Matches in SemOpenAlex for { <https://semopenalex.org/work/W2012373306> ?p ?o ?g. }
- W2012373306 endingPage "344" @default.
- W2012373306 startingPage "323" @default.
- W2012373306 abstract "FK 506 (Prograf) is a novel macrolide antibiotic isolated from the soil fungus Streptomyces tsukubaensis [24]. Although it is totally distinct in molecular structure from cyclosporin (CsA) (Sandimmune), a cyclic endecapeptide extracted from the fungus Tolypocladium inflatum (Fig. 1), the two drugs share a remarkably similar, selective inhibitory action on the activation and proliferation of CD4+ T helper (TH) lymphocytes [25, 41, 50, 51, 56]. These cells play an essential, central role both in antigen recognition and as the sources of soluble, hormone-like mediators (cytokines) of the cascade of events leading to the expression of immune reactivity. By inhibiting the activation of CD4+ TH cells, FK 506, like CsA, exerts a wide-range of immunosuppressive activities. It is recognized that both drugs prolong solid-organ allograft survival in experimental animals and in man. FK 506, however, is considerably more powerful as an antilymphocytic agent than CsA, as evidenced by the superior potency of the former drug in inhibiting antigen-driven T cell activation, cytokine production and lymphocyte proliferation in vitro [50]. Moreover, the systemic levels of FK 506 required to induce and maintain immune suppression are approximately 100-fold lower than are the blood levels of CsA to achieve the same effect. The immunosuppressive efficacy of CsA in man (in renal transplant recipients and patients receiving bone marrow transplants) was first reported in 1978; in 1989, the first account of the ability of FK 506 to prevent or reverse organ allograft rejection was published [44]. Data obtained over the last 3 years provide good clinical evidence that FK 506 exhibits a narrower range of side effects than does CsA and that, as compared with CsA, FK 506 has greater steroid-sparing activity [45, 46]. Whilst the potential benefits of FK 506 for the prophylaxis and reversal of organ allograft rejection (in particular liver transplant rejection) are becoming recognized, the value of the drug in the treatment of autoimmune disorders is now also beginning to be assessed. In this article (1) a rationale for the use of FK 506 in autoimmune disease, (2) a description of its molecular action and immunosuppressive activities, (3) a consideration of the biological and pharmacological properties of FK 506, (4) a review of its capacity to inhibit a wide variety of experimental autoimmune disorders, and (5) a report on the early clinical experience with FK 506 in the clinical management of a panoply of autoimmune disease seen at the University of Pittsburgh Medical Center (UPMC) will be presented. Moreover, a brief outline of laboratory investigations utilized to monitor the status of T lymphocytes in these patients and a discussion of the side effects of FK 506 will be presented. Throughout, we shall draw upon comparisons between FK 506 and CsA which have been documented in the literature.Fig. 1The molecular structure of the immunosuppressive macrolide FK 506 (mol. wt. 822 daltons) and of the less powerful, but similarly acting cyclic endecapeptide cyclosporin A (mol. wt. 1203 daltons)Rationale for the use of FK 506 in autoimmune diseasesThe role of T cells in autoimmunityThe therapeutic use of FK 506 in the treatment of autoimmune disease is based on the premise that all of these disorders are T cell driven [39]. It is, therefore, important to examine the evidence that activated CD4+ TH cells and their cytokine products are important both in the induction and maintenance of various diseases such as psoriasis, uveitis, insulin-dependent type-1 diabetes, chronic active hepatitis-autoimmune (CAH-A), rheumatoid arthritis and multiple sclerosis – diseases that are currently being treated with FK 506. In uveitis [11], type-1 diabetes [6], multiple sclerosis [16] and psoriasis [3] for example, T cells are believed to play an important pathogenic role. Much of the evidence to support this view comes from studies in experimental animal models and from in vitro investigations of the adverse or destructive interactions between T cells, antigen-stimulated cytokines and the target tissue affected by the disease process. In the autoimmune liver diseases [26], CAH-A and primary biliary cirrhosis (PBC), and in rheumatoid arthritis [9], there is abundant evidence for the involvement of T cells in the pathogenesis of each disease and, therefore, a rationale for the use of FK 506 in each exists. In recent years the therapeutic efficacy of CsA in uveitis, psoriasis, PBC, CAH-A, and rheumatoid arthritis has been demonstrated [52]. Moreover, CsA has been shown to alter the natural history of type-1 diabetes [4]. The drug has not, however, made a significant impact upon the clinical management of patients with most of these diseases.In autoimmune diseases such as systemic lupus erythematosus (SLE) or the nephrotic syndrome, the rationale for the use of CsA or FK 506 is less clear. Thus, in SLE, humoral immunity appears to be more important than cellular immunity in the pathogenesis of the disease, and in idiopathic nephrotic syndrome the pathogenic mechanisms responsible for the disease process are far from clear. Nevertheless, in nephrotic syndrome, T cell dysfunction, recruitment of B cells, immunoglobulin deposition within the kidney and a central role for lymphokines have been implicated by various authors [7, 8, 18, 54]. Moreover, CsA has been shown to be very effective in the steroid-sensitive nephrotic syndrome, although less so in steroid-resistant patients [52].A spectrum of autoimmune disorders is shown in Table 1. The predicted efficacy of FK 506 in their treatment is based on the assumption that the role of T cells in these various disease processes is central, and also on experience in animal models of these diseases with either CsA or FK 506. Account is also taken of clinical experience with CsA in these autoimmune disorders.Table 1Possible mechanisms of autoimmune diseases and predicted responses to FK 506aEvidence that autoimmune diseases are T cell drivenThere is a large body of additional experimental data which provides supportive evidence to the thesis that autoimmune diseases are driven by T cells and their cytokine products. In addition to the proven efficacy of CsA or FK 506 in many experimental autoimmune diseases, antibodies directed against CD4+ T cells or against the interleukin 2 receptor (IL-2R; expressed on activated T cells) have been shown to be effective therapeutic agents in these animal models. When stimulated with appropriate antigen or monoclonal antibody, T cell clones derived from lesional tissue or peripheral blood secrete cytokines which effect the pathological changes observed in target tissue (e.g., fibroblasts in scleroderma, keratinocytes in psoriasis or islet cells in type-1 diabetes) that are relevant to the disease process observed in vivo. Such antigen-stimulated T cell clones can induce disease when transferred to healthy recipients (e.g., induction of type-1 diabetes, experimental arthritis or allergic encephalomyelitis). Furthermore, in many experimental models of autoimmunity, it can be shown that neonatal thymectomy has a pronounced beneficial effect in preventing development of the disease. For references and discussion see [40]." @default.
- W2012373306 created "2016-06-24" @default.
- W2012373306 creator A5032714638 @default.
- W2012373306 creator A5051557421 @default.
- W2012373306 creator A5059279421 @default.
- W2012373306 creator A5069651723 @default.
- W2012373306 creator A5076663918 @default.
- W2012373306 creator A5081289232 @default.
- W2012373306 creator A5084646949 @default.
- W2012373306 date "1993-04-01" @default.
- W2012373306 modified "2023-10-15" @default.
- W2012373306 title "FK 506: a novel immunosuppressant for treatment of autoimmune disease" @default.
- W2012373306 cites W1539977736 @default.
- W2012373306 cites W1562075782 @default.
- W2012373306 cites W1764917507 @default.
- W2012373306 cites W1969971113 @default.
- W2012373306 cites W1973356939 @default.
- W2012373306 cites W1984754431 @default.
- W2012373306 cites W1986603297 @default.
- W2012373306 cites W1999144966 @default.
- W2012373306 cites W2006069908 @default.
- W2012373306 cites W2007179975 @default.
- W2012373306 cites W2011470431 @default.
- W2012373306 cites W2015352911 @default.
- W2012373306 cites W2015865068 @default.
- W2012373306 cites W2023954622 @default.
- W2012373306 cites W2036516959 @default.
- W2012373306 cites W2039382979 @default.
- W2012373306 cites W2046436286 @default.
- W2012373306 cites W2050150248 @default.
- W2012373306 cites W2053132428 @default.
- W2012373306 cites W2061839289 @default.
- W2012373306 cites W2061999399 @default.
- W2012373306 cites W2065829328 @default.
- W2012373306 cites W2067504164 @default.
- W2012373306 cites W2070048147 @default.
- W2012373306 cites W2094633801 @default.
- W2012373306 cites W2106050461 @default.
- W2012373306 cites W2108794906 @default.
- W2012373306 cites W2114344760 @default.
- W2012373306 cites W2143390223 @default.
- W2012373306 cites W2156013790 @default.
- W2012373306 cites W2160885872 @default.
- W2012373306 cites W2167839140 @default.
- W2012373306 cites W2172466148 @default.
- W2012373306 cites W2174528613 @default.
- W2012373306 cites W2244502954 @default.
- W2012373306 cites W2252322225 @default.
- W2012373306 cites W2329573625 @default.
- W2012373306 cites W2406464018 @default.
- W2012373306 cites W2416945773 @default.
- W2012373306 cites W2419638541 @default.
- W2012373306 cites W2428394660 @default.
- W2012373306 cites W2460087702 @default.
- W2012373306 cites W2782175582 @default.
- W2012373306 cites W42278022 @default.
- W2012373306 cites W4234658163 @default.
- W2012373306 cites W4239469316 @default.
- W2012373306 cites W4301165149 @default.
- W2012373306 cites W70254986 @default.
- W2012373306 cites W826302580 @default.
- W2012373306 cites W83520551 @default.
- W2012373306 doi "https://doi.org/10.1007/bf00192307" @default.
- W2012373306 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2966151" @default.
- W2012373306 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/7686690" @default.
- W2012373306 hasPublicationYear "1993" @default.
- W2012373306 type Work @default.
- W2012373306 sameAs 2012373306 @default.
- W2012373306 citedByCount "58" @default.
- W2012373306 countsByYear W20123733062013 @default.
- W2012373306 countsByYear W20123733062014 @default.
- W2012373306 countsByYear W20123733062015 @default.
- W2012373306 countsByYear W20123733062016 @default.
- W2012373306 countsByYear W20123733062017 @default.
- W2012373306 countsByYear W20123733062018 @default.
- W2012373306 countsByYear W20123733062019 @default.
- W2012373306 countsByYear W20123733062021 @default.
- W2012373306 countsByYear W20123733062023 @default.
- W2012373306 crossrefType "journal-article" @default.
- W2012373306 hasAuthorship W2012373306A5032714638 @default.
- W2012373306 hasAuthorship W2012373306A5051557421 @default.
- W2012373306 hasAuthorship W2012373306A5059279421 @default.
- W2012373306 hasAuthorship W2012373306A5069651723 @default.
- W2012373306 hasAuthorship W2012373306A5076663918 @default.
- W2012373306 hasAuthorship W2012373306A5081289232 @default.
- W2012373306 hasAuthorship W2012373306A5084646949 @default.
- W2012373306 hasBestOaLocation W20123733062 @default.
- W2012373306 hasConcept C142724271 @default.
- W2012373306 hasConcept C159654299 @default.
- W2012373306 hasConcept C203014093 @default.
- W2012373306 hasConcept C2779075594 @default.
- W2012373306 hasConcept C2779134260 @default.
- W2012373306 hasConcept C2780130043 @default.
- W2012373306 hasConcept C2780648854 @default.
- W2012373306 hasConcept C71924100 @default.
- W2012373306 hasConcept C8891405 @default.
- W2012373306 hasConceptScore W2012373306C142724271 @default.
- W2012373306 hasConceptScore W2012373306C159654299 @default.