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At least 811 records · Page 45Linked to original sources
PubMed2003

LF 15-0195, a novel immunosuppressive agent prevents rejection and induces operational tolerance in a mouse cardiac allograft model.

BACKGROUND: LF 15-0195 (LF) is a new analogue of 15-deoxyspergualin (DSG) that is less toxic and more potent than DSG. The present study was undertaken to determine (1). the dose response of LF monotherapy, (2). its ability to induce tolerance, and (3) its interaction with cyclosporine (CsA), FK 506 (FK), and rapamycin (RAPA). METHODS: Varying doses of LF were administered to determine dose-dependent effects on graft survival in a C57BL/6 to BALB/c heterotopic heart allograft mouse model. Transplanting-donor and third-party skin grafts into long-term survivors were used to assess the tolerance status. CsA, FK, and RAPA were combined with LF to determine their interactive effects on graft survival. RESULTS: The efficacy and toxicity of LF was dose dependent. High-dose LF monotherapy (>2 mg/kg) induced donor-specific operational tolerance, but it was associated with high mortality. Simultaneous administration of high-dose calcineurin inhibitors (CsA FK) prevented tolerance induced by LF. In contrast, a short course of LF combined with a subtherapeutic dose of CsA FK achieved indefinite survival of C57/BL6 cardiac allografts. RAPA and LF had a synergistic effect in induction of tolerance. CONCLUSIONS: The efficacy and toxicity of LF were dose dependent. A short course of LF significantly reduced the requirement of CsA or FK to prevent rejection. RAPA and LF had synergy in induction of tolerance. These data indicate that LF may be a promising agent that warrants further studies in nonhuman primate models of transplantation.

Animals↗
PubMed2004

[Nocardiosis--is it frequently observed after the introduction of new immunosuppressive agents in renal transplantation?].

In our series of 1374 renal transplantations performed between February 1970 and December 2002, we observed 6 cases of infection due to Nocardia asteroides. There were 4 males and 2 females, aged 49.8 +/- 12 years (29 to 63 years). One patient received his first transplantation and the 5 others retransplants. Three patients had PRA > 80%, one 28% and one 40%. One patient was diabetic and two had HCV infection. Two of 6 patients experienced acute rejection episodes. Nocardiosis localisation was pulmonary in 5 cases, cerebral in two and mediastinal in one. All patients recovered after reduction of immunosuppression and appropriate antibiotherapy with trimethoprim-sulfamethoxasole (TMP-SMX). When we analyzed the role of immunosuppression, we observed that only two cases were observed in the 933 recipients transplanted between 1985 and 2002 and receiving cyclosporin, contrasting with 4 cases among 174 recipients transplanted between 1996 and 2002 and receiving tacrolimus. Our data suggest that high immunologic risk patients, heavy immunosuppression, and perhaps tacrolimus-based immunosuppression are risk factors of nocardial infection. Early diagnosis of this severe infection, reduction of immunosuppression and appropriate therapy with TMP-SMX resulted in complete recovery in all our patients.

Adrenal Cortex Hormones↗
PubMed1988

Increase of corneal graft survival by use of topically immunosuppressive agents in rabbits.

Corneal graft survival in rabbits was significantly prolonged by topical treatment of the recipient eye with cyclophosphamide (0.1% in sterile isotonic NaCl) and methotrexate (0.1% in arachis oil) applied four times daily for 4 weeks. A control group of animals was treated with dexamethasone in the same way. The mean graft survival time was 52 +/- 18.5 days in the group treated with dexamethasone and 80 +/- 18.2 and 73 +/- 23.5, respectively, in the groups treated with cyclophosphamide and methotrexate. Cyclophosphamide and methotrexate applied topically produced no systemic side effects, and only one mild and transient local side effect in the form of hyperemia of the bulbar and palpebral conjunctiva. These two immunosuppressive drugs were more effective than the corticosteroid currently in clinical use, i.e., dexamethasone.

Animals↗
PubMed1982

The immunomodulatory action of frentizole, a novel immunosuppressive agent.

The in vitro effects of frentizole and methylprednisolone on human PBL were examined. Both drugs exhibited differential effects on lymphocyte subpopulations. Frentizole was more effective in suppressing human lymphocytes responding to Con A and PWM, than it was in cells activated by PHA, specific antigen, or alloantigen. Methylprednisolone, on the other hand, was more inhibitory for cells stimulated by PHA, specific antigen, or alloantigen. These data suggest that frentizole has a preferential effect on the cytotoxic/suppressor subpopulation of human T lymphocytes while methylprednisolone appears to preferentially affect the helper/inducer subset. Differences in potency between the two drugs were also observed. Methylprednisolone was better able to maintain its inhibitory effects during longer periods of culture than frentizole. Both agents were less effective if their addition to the culture was delayed 24-48 hrs and neither drug was very effective in overcoming the adjuvant action of poly A:U on mitogenically activated human PBL.

Adjuvants, Immunologic↗
PubMed2003

The potential of antibody-based immunosuppressive agents for corneal transplantation.

Corneal transplantation is a sight-restorative procedure but its success is limited by irreversible graft rejection, which accounts for up to 50 per cent of failures. The normal eye is an immune-privileged site. Multiple mechanisms maintain ocular privilege, including the blood-eye barrier, the lack of blood vessels and lymphatics in the normal cornea, the relative paucity of mature antigen-presenting cells in the central cornea, the presence of immunomodulatory factors in ocular fluids, and the constitutive expressive of CD95L (Fas ligand) within the eye. However, privilege can be eroded by the sequelae of inflammation and neovascularization. Corneal graft rejection in humans is currently suppressed with topical glucocorticosteroids, which are moderately effective. Systemically administered immunosuppressive therapy is of limited efficacy and may be accompanied by unacceptable morbidity. Alternative therapies are needed to improve outcomes. Corneal graft rejection is primarily a cell-mediated response controlled by the CD4+ T cell, and thus CD4 and costimulatory molecule blockade are appealing targets for new therapeutic interventions. A number of monoclonal antibodies have shown promise as immunosuppressants to prolong corneal graft survival in experimental animal models, and may eventually prove to be useful adjuncts to corticosteroids.

Antibodies, Monoclonal↗
PubMed1996

Epstein-Barr virus DNA in serum after liver transplantation--surveillance of viral activity during treatment with different immunosuppressive agents.

In immunocompromised HIV-infected and transplanted patients, there is a risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) and lymphomas. EBV has previously been detected by the polymerase chain reaction (PCR) in cerebrospinal fluid from all AIDS patients with EBV-associated cerebral lymphomas. We therefore thought it would be of interest to determine whether transplant patients with extracerebral EBV-associated LPD have detectable EBV genomes in serum. Nested PCR (nPCR) showed that 58% (18/31) of liver transplant (LTX) patients had EBV DNA in 17% (21/125) of serum samples obtained within the first 3 months after LTX. In 39% (7/18) of the patients, the first EBV nPCR-positive sample was found within 2 weeks post-LTX. Basic immunosuppression with cyclosporin A or FK506 did not seem to influence the frequency of detectable EBV genomes in serum. In contrast, positive EBV nPCR correlated to secondary OKT3 treatment for severe acute rejection (P = 0.009). EBV-associated malignant lymphoma developed in three patients 2-6 months post-LTX. In all of them, EBV DNA was amplifiable within 12-14 days after LTX. The EBV antibody titers were not directly related to detectable EBV DNA in serum. We conclude that monitoring of LTX patients receiving increased immunosuppression by nPCR for EBV DNA in serum may help in the early identification of those at risk of developing EBV-associated LPD.

Adolescent↗
PubMed1986

Imidazo[2,1-b]benzothiazoles. 2. New immunosuppressive agents.

A series of 2-phenylimidazo[2,1-b]benzothiazole derivatives was prepared and tested for immunological activities. Some of the compounds showed significant suppressive activity of delayed type hypersensitivity (DTH) without inhibition of humoral immunity in mice by oral administration. The most active compound was 2-(m-hydroxyphenyl)imidazo[2,1-b]benzothiazole (20).

Animals↗
PubMed1977

[Use of immunosuppressive agents in systemic diseases].

The use of immuno-suppressive agents in systemic diseases where the auto-immune origin is probable or certain is not yet based on definite physiopathological evidence. Therefore, it seems essential to use this treatment which has definite side effects only in cases where the progressive nature of the disease, renal complications or the incomplete or nil efficacy of less agressive treatments, leave no choice.

Cyclophosphamide↗
PubMed1989

Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro. I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity.

The effect of FK506 on in vitro human lymphocyte responses was assessed in comparison with cyclosporine. FK506 suppressed, in a dose-dependent fashion, the lymphocyte response to stimulation with PHA and with alloantigens in primary mixed lymphocyte reactions at a 70-100-fold lower concentration than CsA--namely, 50% inhibition (IC50) was obtained with 8.6 nM FK506 and with 750 nM CsA in the PHA response, and with 0.21 nM FK506 and with 20 nM CsA in MLR. Allocytolytic T lymphocyte induction was also inhibited by FK506, whereas the ability of CTL to lyse targets was not affected by the agent, indicating that FK506 did not affect the recognition and binding of alloantigen by CTL. FK506 inhibited, in a dose-dependent fashion, both IL-2 receptor and transferrin receptor expression on the alloactivated lymphocytes--whereas this agent inhibited only incompletely both expression of both receptors on lymphocytes stimulated with PHA. Lymphocytes from primary MLR cultured in the presence of FK506 were tested for suppressor cell activity on day 8 of culture. FK506 did not allow for the expression of alloantigen-activated suppressor cells when used in a dose sufficient to inhibit CTL generation.

Adult↗
PubMed1995

[Cutaneous periarteritis nodosa resistant to combined corticosteroids and immunosuppressive agents. Efficacy of treatment with intravenous immunoglobulins].

INTRODUCTION: Cutaneous polyarteritis nodosa is a subset of polyarteritis nodosa (PAN) characterized by a good prognosis because of the absence of severe visceral involvement. Dapsone, colchicin, non steroidal anti-inflammatory drugs are the first line treatments of cutaneous PAN. Corticosteroids are an alternative therapy. CASE-REPORT: A case of cutaneous PAN followed for 6 years is reported. Dapsone, colchicin, corticosteroid and cyclophosphamide have failed to control cutaneous lesions. Intravenous immunoglobulins 400 mg/kg/d five day monthly for 5 months was successful, but a cutaneous relapse occurred 3 months later which was another time controlled with intravenous immunoglobulins. DISCUSSION: Some cases of necrotizing vasculitis have been treated with intravenous immunoglobulins. This is the first reported case of cutaneous PAN treated with intravenous immunoglobulins. Because of the lack of controlled studies, the indications of intravenous immunoglobulins in vasculitis are restricted to those resistant to corticosteroids and immunosuppressive therapy.

Cyclophosphamide↗
PubMed1978

Suppressive effects on simian virus 40-induced oncogenesis of several immunosuppressive agents and hormonal modifications applied during the latent period.

The long latent period required for tumor induction with Simian virus 40 (SV40) in the subcutis of hamsters can be used to investigate whether host factor(s) participate in oncogenesis. Several treatments were applied during this period, and the results were compared with those of the same treatment applied in another series of experiments, homologous SV40 tumor grafting in hamsters. The results obtained were as follows: (a) the latent period for SV40 tumor induction in the female was shorter than that in the male; tumor development was delayed significantly by oophorectomy but was little affected by orchiectomy. Tumor development was markedly delayed in animals of both sexes by estrone given at birth but was accelerated by testosterone given in the adult male; (b) by each of these hormonal modifications, growth of transplanted SV40 tumors was influenced in a different way from that of tumor induction; (c) immunosuppressive treatments, such as thymectomy, administration of antilymphocyte sera, cyclophosphamide, or cortisone acetate delayed and decreased tumor development when applied in the latent period, and the degree or pattern of this effect varied from one procedure to another, depending on the sex and age of the animals; (d) in contrast, tumor growth was markedly accelerated in thymectomized or cortisone-treated hosts irrespective of sex. The different and almost reverse effect of the same procedure in the two phases of tumorigenesis may indicate two discriminating mechanisms operating in the host during these phases. This different effect may be due to virtual absence of any "mature" neoplastic cell in the latent period, except for a few weeks before the appearance of a palpable tumor. These results suggest that the long period of latency may be spent to complete SV40-induced neoplastic conversion of cells, receiving some help by host factors.

Age Factors↗
PubMed2002

[Successful use of immunosuppressive agents for the treatment of progressive rheumatoid interstitial lung disease: a case report].

Interstitial pneumonia (IP) is sometimes a fatal complication of rheumatoid arthritis (RA). We describe a patient with progressive rheumatoid interstitial pneumonia, who responded to intravenous intermittent cyclophosphamide (IV-CY) and cyclosporine (CsA). A 62-year-old man with rheumatoid arthritis was admitted to this hospital because of dyspnea. Examinations on admission revealed that he had active RA with vasculitis and IP Initially, he responded to high-dose corticosteroid therapy. A lung biopsy performed after initial corticosteroid therapy revealed diffuse interstitial pneumonia with marked infiltrations of macrophages into the air spaces. On corticosteroid therapy with prednisolone 30 mg/day, the IP became exacerbated and was refractory to the current high-dose steroid treatment. He responded to intravenous cyclophosphamide, but his IP remained unstable. After CsA treatment was started, a clinical remission was obtained. In this case, CsA was the most effective agent tried. Clinical and pathological considerations led us to speculate that activated alveolar macrophages played a crucial role in the pathogenesis of steroid-resistant IP in this patient, and that the clinical remission induced by CsA may have been due to its inhibitory effect on alveolar macrophages.

Arthritis, Rheumatoid↗
PubMed1978

Deoxyribonucleoside toxicity in adenosine deaminase and purine nucleoside phosphorylase deficiency: implications for the development of new immunosuppressive agents.

The immunodeficient state associated with adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency may result from the selective phosphorylation by thymus-derived lymphocytes of the ADA substrate deoxyadenosine and the PNP substrate deoxyguanosine, leading to the intracellular trapping of toxic deoxyribonucleoside triphosphates. Agents such as deoxycytidine might be able to favourably modify the immunodeficient state by inhibiting deoxyribonucleoside phosphorylation. Deficiencies of other nucleotide catabolic enzymes, if selectively expressed by lymphocytes, might also lead to immunodeficiency via nucleoside trapping in lymphoid tissues. Purine deoxyribonucleoside analogues, either alone or in combination with ADA inhibitors, may have value as lymphospecific antimetabolites.

Adenosine Deaminase↗
PubMed1992

Binding of phycoerythrin-conjugated interleukin-6 to in vitro-activated human peripheral blood mononuclear cells--effect of immunosuppressive agents and of a calcium channel blocker.

We studied the effect of cyclosporine A, prednisolone, and the Ca2+ channel blocker verapamil on interleukin-6 binding to mitogen-activated peripheral blood mononuclear cells, using a flow cytometric technique and phycoerythrin-conjugated IL-6. All mitogenic stimuli up-regulated IL-6 binding to a variable degree. PHA alone or in combination with PMA was the most effective stimulant in up-regulating IL-6 binding in all the experiments performed. The main changes in IL-6 binding were seen in the large cell cluster, which consisted mainly of lymphoblasts. PHA and PHA/PMA, however, also up-regulated the mean fluorescence intensity on the small cell cluster, which consisted mainly of quiescent lymphocytes. The overall effect of the three pharmacological agents on mitogen-up-regulated IL-6 binding was minimal; most significant were a down-regulation by all three agents of IL-6 binding by small lymphocytes in PHA/PMA cultures, a down-regulation of IL-6 binding by CsA in PHA/PMA-induced large PBMC, and an up-regulation by verapamil of PMA-induced IL-6 binding in large PBMC. Measurements of IL-2 binding and of IL-6 production in the same cultures showed a different pattern than that seen with IL-6 binding, as well as different CsA, prednisolone, and verapamil action. In conclusion, by using a new flow cytometric technique providing information both about the quantity of bound cytokine and about the proportion of IL-6-binding cells, we have demonstrated that IL-6 receptor expression in vitro by PBMC can be up-regulated by the use of stimulants differing in the signal transduction pathways they activate. In addition, by using different pharmacological agents and stimuli to dissect different activation pathways of the in vitro immune response, we conclude that IL-6R generation is regulated differently from IL-6 production. Furthermore, since CsA and prednisolone are known inhibitors of in vitro IL-2 production, our results indicate that IL-6R generation does not rely exclusively on the presence of IL-2.

Calcium↗
PubMed2005

Enantioselective total synthesis of (-)-candelalide A, a novel blocker of the voltage-gated potassium channel Kv1.3 for an immunosuppressive agent.

A convergent route to (-)-candelalide A involved the union of a trans-decalin portion (AB ring) and a gamma-pyrone moiety through the C16-C3' bond to assemble the whole carbon framework and subsequent formation of the dihydropyran ring (C ring) as the crucial steps. A strategic [2,3]-Wittig rearrangement was employed for establishing the stereogenic center at C9 and an exo-methylene function at C8 present in the decalin portion. [reaction: see text]

Ascomycota↗