Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

https://science.sciencemag.org/content/sci/226/4674/544.full.pdf

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

The cyclosporins were originally discovered in 1970 by workers at Sandoz Ltd. in Switzerland who were attempting to identify new antifungal agents ( 1). The crude extracts of two new strains of fungi imperfecti, Cylindrocapon lucidum Booth and Tolypocladium inflatum Gams, demonstrated a narrow spectrum of activity in vitro and only marginal fungistatic activity in vivo mainly against clinically irrelevant organisms. However, the antifungal activity was accompanied by an unusually low degree of toxicity, which prompted the investigators at Sandoz to submit the compound to a limited pharmacological screening program. In 1972, Borel discovered that the fungal extract was capable of markedly inhibiting hemagglutinin formation against sheep erythrocytes in vivo but appeared to be selective in its immunosuppressive effects because it had no effect on the survival of mice that had been inoculated with the L1210 leukemia line. This observation formed the basis for a series of extensive studies of the effects of cyclosporin (CY A) on the immune system. In 1973, cyclosporin A was purified from the fungal extract, and in 1975 complete structural analysis was performed (2). CY A was successfully synthesized in 1980. CY A (Mr 1203) is a neutral, hydrophobic, cyclic peptide composed of 11 amino acid residues all having the S-configuration of the natural L-amino acids with the sole exception of the D-alanine in position eight, which has the R-configuration. Ten of the amino acids are known aliphatic amino acids while one of the amino acids had never

The Effects of Cyclosporin A on the Immune System

https://www.gastrojournal.org/article/0016-5085(86)90205-2/pdf

Phenotypic analysis of lamina propria lymphocytes. Predominance of helper-inducer and cytolytic T-cell phenotypes and deficiency of suppressor-inducer phenotypes in Crohn's disease and control patients.

Phenotypic analysis of lamina propria lymphocytes

Reading is a hobby to open the knowledge windows. Besides, it can provide the inspiration and spirit to face this life. By this way, concomitant with the technology development, many companies serve the e-book or book in soft file. The system of this book of course will be much easier. No worry to forget bringing the human hybridomas and monoclonal antibodies book. You can open the device and get the book by on-line.

Human hybridomas and monoclonal antibodies

To probe the mechanism of suppressor T cell generation in man, we have carried out mixed leukocyte reactions (MLR) in the presence of cyclosporin (CsA), a fungal metabolite which prevents the generation of cytotoxic lymphocytes while permitting activation of suppressor cells. After a 12-d MLR in the presence of 1 microgram/ml CsA, T cells were fractionated into subsets with monoclonal antibodies, and each subset was tested for the ability to inhibit a second fresh MLR that is devoid of CsA. The results show that Leu 2+ T cells derived from the first culture suppress the second MLR in an HLA-DR antigen-specific manner and in the absence of detectable lysis of stimulator cells. However, Leu 2+ cells do not develop into suppressor cells unless acted upon by alloantigen-primed Leu 3+ inducer cells. Furthermore, only those Leu 3+ cells that also express the Leu 8 marker (Leu 3+, 8+) are capable of inducing suppressor cells. Thus, antigen-specific feedback inhibition of an immune response in man results from an ordered series of interactions between T cells of distinct phenotype.

/pdf/activation-of-antigen-specific-suppressor-t-cells-in-the-1n9vsfkkh3.pdf

Activation of antigen-specific suppressor T cells in the presence of cyclosporin requires interactions between T cells of inducer and suppressor lineage.

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Activation of antigen-specific suppressor T cells in the presence of cyclosporin requires interactions between T cells of inducer and suppressor lineage.