Hydrophobic Immunosuppression

Cyclosporins, produced by the filamentous fungus Tolypocladium niveum and by numerous strains of Fusaria and Neocosmospora, are a class of cyclic undecapep-tides which are composed of hydrophobic aliphatic amino acids [73-75], They exhibit antiinflammatory, immunosuppressive, antifungal, and antiparasitic properties [74], The main metabolite, cyclosporin A, is in clinical use worldwide under the trade name SANDIMMUN to prevent allograft rejection [77,78], Besides cyclosporin A, there are 24 naturally occuring cyclosporins which have substitutions of amino acids in positions 1, 2, 4, 5, 7, and 11 and/or contain unmethylated peptide bonds in positions 1,4,6,9,10, or 11 [79-82], Cyclosporin A contains three nonproteinogenic amino acids D-alanine in position 8, L-a-aminobutyric acid in position 2, and, in position 1, the unusual amino acid 4(R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt) (Fig. 8). All three amino acids have to be synthesized by a pathway independent of the primary metabolism. In addition, several peptide bonds of the cyclosporin molecule are A -mcthylated similar to the depsipeptides enniatin, beauvericin and PF1022A-related peptides. 

Functioning as detergents, hydrophobic (Hpophiiic) bile acids (cholic add, chenodeoxycholic add, deoxychohc add, hthochohc acid) exert toxic efifects on the biomembranes of liver cells and mitochondria. At the same time, these bile acids display an immunosuppressive elfect and influence the humoral and cell-mediated defence (e.g. inhibition of monocytes). As in the case of PBC, hydrophobic bile acids also induce an excessive expression of MHC-I and MHC-II molecules from hepatocytes and bihary cells. 

Cyclosporins, produced as secondary metabolites by various fungi imperfecti and a few ascomycetes, represent a class of neutral cyclic peptides that are composed of 11 aliphatic hydrophobic amino acids. Cyclosporins exert remarkable biological effects such as antb fungal, antiparasitic, anti infammatory, and immunosuppressive activities (1). 

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