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PubMedDate not supplied

In vitro bone formation induced by immunosuppressive agent tacrolimus hydrate (FK506).

When rat bone marrow cells were cultured with an immunosuppressive agent, tacrolimus hydrate (FK506), as well as with beta-glycerophosphate and vitamin C, numerous cell clusters became positive for alkaline phosphatase activity. Scanning electron microscopy revealed mineralized bone matrix in the cell clusters, which was identical to that of living bone. High levels of alkaline phosphatase (ALP), indicating osteoblastic activity, and high levels of osteocalcin (Oc) and calcium were found in the mature bone matrix of the cultures. There was significantly increased expression of mRNAs for ALP and Oc. These results indicate that the cultures contained both bone matrix and high osteoblastic activity, suggesting that FK506 induces ossification.

Animals↗
PubMed1987

[The role of immunosuppressive agents in the treatment of nephrosis in children].

Good clinical results are well known with the use of immunosuppressive therapy in children with idiopathic nephrotic syndrome; more recently, biological data have enhanced immunological anomalies, concerning mainly T helper lymphocytes. The need for steroids may decrease when relapsing nephrotic syndrome is associated with steroid intoxication and is absent when corticoresistance occurs. In these cases, the use of immunosuppressive agents is justified, but limited by side effects and toxicity. In patients treated with alkylating agents and now cyclosporine, good responses are often seen in frequently relapsing children whereas the course of steroid-resistant nephrotic syndrome is not significantly modified. However, the definite appreciation of such therapeutic results has to be further precised by both histological data and multicentric studies concerning new protocols.

Adrenal Cortex Hormones↗
PubMed1999

Review--the use of immunosuppressive agents to prevent neutralizing antibodies against a transgene product.

A potential obstacle to successful gene therapy for some patients is the in vivo production of neutralizing antibodies against the recombinant therapeutic product delivered. This is a problem inherent to all gene therapy methods, regardless of the vector used to deliver the protein. This clinical situation can be mimicked in animal models by delivering a foreign protein (i.e., a human protein) to the animal to provoke anti-human protein antibody production. The efficacy of different immunosuppressive treatments to inhibit the development of neutralizing antibodies can then be investigated. The immunosuppressive agents examined here include drugs (e.g., cyclophosphamide, FK506), cytokines (e.g., interferon-gamma, interleukin-12), and monoclonal antibodies (e.g., anti-CD4, anti-gp39, CTLA4-Ig). It has been found that a high level of antibody suppression is necessary to allow prolonged delivery of a foreign protein. Immunosuppressive agents capable of this high level of suppression will be important adjuncts to prevent treatment failures in situations where patients are at risk of developing neutralizing antibodies.

Animals↗
PubMed1968

Effect of immunosuppressive agents on normal phage-neutralizing antibody in the mouse.

The actions of three immunosuppressive drugs on normal antibody synthesis in the adult mouse were determined. Inbred mice were given daily intraperitoneal injections of actinomycin D, uracil mustard, or cyclophosphamide for extended periods. The sera of treated and untreated mice were assayed for phage-neutralizing activity to monitor the effect of each drug on the amount of circulating normal antibody. Except for an initial decrease in titer of normal anti-phage MSP2 activity, actinomycin D had no significant effect on normal antibody activity. Uracil mustard caused alternating elevation and depression of normal antibody titers. Cyclophosphamide caused a prolonged depression of normal antibody. The response patterns to the three immunosuppressive agents were the same for both induced and normal antibody.

Animals↗
PubMed1983

Effect of immunosuppressive agents on human T and B lymphoblasts.

We have studied the effects of various immunosuppressive drugs on the growth of human-derived T (MOLT-4) and B (MGL-8) lymphoblasts. In addition, we have examined whether the lymphotoxic effect of any of these drugs could be attributed to inhibition of either adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP). Results indicated that 1-beta-D-arabinofuranosylcytosine (Ara-C), methotrexate and chlorambucil were four to seven times more toxic for T than for B cells, while azathioprine, 6-thioguanine, 6-mercaptopurine, and 5-fluorouracil were highly toxic for both T and B cells. Cyclophosphamide and oxisuran were lymphotoxic only at concentrations exceeding 300 microM. Deoxyadenosine (50 microM), deoxyguanosine (10 microM) and deoxycoformycin (10 microM) failed to enhance T cell toxicity when individually combined with each drug. None of the drugs tested inhibited T or B lymphoblast ADA or PNP activity. With the exception of Ara-C, neither dATP nor dGTP accumulated in T lymphoblasts incubated in the presence of any of the drugs. We conclude that the cell culture system used in this investigation is useful for identifying lymphotoxic and T cell-specific immunosuppressive agents. However, none of the drugs studied appeared to function as an inhibitor of, or a competitive substrate for, either ADA or PNP.

Adenosine Deaminase Inhibitors↗
PubMed1996

Regulation of B cell function by the immunosuppressive agent leflunomide.

Leflunomide is an immunosuppressive drug capable of inhibiting cellular and humoral mediated responses in vivo. The mechanism responsible for suppression of B cell antibody responses in vivo has not been identified. In this study we demonstrate that leflunomide functions to inhibit murine B cell antibody production by directly acting on the B cell. Experiments performed in vivo showed that both T cell-dependent as well as T cell-independent antigen responses were suppressed by leflunomide. Initial in vitro experiments demonstrated that leflunomide inhibited B cell antibody production by decreasing B cell proliferation. The suppression of B cell proliferation induced by a variety of stimuli that use different signal cascade components suggested that leflunomide was acting on a common component required for B cell proliferation. Kinetic studies with LPS activated B cells revealed that leflunomide retained its inhibitory activity when added as late as 24 hr after stimulation in an 88-hr assay. By analyzing the cell cycle of LPS-stimulated B cells we observed that leflunomide targets two different stages in cell cycle transition: (1) from G1 to S phase and (2) from S phase to G2/M phase. Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation. These data further confirmed that leflunomide inhibited B cell progression through the S phase. We also present evidence that the addition of exogenous uridine reversed the antiproliferative activity of leflunomide. This indicated that leflunomide acted as a pyrimidine synthesis inhibitor, thereby inhibiting B cell proliferation and cell cycle progression.

Animals↗
PubMedDate not supplied

Sirolimus, a new, potent immunosuppressive agent.

Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in phase III trials for prophylaxis of renal transplant rejection. The mechanism of action of SRL is a blockade of the response of T and B cells to cytokines, thereby preventing cell cycle progression in G1 and consequently cell proliferation. There seems to be a good correlation between SRL concentrations, estimated as exposure by the area under the concentration versus time curve, and trough whole blood concentration, so that therapeutic monitoring may be done by trough levels only. Because of the low frequency of allograft rejection, there has been no documented correlation between trough concentrations and efficacy. Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an increased frequency of adverse effects. Drug-associated toxicities include thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in animal and clinical studies. In phase II trials the combination of SRL-CsA therapy reduced the frequency of acute rejection episodes, permit withdrawal of concomitant corticosteroid therapy, and allowed reduction of CsA dosages in nonblack patients.

Animals↗
PubMed1997

Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases.

An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.

Animals↗
PubMed1991

Assessment of the inhibitory effect of immunosuppressive agents on rat T cell interferon-gamma production using an ELISPOT assay.

The immunospot (ELISPOT) assay has proven to be an efficient and sensitive method for the enumeration of single cells secreting antibodies or cytokines. Here we show that the generation of interferon-gamma producing cells (IFN-gamma pc) in rat spleen cell cultures stimulated with concanavalin A (ConA) is dose-dependently inhibited by a wide variety of immunosuppressants such as cyclosporin A, FK506, hydrocortisone, dexamethasone, azathioprine and ART-18, a monoclonal antibody (mAb) with established immunosuppressive activity in organ transplantation and autoimmunity. The minimal inhibitory concentration (m.i.c.) correlated well with the reported m.i.c. in the mixed lymphocyte reaction (MLR) assay and the therapeutically effective plasma levels in vivo. Our data indicate that the IFN-gamma-specific immunospot assay is a powerful tool for determining the potency of immunosuppressive agents in vitro and provides a simple and accurate method for screening large numbers of agents with suspected immunosuppressive properties. The assay may additionally prove to be of value for determining the therapeutically effective doses of immunosuppressants that should be administered in vivo.

Animals↗
PubMed2005

Combination of immunosuppressive agents in treatment of steroid-resistant minimal change disease and primary focal segmental glomerulosclerosis.

BACKGROUND: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most prevalent histopathological lesions in idiopathic nephrotic syndrome (INS). The latter is associated with high morbidity and mortality due to symptomatic anasarca, bacterial infections, venous and arterial thromboembolism, and potential progression to end-stage renal disease in the case of FSGS. Traditionally, most patients are treated with corticosteroids, cyclophosphamide (CTX) or calcineurin-inhibitors (C-I). Unfortunately, many patients become steroid or C-I dependent, with the inherent risk of long-term side effects, or are resistant to both. The aim of this paper is to report on our experience with a new protocol of a combination of immunosuppressive agents added sequentially to improve the response of steroid and C-I refractory or resistant-INS and to minimize the long-term side-effects of single-agent treatment. METHODS: Twenty-one patients with corticosteroid-resistant and C-I refractory INS (6 with MCD and 15 with FSGS) were treated prospectively over 6 and a half years. Our protocol consisted of an initial regimen of C-I followed by the addition of mycophenolate mofetil (MMF) and then by monthly intravenous CTX for 3 consecutive months. Dose reduction of C-I or/and MMF was attempted afterwards at 4-months intervals. Patients who remained refractory to the previously mentioned protocol were treated with an additional course of pulse Solu-Medrol given for 3 days followed by oral corticosteroids tapered over 6 months in addition to a second course of intravenous CTX given for 3 consecutive months. RESULTS: With the initial regimen, two patients with MCD, remained in complete remission (CR) without any therapy after the course of CTX. Fifteen patients had variable response to C-I and MMF, but they achieved CR after CTX and their initial dosage of C-I and MMF were reduced to nearly one half. The remaining four patients had refractory form of FSGS even after the initial regimen, yet responded with CR to the additional course of steroid/CTX. However, no success with dose-reduction, in C-I and MMF, was achieved in the latter four patients. CONCLUSION: Our study represents the first clinical trial with prospective and adequate follow-up of combination therapy of immunosuppressive agents in INS. This method is effective and safe for treatment of patients who are refractory to the conventional single-agent therapy.

Adolescent↗
PubMed2006

Retention time for corticosteroid-sparing systemic immunosuppressive agents in patients with inflammatory eye disease.

BACKGROUND: Multiple immunosuppressive drugs have been used to manage inflammatory eye disease when control cannot be achieved by corticosteroid alone. However, although clinical studies support the effectiveness of most of these agents, comparative studies have not been undertaken. Retention time, a measure of the duration of treatment with any given drug, is a crude indicator of drug effectiveness and tolerability that facilitates such a comparison. The retention time was compared for corticosteroid-sparing immunosuppressive agents in patients attending our tertiary referral inflammatory eye disease clinic. METHODS: The clinical records of all patients attending an inflammatory eye disease clinic at the Casey Eye Institute over a 1-year period (2003) were reviewed. From these records, we collected the following clinical data: age; sex; ocular diagnosis; and use of steroid-sparing systemic immunosuppression, including drugs, duration of treatment and, if ceased, reasons for cessation. Cox regression analysis, adjusted for clustering, was used to compare other drugs against methotrexate. RESULTS: 107 of 302 (35%) patients seen at the inflammatory eye disease clinic in 2003 had a total of 193 current or past prescriptions for systemic steroid-sparing immunosuppressive agents. The treated group, most of whom had uveitis, included 32 men and 75 women, aged 5-86 years. Most commonly prescribed were methotrexate (66 uses, 34%), ciclosporin (37 uses, 19%), azathioprine (26 uses, 13%), mycophenolate mofetil (22 uses, 11%) and cyclophosphamide (15 uses, 8%). Patients were retained significantly less on ciclosporin (p = 0.004), azathioprine (p = 0.04), mycophenolate mofetil (p = 0.04) and cyclophosphamide (p<0.001) compared with methotrexate. Reasons for cessation included adverse events, lack of effectiveness, success or remission, cost and desire for fertility. CONCLUSIONS: In patients with inflammatory eye disease, methotrexate may offer a superior combination of effectiveness and tolerability over other commonly used corticosteroid-sparing immunosuppressive agents. In this study, there was a twofold risk of not being retained on azathioprine, mycophenolate mofetil and ciclosporin and a fourfold risk of not being retained on cyclophosphamide compared with methotrexate.

Adolescent↗
PubMed1997

Influences of immunosuppressive agents, FK506 and cyclosporin on systemic Candida albicans infection in mice.

The effects of the immunosuppressive agents FK506 (tacrolimus) and cyclosporin (CyA) on Candida albicans infection in mice were compared with those of cyclophosphamide. FK506 and CyA did not exacerbate C. albicans infection in mice when the effects were determined on the basis of survival ratio and colony forming units (CFU) in the kidney, although cyclophosphamide (CY) impaired the host defence mechanisms of mice against C. albicans infection. The effects of FK506 and CyA on the body weight of mice, histopathological changes of lymphoid tissues and formation of granulomas in kidney were also studied in comparison with those of CY.

Animals↗
PubMed2004

Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation.

Development of cancer is a feared, and increasingly apparent, complication of long-term immunosuppressive therapy in transplant recipients. In addition to the need to reduce cancer occurrence in these patients, therapeutic protocols are lacking to simultaneously attack the malignancy and protect the allograft when neoplasms do occur. In this overview, we present the current literature regarding the pro- and anti-neoplastic effects of immunosuppressive agents on cancer growth and development. Recent experimental findings are paving the way for new therapeutic strategies aimed at both protecting an allograft from immunologic rejection and addressing the problem of cancer in this high-risk population.

Adrenal Cortex Hormones↗
PubMed2003

A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells.

1. Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis. 2. Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time- and concentration-dependent manner. FTY720 also induced Bad (Ser(136)) and ribosomal p70S6 kinase (p70(S6k)) (Thr(389)) dephosphorylation. 3. FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3'-kinase (PI 3-kinase) pathway inhibition. 4. FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis. 5. Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70(S6k), suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. 6. OA partially inhibited FTY720-induced caspase-3 activation. 7. PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 8. Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria.

Blood Cells↗
PubMed1987

Application of irradiation as an immunosuppressive agent.

The concept of using total lymphoid irradiation (TLI) for immunosuppression is based on the prolonged and profound immunosuppressive effects observed after TLI in the treatment of patients with Hodgkin's disease. Pre-operative TLI of allograft recipients has been shown to be immunosuppressive when used alone or together with chemical immunosuppression. Fractionated TLI and allogeneic bone marrow injections produce stable chimaerism without graft-versus-host disease in inbred mice, rats and mongrel dogs and transplantation tolerance of skin and cardiac grafts in rats. In the primate, TLI and bone marrow injection result in significant tolerance of liver and kidney allografts. In 1959 sublethal whole-body irradiation was used as an immunosuppressive agent for the first successful related-human renal allografts between non-identical twins. Despite the dangers of myelosuppression, recent clinical experience has shown TLI to be a useful immunosuppressant for organ transplantation, allowing decreased dosage of concomitant immunosuppressive drugs.

Animals↗