunosuppressive action in humans, which has implications for further unraveling the pathogenesis of these infections. Corroborative clinical data suggest that despite the apparent paradox between the antifungal activity of the immunosuppressive agents and the occurrence of fungal infections during their administration, the antifungal attributes of these drugs may influence the spectrum and clinical characteristics of these infections after organ transplantation. Finally, the potent synergistic interactions between the immunosuppressive agents and antifungal drugs against many pathogenic fungi, including those that are typically resistant to traditional antifungal agents, could potentially have a role in devising novel therapeutic strategies for opportunistic mycoses in transplant recipients.

Antifungal Agents↗

PubMed1995

Influence of various immunosuppressive agents on the occurrence of endogenous bacteraemia in mice.

The influence of six immunosuppressive agents on the occurrence of endogenous bacteraemia in mice was evaluated. The mortality rates in conventional ddY mice given cyclophosphamide (CY), fluorouracil (5-FU), methotrexate (MTX), cisplatin (CDDP) or FK-506 intraperitoneally, or dexamethasone (DXM) subcutaneously were 70, 100, 100, 100, 0 and 0%, respectively. Pseudomonas aeruginosa was isolated from 70% of mice treated with CY but from only 10% of mice treated with 5-FU and 30% treated with MTX. Enterobacteria were isolated from 90% of mice treated with 5-FU. Specific-pathogen-free (SPF) mice fed P. aeruginosa were also treated with these agents. All mice in the CY, 5-FU, MTX and CDDP groups died whereas mice treated with DXM and FK-506 showed 20% and 0% mortality, respectively. Pure cultures of P. aeruginosa were obtained from all of the mice treated with CY. Polymicrobial bacteraemia with P. aeruginosa and enterobacteria occurred in 5, 25, 5 and 5% of mice treated with 5-FU, MTX, CDDP and DXM, respectively. Enterobacterial bacteraemia was observed in 70% of mice treated with CDDP and in 5% of the DXM group. Different types of bacteraemia were induced by different immunosuppressive agents. The mechanism of immunosuppression may affect the frequency of bacteraemia and the causative organism.

Animals↗

PubMed2002

Mycophenolate mofetil for systemic lupus erythematosus refractory to other immunosuppressive agents.

BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive drug widely used in solid organ transplantation, and it may play an increasing role in autoimmune disease. MMF has been introduced as a novel immunosuppressive agent in systemic lupus erythematosus (SLE), often in patients intolerant of or resistant to conventional immunosuppressive regimens. METHODS: We studied 21 patients with SLE, most of whom had previously received courses of cyclophosphamide therapy and had also received courses of azathioprine or methotrexate. Indications for treatment included uncontrolled disease activity and worsening renal involvement. RESULTS: MMF treatment resulted in reduced disease activity, as assessed by the SLEDAI (SLE disease activity index) (P=0.0001) and decreased proteinuria (P=0.027) while allowing a significant reduction in oral corticosteroid dose (P=0.0001). Levels of complement factors C3 and C4 and anti-double-stranded DNA antibodies were not significantly affected. CONCLUSION: MMF appears to be a safe and effective alternative immunosuppressant for extra-renal and renal disease in SLE not responding to conventional immunosuppressive treatment.

Adult↗