As immunosuppressants

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC q values are approximately 100-fold lower. This neutral macroHde suppresses the mixed lymphocyte reaction T-ceU proliferation generation of cytotoxic T-ceUs production of T-ceU derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). StmcturaHy, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspergualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the deterrnination of their utiUty as immunosuppressive agents. 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

The ghicocorticoids are used as replacement therapy for adrenocortical insufficiency, to treat allergic reactions, collagen diseases (eg, systemic lupus erythematosus), dermatologic conditions, rheumatic disorders, shock, and other conditions (see Display 50-1). The anti-inflammatory activity of these hormones make them valuable as anti-inflammatories and as immunosuppressants to suppress inflammation and modify the immune response... 

Interleukin-2-inducible T cell kinase (ITK) is expressed mainly in T-lymphocytes and plays a major role in the activation of T-cells. Thus inhibitors of ITK should be useful as immunosuppressives and antiinflammatory agents. Snow et al. [67] describe a novel series of 2-aminobenzimidazole ITK inhibitors which is optimized... 

Posttransplant diabetes Insulin Oral hypoglycemics Risk factors obesity, family history, African-American race, cadaveric kidney, TAC greater than CSA May resolve/improve as immunosuppressive doses decrease... 

Basketter, D.A. et al., Pathology considerations for, and subsequent risk assessment of, chemicals identified as immunosuppressive in routine toxicology, Food Chem, Toxicol., 33, 239,1995. 

GC regulate a wide variety of immune cell functions. GC modulate cytokine expression, adhesion molecule expression and immune cell trafficking, immune cell maturation and differentiation, expression of chemoattractants and cell migration, and production of inflammatory mediators and other inflammatory molecules [35], At pharmacological concentrations, GC are routinely used as immunosuppressive therapeutic agents in many acute and chronic inflammatory and autoimmune diseases, in transplant patients and in the treatment of leukemias and lymphomas [reviewed in 29].. 

Microbial natural product chemistiy has generated a number of bioactive natural products. For instance cyclosporine A FK506 and rapamycin are used as immunosuppressants [16]. Other examples of microbial metabolites, having potential biomedical application include antihyperlipidemics, lovastatin and guggulsterone [17, 18]. The crude extracts of Mucor plumbeus exhibited acetylcholinesterase (AChE) enzyme inhibition activity. Our detailed chromatographic work on this crude extract resulted in the isolation of mucoralactone A (11), a novel steroid containing a lactone moeity incorporated in its structure. 

Cytotoxic agents Since proliferation of cells is essential for the immune response, agents that inhibit DNA synthesis have been used as immunosuppressive agents for many years. The first were used in the 1960s, particularly to prevent rejection of a transplanted organ, for example purine and pyrimidine analogues. These agents are not now used in autoimmune diseases but are stiU used in cancer chemotherapy (Chapter 21). 

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

Lung transplantation-bronchial anastomotic dehiscence Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended. 

It is a purine antimetabolite which has marked effect on T-lymphocytes, suppresses cell mediated immunity (CMI). It selectively affects differentiation and functions of T cells and inhibits cytolytic lymphocytes. It is used primarily as immunosuppressant in organ transplantation, progressive rheumatoid arthritis and some other autoimmune diseases. 

The health risks associated with ozone depletion will principally be those due to increased ultraviolet-B (UV-B) radiation in the environment, that is, increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). However, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. 

MABs Used as Immunosuppressants and Anti-Inflammatory Agents... 

Many macrolides of marine origin have been reported to show other interesting biological properties, such as immunosuppressive [473,474], antifungal [323,475,476], anti-actin [477], and anti-inflammatory activity... 

The initial organ transplantation was performed in 1933 when a kidney was transplanted from a cadaver. Total lymphoid irradiation was used for the immune suppression but the tissue was rejected and the patient eventually died. This was followed by the use of corticosteroids as immunosuppressive agents, but unfortunately steroids by themselves also did not produce positive results. In the early 1960s, cytotoxic agents were introduced for immune suppression these were followed by the use of a combination of cytotoxic agents and corticosteroids until the mid-1980s when cyclosporine was discovered by Borel. 

The monoclonal antibodies used as immunosuppressive agents in tissue transplantation include muromonoab-CD3, daclizumab and basiliximab. Muromonoab-CD3 binds to a specific site on CD3 receptors and interferes with the ability of the TCR to bind the antigen and also inhibits CD3 receptor-dependent signal transduction mechanisms, all of which result in immune suppression. Both daclizumab and basiliximab are monoclonal antibodies directed against IL-2 receptors and consequently inhibit IL-2-dependent responses after tissue transplantation, resulting in immune suppression. The monoclonal antibodies used as immunosuppressive agents are described in detail in Chapter 5. 

Glucocorticoids commonly used as immunosuppressants include the following ... 

Experimental studies in laboratory rodents have demonstrated that a diverse array of chemical exposures suppress immune function (Table 19.2). In addition a limited number of clinical and epidemiologic studies have reported suppression of immune function and/or increased frequency of infectious and/or neoplastic disease following exposure of humans to some of these agents. From the description above it is clear there are a number of cellular and molecular targets for chemicals that act as immunosuppressants. Clearly, a chemical that disrupts cell proliferation would affect clonal expansion. Disruption of T cell maturation in the thymus is another potential mechanism for immune suppression. Chemicals may also interfere with receptor ligand binding at the cell... 

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