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PubMed1999

[New immunosuppressive agents].

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.

Bone Marrow Transplantation↗
PubMed1997

Invasive fungal infections in liver transplant recipients receiving tacrolimus as the primary immunosuppressive agent.

Invasive fungal infections and their risk factors were prospectively assessed in 130 consecutive liver transplant recipients receiving tacrolimus as the primary immunosuppressive agent. Eleven percent (14) of the 130 patients had 17 episodes of invasive fungal infections. These included candidiasis (5%; 6 patients), cryptococcosis (5%; 6), aspergillosis (3%; 4), and chromomycosis (1%; 1). An elevated pretransplantation creatinine level, requirement of dialysis (pretransplantation or posttransplantation), duration of intensive care unit stay after transplantation surgery, and antibiotic use (other than for prophylaxis) within 4 weeks of transplantation were significant risk factors for fungal infections occurring within 100 days of transplantation. For fungal infections occurring after 100 days, persistence of renal dysfunction (serum creatinine level of >2.5 mg/dL at 3 months), dialysis, and histopathologically documented recurrence of hepatitis C virus hepatitis were significant risk factors. Mortality was significantly higher among patients with fungal infections than among all other patients (57% vs. 15%; P = .0009). Our study identified specific risk factors for invasive fungal infections in liver transplant recipients receiving tacrolimus; strategies to prevent fungal infections or to initiate early antifungal therapy might be most effectively targeted at these patients.

Adult↗
PubMed2005

The immunosuppressive agent FK506 enhances the cytolytic activity of inhibitory natural killer cell receptor (CD94/NKG2A)-expressing CD8 T cells.

Tacrolimus (FK506) is a potent immunosuppressive agent that inhibit transcription of cytokines such as IL-2 in T cells. The C-type lectin superfamily inhibitory NKR CD94/NKG2A-expressing cells can monitor the global status of HLA class I on tumor and leukemic cells through the recognition of HLA-E and induce cytolytic attack without an inhibitory signal against HLA class I-decreased target cells. We found that there was no effect of FK506 on the expansion of inhibitory NKR CD94/NKG2A-expressing T cells from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs). However, cytolytic activity levels of purified CD94-expressing cells from 7-day cultures with FK506 were much higher than those from 7-day cultures without FK506. These data suggested that FK506 did not inhibit cytolytic activities of inhibitory NKR-expressing T cells and that there was a possibility of cytolytic activities being enhanced through the induction of cytotoxic molecules such as NKG2D and granzyme during a seven-day culture with FK506.

CD8-Positive T-Lymphocytes↗
PubMed2003

The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase.

Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.

Animals↗
PubMed2006

Surfactant as a carrier: influence of immunosuppressive agents on surfactant activity.

INTRODUCTION: It has been proposed that exogenous pulmonary surfactant can be used as a drug delivery system for immunosuppressive agents to the alveolar compartment of the lung while reducing the risk of systemic toxicity. Before using this combination, however, alterations in activity of both substances should be examined. Therefore, this study investigated whether the activity of a natural derived surfactant preparation is changed after it is mixed with cyclosporine A (CsA) or rapamycin (RPM). METHODS: A surfactant suspension was mixed with CsA or RPM and minimal surface tension of these mixtures was measured in vitro. Surfactant activity was evaluated in vivo by its capacity to restore gas exchange in an established model of surfactant deficiency in rats. CsA-surfactant, RPM-surfactant or surfactant alone was instilled intratracheally and blood gases were measured under standardized ventilatory conditions. RESULTS: Minimal surface tension of surfactant-CsA was comparable with that of surfactant alone, whereas minimal surface tension of the surfactant-RPM mixture was increased. In vivo partial arterial oxygen pressure levels increased immediately to prelavage values after instillation of CsA-surfactant, RPM-surfactant and surfactant only and were comparable during the entire study period. CONCLUSION: The activity of a naturally derived surfactant was affected when mixed with RPM but not when mixed with CsA at the used concentrations.

Acute Disease↗
PubMed1997

Use of CTLA4-Ig in combination with conventional immunosuppressive agents to prolong allograft survival.

BACKGROUND: The objective of our study was to determine the effectiveness of CTLA4-Ig, a novel immunosuppressive agent, in augmenting allograft survival when combined with either cyclosporine, sirolimus, donor-specific bone marrow alone (BM), or bone marrow in conjunction with antilymphocyte serum (ALS). METHODS: Full-thickness skin allografts were used in C3H to B6AF1 (class I mismatch) and AKR to C57BL/6 (complete mismatch) models. Groups of mice (n=6-14) were treated with various combinations of the following treatment protocols: murine CTLA4-Ig, L-6 control Ig, sirolimus, cyclosporine, ALS, or ALS/BM. RESULTS: In the class I mismatch model, L-6 control Ig had no effect whereas use of CTLA4-Ig alone resulted in a doubling of the median graft survival compared with controls. The addition of either sirolimus or cyclosporine to CTLA4-Ig increased graft survival over that achieved with CTLA4-Ig alone. CTLA4-Ig demonstrated no efficacy when used in combination with BM, ALS, or ALS/BM. CTLA4-Ig was clearly less effective in the complete mismatch model. CONCLUSION: These data suggest that CTLA4-Ig may be effective clinically in combination with cyclosporine or sirolimus but offers no additional effectiveness in combination with antilymphocyte serum with or without donor-specific bone marrow.

Abatacept↗
PubMed1997

Effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems in rat liver microsomes.

The effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems with respect to three cytochrome P-450 isozymes in rat liver microsomes were investigated. FK-506 non-competitively inhibited the aniline p-hydroxylase, p-nitroanisole O-demethylase and lidocaine N-deethylase activities of cytochrome P-450-linked monooxygenase systems, these activities being mainly catalyzed by cytochromes P-450 CYP2E1, CYP2C11 and CYP3A4, respectively, and the Ki values of the activities for FK-506 were determined to be 605, 491 and 97 microM, respectively. The inhibition of cytochrome P-450-linked monooxygenase systems by FK-506 seemed to involve the direct inhibition of cytochromes P-450 because the NADPH-cytochrome c reductase and NADPH-ferricyanide reductase activities of NADPH-cytochrome P-450 reductase were not affected by the presence of 1 mM FK-506 at all. A spectrophotometric study showed that a reverse type I spectral change was induced on the addition of FK-506 to rat liver microsomes, and the Ks value was apparently 125 microM. On the other hand, the EPR spectra of cytochromes P-450 in rat liver microsomes were not affected by 1 mM FK-506. These results suggest direct interaction between FK-506 and cytochrome P-450 apoproteins, except for the heme iron regions of cytochromes P-450, resulting in inhibition of the drug-metabolism activities catalyzed by cytochromes P-450.

Aniline Hydroxylase↗
PubMed1979

Skin cancer development in mice exposed chronically to immunosuppressive agents.

Inbred female C3Hf/HeN, murine mammary tumor virus-negative mice exposed to either UV light or benzo[a]pyrene (BP), were subjected to four different chronic immunosuppressive regimens to determine their effect on skin cancer development. The immunosuppressive agents were cyclophosphamide, methotrexate, cortisone, and heterologous antilymphocyte globulin. Because of an unexpectedly high morbidity and mortality of mice exposed to chronic immunosuppressive measures, the dosages were kept at a level that permitted them to survive but did not prolong allogeneic skin graft survival and lower antibody titers, nor did this level diminish proliferative responses of lymphocytes to mitogens or allogeneic lymphocytes. Nevertheless, the latency periods (time interval between beginning of medication and appearance of skin tumors) of tumors in mice exposed to immunosuppressant measures were significantly shortened in several groups of mice exposed to UV and subjected to cyclophosphamide, cortisone, or antilymphocyte globulin and mice exposed to BP and subjected to cortisone acetate. In 3 groups, spindle cell tumors (fibrosarcomas) shifted to squamous cell carcinomas. A suppressed immune function would not be regarded as the mechanism for the observed responses because immunosuppression was not detected in the experimental mice.

Animals↗
PubMed1991

The effect of two new immunosuppressive agents, FK506 and didemnin B, in murine pregnancy.

The purpose of this study was to investigate two promising immunosuppressive agents, didemnin B (DB) and FK506 (FK), during pregnancy to assess potential adverse maternal or fetal effects. Pregnant C3H mice were randomized into control and high- and low-dose treatment groups for each drug. Animals received daily injections from day 1 to day 16, and on day 17 of gestation the maternal condition, litter size, fetal resorption rates, and fetal/placental unit weights were determined. Immunoglobulin (IgG) levels were obtained for DB treatment groups. Delayed type hypersensitivity was assessed in virgin females. Both DB and FK had dose-dependent immunosuppressive activity in the DTH assay, and DB caused elevated IgG concentrations. High doses of DB caused diarrhea and maternal wasting with no fetal survival; with low-dose DB, maternal weight gain was depressed, but pregnancy outcome was not different from control animals. High-dose FK had no obvious detrimental effects on maternal health but caused resorption of all fetuses; administration of low-dose FK resulted in a higher number of resorptions, but fetuses that survived did not appear different from controls. We conclude that these immunosuppressive drugs can have adverse effects on pregnancy, but the maternal and fetal toxicity are dose-dependent.

Animals↗
PubMed1991

Effect of the immunosuppressive agent, ciclosporin, on experimental immune complex glomerulonephritis in rats.

Effect of the immunosuppressive agent, ciclosporin (CS), on bovine serum albumin (BSA) nephritis in rats was evaluated. Eight weeks after immunization, 19 male Wistar rats received a daily intravenous dose of BSA (2 mg). Two weeks later, 11 rats received BSA and an oral dose of CS (10 mg/kg), and 8 rats received only BSA for 2 weeks. Urinary protein was measured weekly and serum anti-BSA antibody was measured by passive hemagglutination biweekly. The animals were killed at the 12th experimental week and blood samples and kidney specimens were obtained. BUN and serum creatinine were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. Urinary protein excretion was significantly less in CS-treated rats than in nontreated controls at the 2nd week after treatment (5.3 +/- 1.3 vs. 25.6 +/- 10.3 mg/day, p less than 0.05). Anti-BSA antibody titers were lower in treated rats than in controls at the 2nd week after the treatment. There were no significant differences in the levels of BUN and serum creatinine between two groups. Glomerular hypercellularity and mesangial widening were milder in treated rats than in controls, and glomerular deposition of BSA was less intense in treated rats than in controls. These results suggest that CS suppressed the antibody production and the development of glomerular changes in rats with immune complex glomerulonephritis.

Animals↗
PubMed1981

A prospective study of methylprednisolone and prednisone as immunosuppressive agents in clinical renal transplantation.

A prospective double blind crossover study was carried out in 65 patients comparing methylprednisolone (Medrol) and prednisone as immunosuppressive agents in clinical renal transplantation to determine their relative merits vis-a-vis graft survival, hypertension, weight gain, sepsis and patient preference in the posttransplant period. Patients receiving renal allografts were randomly assigned to receive initial treatment with one of the drugs. Once maintenance doses were employed, the drug was switched for a 3-month period. There was no difference in overall graft survival at 1 year, 68% versus 56% (p greater than 0.4), for the two patient groups. Likewise, there was no difference in blood pressure during the maintenance therapy crossover period, mean BP 129/86 during Medrol therapy and 129/86 during prednisone therapy. Overall weight gain was not statistically different with the two drugs, 3.8 kg with prednisone and 2.3 kg with Medrol, p greater than 0.1. However, when Medrol was used in the late posttransplant period, the patient had a significantly smaller weight gain, 0.95 kg versus 3.5 kg with prednisone, p greater than 0.05. The incidence of bacterial sepsis was significantly greater (p less than 0.02) during the early posttransplant period in those patients treated with Medrol. Finally, the majority of patients (65%) had no preference for either drug. Of those with a preference, the majority (69%) preferred Medrol. We conclude that therapy with Medrol does not offer superior graft survival, less hypertension or overriding patient preference but does apparently lead to an increased incidence of bacterial sepsis in the early posttransplant period. Thus it appears that prednisone is the initial drug of choice as an immunosuppressive steroid in clinical renal transplantation.

Clinical Trials as Topic↗
PubMed2001

Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide.

BACKGROUND: Despite advances in antiviral chemotherapy, herpes simplex virus type 1 (HSV-1), continues to complicate the clinical course of many allograft recipients. We have previously demonstrated that the experimental immunosuppressive agent leflunomide inhibits production of cytomegalovirus by interference with virion assembly. We test the hypothesis that this agent exerts similar antiviral activity against HSV-1. METHODS AND RESULTS: Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide. DNA dot blot and biochemical assay of viral DNA polymerase activity indicated that A77 does not inhibit viral DNA synthesis. Rather, as visualized by transmission electron microscopic method, this agent seems to disrupt virion assembly by preventing nucleocapsid tegumentation. CONCLUSIONS: These findings, in demonstrating that leflunomide exerts antiviral activity against HSV-1 by mechanisms similar to those we have previously shown with cytomegalovirus, imply that this agent may possess broad spectrum activity against other herpesviruses.

Animals↗
PubMed2002

Secretory defects induced by immunosuppressive agents on human pancreatic beta-cells.

Despite the considerable interest for islet and pancreas transplantation, remarkably little is known about the direct effects of immunosuppressive drugs on human beta-cell function. We measured different insulin secretory parameters and insulin gene expression of human islets cultured for 5 days in the presence of mycophenolate mofetil (MMF), cyclosporin A (CsA), tacrolimus (FK506) or a mixture of 3 cytokines. Basal insulin release after exposure to cytokines and FK506 was significantly higher than in control islets. Responsiveness to an acute glucose stimulus did not differ significantly between control and treated islets. However, absolute incremental insulin responses (delta-AUCs) of islets exposed to cytokines or FK506 were significantly higher compared to islets exposed to CsA or MMF, mainly because of the higher basal release. Indeed, maximal over basal release (stimulation index, SI) tended to be lower in islets exposed to FK506 than in control islets. Insulin gene expression was significantly reduced only in islets exposed to CsA. FK506 was, among those tested, the immunosuppressive drug that most profoundly altered the normal insulin secretory pattern of human beta-cells, whereas CsA was the only inhibiting insulin gene expression. Although the abnormalities induced by the immunosoppressive drugs utilized in this study were modest, these in vitro data are consistent with the reported in vivo diabetogenicity of CsA and FK506 and point to MMF as the ideal immunosuppressive agent from a pancreatic beta-cell point of view.

Adult↗
PubMed2000

Requirements for therapeutic drug monitoring of sirolimus, an immunosuppressive agent used in renal transplantation.

BACKGROUND: On September 15, 1999, sirolimus received approval from the US Food and Drug Administration (FDA) for marketing as an immunosuppressive agent. As with any chronically administered medication, the question arises whether therapeutic drug monitoring (TDM) is required for optimal therapy. In the case of sirolimus, there are data to suggest that TDM may be beneficial in some patients. OBJECTIVE: To assess the need for monitoring sirolimus concentrations, this paper reviews the following factors influencing the usefulness of TDM: wide pharmacokinetic variability; toxicity; suspected noncompliance; suspected drug interactions; and specific demographic characteristics. Data supporting the correlation between sirolimus concentration and immunosuppressive efficacy are also discussed. RESULTS: The available literature on sirolimus suggests that TDM may be required in some cases. Studies have shown that there is wide interindividual variability in the pharmacokinetic behavior of drugs in transplant patients; that there is a relationship between blood concentrations of sirolimus and adverse events; and that coadministration of cyclosporine alters the pharmacokinetics of sirolimus. Additionally, the correlation between sirolimus concentration and immunosuppressive efficacy in phase III trials suggests a benefit in transplant patients when sirolimus concentrations reach appropriate levels. Finally, noncompliance is a common occurrence in the transplant population, and monitoring is often necessary in suspected noncompliers. CONCLUSION: Although additional clinical studies are needed, it appears that TDM is an important aspect of treatment with sirolimus.

Drug Interactions↗
PubMed2006

FK506: an immunosuppressive agent preserving HIF-1 activity.

During transplantation, donor organs or cells are subjected to hypoxia. Hypoxia-inducible factor-1 (HIF-1) is essential for cellular adaptation to hypoxia. Immunosuppressive agents should be used for preventing graft rejection, but of these, rapamycin and cyclosporine A have been reported to inhibit HIF-1. We examined whether or not another important immunosuppressant, FK506, inhibits HIF-1. In contrast to cyclosporine A, FK506 neither inhibits HIF-1alpha expression in 8 different cell lines, nor represses the transcriptional activity of HIF-1. Compared with cyclosporine A, FK506 significantly reduced the apoptotic cell death by hypoxia. FK506 could preserve HIF-1 activity in donor organs subjected to hypoxia.

Animals↗
PubMed2005

A combination therapy of PEGylation and immunosuppressive agent for successful islet transplantation.

Several immunosuppressive medications are used simultaneously to protect transplanted islets. However, reports of severe side effects induced by immunosuppressive drugs have prompted attention on developing ways to reduce their toxicities. Toward attenuating the immunogenicity of islets, we studied a combination therapy of PEGylation and cyclosporin A (CsA) as a new immunoprotective strategy. This study aimed to find out whether PEGylation combined with cyclosporine and applied on islet surfaces could bring about a synergistic effect of reducing the dose of immunosuppressive medications as well as enhancing their medical effects. After islets were transplanted into the kidney of diabetic rats, different doses of CsA were administered daily. When 3 mg/kg of CsA was administered for 2 weeks, unmodified islets were completely rejected within 2 weeks, whereas the PEGylated islets survived for 32+/-14.6 days. When 1 mg/kg of CsA was further administered following the initial, 2-week CsA treatment of 3 mg/kg, the PEGylated islets in all recipients survived up to 100 days prior to nephrectomy and also rapidly responded to the fluctuation of blood glucose level. PEGylated islets were also present in large numbers in the transplantation site without causing the infiltration of immune cells. Therefore, these findings suggest that, when combined with an immunosuppressive drug, PEGylation of islets could have a dose reducing effect on the immunosuppressive medication and thus synergistically improve the survival time of islets.

Animals↗
PubMed2004

Alterations in the immune system of children from mothers treated with immunosuppressive agents during pregnancy.

Many of the immunosuppressive drugs that are used during pregnancy can cross the placental barrier and enter the foetal circulation, with a possible impact on the foetal immune system. We have evaluated the immune function of children born from mothers treated with immunosuppressants for connective tissue diseases. A total of nine babies, whose six mothers had been taking cyclosporine A (two), azathioprine (one) and dexamethasone (three) during pregnancy, together with 14 babies from mothers with similar diseases but who had not been treated (controls) were investigated. Complete blood count, IgA, IgG, IgM, IgG subclasses, and lymphocyte subpopulations were determined in all cases. Moreover, serum levels of anti-HBsAg and presence of autoantibodies (ANA, ENA) were also evaluated. Patients were tested at a mean age of 11 months (range, 1-17). Only a minor proportion of our patients displayed low values for age (mainly, IgA and IgG2), but none of the parameters tested resulted significantly different in patients than in controls. All children responded satisfactorily to hepatitis B vaccination. Although our results are preliminary, we conclude that prenatal exposure to immunosuppressive drugs does not have a profound effect to the developing immune system. More data and a longer follow-up are needed to confirm these results.

Adult↗