Antilymphocyte serum (ALS) as an immunosuppressive agent in transplantation of the canine larynx. I. Preparation of antilymphocyte serum.
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Animals↗
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Preclinical evaluation of a new potent immunosuppressive agent, rapamycin.
Since individual immunosuppressive agents display pleiotropic arrays of nonimmunologic toxic complications when used at therapeutic concentrations, synergistic drug combinations proffer an attractive strategy. RAPA is a good candidate for this enterprise, because of its unique action to inhibit lymphokine signal transduction. Initial in vivo and in vitro studies using the rigorous pharmacologic tool, the median effect analysis, document a synergistic relation between RAPA and CsA in rodent and canine models. These preclinical findings compel careful Phase I trials, in order to assess the safety and synergistic efficacy of RAPA in combination drug regimens with other immunosuppressive agents.
Animals↗
Magnetic resonance imaging in cases with encephalopathy secondary to immunosuppressive agents.
The neurotoxic effects of immunosuppressive agents used after transplantation are well known. In most cases a decrease in drug dosage results in resolution of the neurotoxicity. At early stages in the post-transplantation clinical course, neurotoxicity and other complications such as infectious disease, encephalopathy and seizures are sometimes difficult to diagnose with neuroimaging. Recently, diffusion weighted imaging (DWI) has been used in patients with ischemic disease, mitochondrial myopathy, encephalopathy and demyelinating disease. We examined the magnetic resonance images (MRI), including DWI and fluid attenuated inversion recovery image (FLAIR), in three cases of post-transplantation neurological complication: two cases of neurotoxicity and a case of acute disseminated encephalomyelitis (ADEM). Hyper-intense lesions representing neurotoxicity were seen on FLAIR but not on DWI in two cases with neurotoxicity induced by an immunosuppressive agent. In ADEM, hyper-intense lesions were seen on both FLAIR and DWI. Neurotoxicity due to the immunosuppressive agent showed a favorable outcome, although the hyper-intense lesions temporally presented on FLAIR. In the state after transplantation, hyper-intense lesions on FLAIR and DWI represented in the brain from the initial stage, we might be care of other severe complications but for neurotoxicity.
Adolescent↗
Immunosuppressive agents in chronic severe asthma.
Previous immunosuppressive agents utilized as therapies for immune system mediated diseases such as chronic allergic asthma, and rheumatoid arthritis include purine antagonists, methotrexate, and gold salts. These treatment modalities have been shown to elicit either limited treatment efficacy or to produce undesirable side effects in many individuals. Cyclosporin A is a potent immunosuppressive agent which appears to arrest division of T lymphocytes and inhibit mediator release from mast cells. However, like other immunosuppressive agents, cyclosporin A may also produce many potentially serious side effects; among these is the possibility of irreversible renal damage. Nephrotoxicity can be attenuated, because renal pathological changes seem to be high cumulative dose-related. If whole blood levels of cyclosporin A are maintained between 200 and 500 ng/mL, serious renal toxicity is unusual. Investigation of cyclosporin A in individuals who have severe long-term corticosteroid-dependent chronic asthma has demonstrated the efficacy of this agent, resulting in clinically significant improvement in pulmonary function. Therefore, it can be hypothesized that T lymphocytes may act as effector cells in cell-mediated hypersensitivity reactions in atopic allergic inflammation.
Asthma↗
Hepatotoxicity of transplant immunosuppressive agents.
Hepatotoxicity from transplant immunosuppressive agents is infrequent but recognized. Most of the published literature emphasizes hepatotoxicity from cyclosporine and azathioprine. Cyclosporine is associated with cholestasis and possibly biliary calculi. Azathioprine has been associated with a variety of hepatic abnormalities. This article reviews the frequency and pattern of hepatotoxicity associated with these agents.
Humans↗
[Immunosuppressive agents in Horton's disease. Which drug for which indication?].
Corticosteroids remain the cornerstone treatment of giant cell arteritis. Steroid-related toxicity and needs for alternative therapeutic regimens in patients experiencing recurrent active or steroid-resistant diseases, are the main reasons for searching a steroid-sparing agent. Regarding disease pathogenesis, immunosuppressive agents might be useful drugs. Methotrexate is the most widely studied agent in this indication. However, available data are incomplete and studies have included only polymyalgia rheumatica or both polymyalgia rheumatica and giant cell arteritis affected patients. Results of these studies evoke the possibility of using methotrexate in steroid-dependent or resistant diseases, as well as a steroid-sparing agent in order to taper off and stop steroids quickly; with an acceptable toxicity. Azathioprine may be used to control steroid-dependant or resistant diseases, but toxicity appears to be higher. An open prospective study compared azathioprine and methotrexate and concluded to the superiority of methotrexate. Available data concerning cyclophosphamide and cyclosporine A are too incomplete. A satisfactory steroid-sparing agent in giant cell arteritis is still unknown. Currently, methotrexate, and probably azathioprine, appear to be the most useful agents in this indication. However, there is no demonstration that using an immunosuppressive agent in giant cell arteritis could reduce steroid-related morbidity.
Anti-Inflammatory Agents↗
Synthesis, stereochemical determination and biochemical characterization of the enantiomeric phosphate esters of the novel immunosuppressive agent FTY720.
The novel immunosuppressive agent FTY720 (1) is phosphorylated in vivo in a variety of species yielding an active metabolite that is an agonist of four of the five known G-protein-coupled sphingosine-1-phosphate (S1P) receptors. A synthesis amenable to producing gram quantities of the stereoisomeric phosphate esters, a determination of their absolute stereochemistry via an enantioselective synthesis and their characterization as S1P receptor agonists and antagonists is reported.
Animals↗
Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation.
OBJECT: Immunosuppressive agents are believed to play a role in recovery from spinal cord injury, but the underlying mechanisms by which neuronal function is improved by these agents are poorly understood. In this study, the authors evaluate the effect of immunosuppressive medications on neurite outgrowth and cell survival after a pharmacologically induced injury. METHODS: Differentiated human neuroblastoma SH-SY5Y cells were injured using the calcium agonist thapsigargin. After cellular injury, neurite outgrowth in the presence or absence of immunosuppressive agents was measured. Apoptosis was quantified with the aid of a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Neurite outgrowth was severely restricted following thapsigargin injury. Outgrowth was potentiated, however, by the addition of concentrations of 1 and 10 mM cyclosporin A in a dose-dependent fashion. Similarly, addition of 10 nM FK506 increased the percentage of neurites in the 20- to 40-micron range. A low dose (1 mM) of dexamethasone did not have a significant effect on neurite outgrowth, but a higher dose (10 mM) increased the percentage of neurites in the 10- to 45-micron range. These agents also lessened the degree of thapsigargin-induced apoptosis. CONCLUSIONS: Immunosuppressive agents such as cyclosporin A, FK506, and dexamethasone can potentiate neurite outgrowth and protect against apoptotic cell death in a human postmitotic neuronal cell line. Such effects may have implications for lessening neuronal injury after neurotrauma, stroke, or neurodegeneration.
Apoptosis↗
Novel immunosuppressive agent, FK506. In vitro effects on the cloned T cell activation.
The present study shows the in vitro effects of a novel immunosuppressive agent, FK506, in comparison with cyclosporin A (CsA). FK506 inhibited concanavalin A response and allo-mixed lymphocyte reaction of murine splenic lymphocytes in a dose-dependent manner, and at 40- to 200-fold lower concentrations than CsA. Allo-cytolytic T lymphocyte induction from murine thymocytes was also inhibited by FK506, whereas the ability of cytolytic T lymphocyte to lyse targets was not affected by the agent. Immunosuppressive effects of FK506 were further characterized by using antigen specific-proliferative T lymphocyte clones, BC.21 and KO.6. FK506 inhibited the proliferation of T cell clones stimulated with specific antigens in a dose-dependent manner, and at about 100-fold lower concentrations than CsA. However, cloned T cells, once activated, were scarcely affected by the agent; interleukin-2 (IL-2) driven proliferation of cloned T cells was not inhibited. On the other hand, it was found that FK506 inhibited both IL-2 secretion and IL-2 receptor expression of BC.21 after stimulation with the specific antigen. FK506 also inhibited the proliferation of BC.21 stimulated with phorbol 12-myristate 13-acetate plus calcium ionophore, indicating that it directly affected the signaling pathway downward from the perturbation of the Ti/T3 complex. Finally, it was suggested that FK506 and CsA synergistically inhibited the antigen-driven proliferation of cloned T cells. These results indicate that the novel immunosuppressive agent, FK506, affects T cell activation with mechanisms similar to those of CsA but at considerably lower concentrations.
Animals↗
Use of immunosuppressive agents in uveitis.
PURPOSE OF REVIEW: This review summarizes current patterns in the use of immunosuppressive agents in patients with uveitis. RECENT FINDINGS: A number of immunosuppressive agents are currently available for the treatment of uveitis. Reports of safety and efficacy, although numerous, have been largely nonrandomized and performed without controls, limiting, to some extent, the strength and generalizability of their conclusions. Nonetheless, the volume of case reports and case series provides compelling evidence that immunosuppressive agents are effective at providing long-term control in patients with moderate to severe chronic or recurrent uveitis. The choice of immunosuppressive agent is complex, and depends on the cause and severity of the patient's underlying inflammation, the presence or absence of associated systemic inflammation, and the patient's prior response to immunosuppressive treatments. SUMMARY: Although corticosteroids remain the primary initial treatment for patients with uveitis, use of noncorticosteroid immunosuppressive agents in selected patients with uveitis allows for improved control and decreased risk of corticosteroid-induced side effects.
Anti-Inflammatory Agents, Non-Steroidal↗
Effect of immunosuppressive agents on glucocorticoid receptor function in A6 cells.
Immunosuppressive agents such as FK-506 and rapamycin inhibit aldosterone- stimulated Na+ transport in A6 cells. Concentration dependence is consistent with the known affinities of these agents for immunophilins. The inhibition was also dependent on time, requiring preincubation with FK-506 or rapamycin before inhibition was seen. The present studies were designed to determine whether this inhibition was pretranscriptional and whether it was due to an effect on either receptor translocation or nuclear accumulation. Because transport effects of steroids in A6 cells are mediated by glucocorticoid receptors (GRs), we examined the transcriptional response of GR-regulated reporters transfected into these cells. Preincubation of cells with FK-506 and rapamycin completely blocked reporter gene activation, whereas preincubation with cyclosporin A partially inhibited this activation. A minimum of 8 h of preincubation was required before the effect was seen. Using a transiently transfected green fluorescent protein-GR construct, we examined the effect of FK-506 and rapamycin on GR translocation. GR translocation induced by dexamethasone was extremely rapid (<5 min) and was largely unaffected by FK-506 or rapamycin but was completely blocked by geldanamycin. Digital deconvolutions revealed a punctate nuclear accumulation of GR, which was still seen after preincubation with immunosuppressive agents. These agents clearly inhibit steroid action by blocking GR-stimulated gene transcription, but this effect is not mediated by altered translocation or nuclear accumulation of receptors. Inhibition of steroid-regulated gene transcription by immunosuppressive agents may explain the electrolyte abnormalities seen in patients receiving these drugs.
Active Transport, Cell Nucleus↗
Cyclolinopeptide: a novel immunosuppressive agent with potential anti-lipemic activity.
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B-Lymphocytes↗
Pharmacology of rapamycin: a new immunosuppressive agent.
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Animals↗
Modification of serum properdin system by different drugs. 1. Antibiotics, chemotherapeutics, antidiabetics, hypnotics, immunosuppressive agents and thyroid antagonists.
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Animals↗
Potentiation of mitogenesis in adult rat chromaffin cell cultures by immunosuppressive agent FK506.
The immunosuppressive drugs FK506 and cyclosporin inhibit T- and B-lymphocyte proliferation and exert neuritogenic and/or cytoprotective effects on several types of neurons. While the immunosuppressive actions of both drugs are mediated in large part by inhibition of the Ca(2+)-dependent phosphatase, calcineurin, FK506 is known to exert additional effects. In the present study, FK506 is shown to potentiate mitogenic effects of the neurotrophic factor, neurturin, on normal adult rat adrenal chromaffin cells in culture. The effect is not seen with cyclosporin or with a non-immunosuppressive analog of FK506, GPI-1046. The finding of increased mitogenesis in response to FK506 may have applications to the study of normal and neoplastic neuroendocrine cells and to understanding the development of some types of tumors in transplant patients.
Adjuvants, Immunologic↗
Dermatologic therapy with immunosuppressive agents.
The use of powerful immunosuppressive agents such as methotrexate, cyclophosphamide, and azathioprine in the treatment of serious skin diseases is a relatively recent development whose efficacy is borne out in many studies. Using an immunosuppressant often makes possible an appreciable reduction in dosage of steroid necessary to control disease and, in turn, a reduction in incidence of serious side effects of protracted steroid therapy.
Dermatomyositis↗
Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide.
Leflunomide, a novel immunosuppressive drug, is able to prevent and reverse allograft and xenograft rejection in rodents, dogs, and monkeys. It is also effective in the treatment of several rodent models of arthritis and autoimmune disease. In vitro studies indicate that leflunomide is capable of inhibiting anti-CD3- and interleukin-2 (IL-2)-stimulated T cell proliferation. However, the biochemical mechanism for the inhibitory activity of leflunomide has not been elucidated. In this study, we characterized the inhibitory effects of leflunomide on Src family (p56lck and p59fyn)-mediated protein tyrosine phosphorylation. Leflunomide was able to inhibit p59fyn and p56lck activity in in vitro tyrosine kinase assays. The IC50 values for p59fyn (immunoprecipitated from either Jurkat or CTLL-4 cell lysate) autophosphorylation and phosphorylation of the exogenous substrate, histone 2B, were 125-175 and 22-40 microM respectively, while the IC50 values for p56lck (immunoprecipitated from Jurkat cell lysates) autophosphorylation and phosphorylation of histone 2B were 160 and 65 microM respectively. We also demonstrated the ability of leflunomide to inhibit protein tyrosine phosphorylation induced by anti-CD3 monoclonal antibody in Jurkat cells. The IC50 values for total intracellular tyrosine phosphorylation ranged from 5 to 45 microM, with the IC50 values for the zeta chain and phospholipase C isoform gamma 1 being 35 and 44 microM respectively. Leflunomide also inhibited Ca2+ mobilization in Jurkat cells stimulated by anti-CD3 antibody but not in those stimulated by ionomycin. Distal events of anti-CD3 monoclonal antibody stimulation, namely, IL-2 production and IL-2 receptor expression on human T lymphocytes, were also inhibited by leflunomide. Finally, tyrosine phosphorylation in CTLL-4 cells stimulated by IL-2 was also inhibited by leflunomide. These data collectively demonstrate the ability of leflunomide to inhibit tyrosine kinase activity in vitro, and suggest that inhibition of tyrosine phosphorylation events may be the mechanism by which leflunomide functions as an immunosuppressive agent.
Animals↗
Mycophenolate mofetil: a promising immunosuppressive agent.
With avaibility of newer immunosuppressive agents, incidence of acute graft rejection has decreased. Mycophenolate mofetil is one such new drug, now available in the Indian market It has been found to be useful in prevention and treatment of acute and chronic rejection after transplantation. Besides transplant it has been used successfully in primary and secondary glomerulopathies (e.g. SLE) and other autoimmune diseases. The drug is well tolerated with side effects limited mainly to gastrointestinal system in the form of epigastric pain, vomiting and diarrhoea.
Aged↗