Immunosuppression

Immunotoxicological impacts include molecular and structural effects in immune tissues and organs, cellular pathology, reductions in immune cell numbers, retarded maturation of immune system cells, and altered immune system antibody production. These adverse effects are manifest by two types of reaction immunosuppression and immunostimulation. 

In immunosuppression, one or more parts of the immune system are impacted. This results in impaired immune system function and reduced resistance to foreign chemical and biological agents that attack the body and can lead to increased incidence of infectious disease and cancer. 

Carbon tetrachloride Trans-l,2-dichlorothylene 1,2-dichloroethane Methylene chloride Carbon tetrachloride Trichloroethane Tetrachloroethane 2-Methoxyethanol Ethyl acrylate Benzidines 

8-Tetrachlorodibenzo-p-dioxin (TCDD) Polychlorinated biphenyls (PCBs) 

4-Dichlorophenoxyacetic acid (2,4D) 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) Asbestos Silica 

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Miller an d Rich assumed th at cyclosporin A an d its MeHrn t an alogs share a common hioactive con formation. fheir molecular mech an ics calculation s found such a conformation, fh e Boltzmann population of th e proposed hioactive conformation correlates with the immunosuppressive activities of the compounds. 

Ecample Miller and Rich investigated the conformational consequences of substitutions on an amino acid in cyclosporin A, an important immunosuppressive drug. One of the amino acids in this cyclic undecapeptide is (2, 3r, 4r, 6e)-3-Hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (MeBmt). It is essential for biological activity. 

The researchers investigated three MeBmt analogs the C-4 epimer ((45)-MeBmt), the C-4 des methyl analog (MeBth), and the C-4 dimethyl (MeBm2t) analog. The immunosuppressive activity of the analogs follows the order MeBmt > MeBm2t > MeBth > (4 )-MeBmt. 

Secondary immunodeficiencies (9) are much more common than primary ones and frequently occur as a result of immaturity of the immune system in premature infants, immunosuppressive therapy, or surgery and trauma. Illnesses, particularly when prolonged and serious, have been associated with secondary immunodeficiencies, some of which may be reversible. Acquked immune deficiency syndrome (AIDS) (10—12) may be considered a secondary immunodeficiency disease caused by the human immunodeficiency vimses HIV-1 or HIV-2. Hitherto unknown, the disease began to spread in the United States during the latter part of the 1970s. The agent responsible for this infection has been isolated and identified as a retrovims. 

A new generation of antiinflammatory agents having immunosuppressive activity has been developed. The appearance of preclinical and clinical reports suggest that these are near entry to the pharmaceutical market. For example, tenidap (CP-66,248) (12) has been demonstrated to inhibit IL-1 production from human peripheral blood monocytes in culture (55). Clinically, IL-1 in synovial fluids of arthritic patients was reduced following treatment with tenidap. Patients with rheumatoid or osteoarthritis, when treated with tenidap, showed clinical improvement (57,58). In addition to its immunological effects, tenidap also has an antiinflammatory profile similar to the classical NSAIDs (59). Other synthetic inhibitors of IL-1 production are SKF 86002 (20) andE-5110 (21) (55). 

Another natural product, mizoribiae (39), a nucleoside antibiotic produced by the fungus Eupenicillium brefeldianum has cytotoxic and immunosuppressive activity. It has been evaluated for use ia renal transplantation and neoplasia (68). 

Although there is no rehable method as of this writing for induction of Ag-speciftc unresponsiveness, some degree of tolerance has been observed by use of nonspecific immunosuppressive therapy. This conclusion is supported by a decrease in the frequency of precursor T-ceUs reactive with graft HLA Ags in long-term recipients of organ transplants. 

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

A number of fungal immunosuppressives have been isolated from fermentation broths and demonstrated to have immunotherapeutic efficacy. Other than cyclosporin (35), two fungal metaboHtes, sirolimus (36), previously known as rapamycin (80), and FK-506 (37) (81) are in various stages of development (see Antibiotics, macrolides). 

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

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. 

Opiates are useful analgesics because they reduce pain sensation without blocking feeling or other sensations. However, they also affect mood, iaduce euphoria, reduce mental acuity, and iaduce physical dependence. They can be immunosuppressive and dismpt other homeostatic processes through... 

Chemical conversion of compounds to intermediates of known absolute configuration is a method routinely used to determine absolute configuration (86). This is necessary because x-ray analysis is not always possible suitable crystals are required and deterrnination of the absolute configuration of many crystalline molecules caimot be done because of poor resolution. Such poor resolution is usually a function of either molecular instability or the complex nature of the molecule. For example, the relative configuration of the macroHde immunosuppressant FK-506 (105) (Fig. 8), which contains 14 stereocenters, was determined by x-ray crystallographic studies. However, the absolute configuration could only be elucidated by chemical degradation and isolation of L-pipecoUc acid (110) (80). 

Cardiomyoplasty could gready reduce the overwhelming need for heart transplants. It might also eliminate the need for immunosuppressive dmgs. 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

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