https://www.cell.com/trends/immunology/pdf/0167-5699(92)90111-J.pdf

The mechanism of action of cyclosporin A and FK506

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

Suppression of allograft rejection is central to successful organ transplantation; thus, immunosuppressive agents are crucial for successful allograft function. Immunosuppressive drugs are used for induction (intense immunosuppression in the initial days after transplantation), maintenance, and reversal of established rejection. This review considers the use of immunosuppressive drugs in organ transplantation, focusing on renal transplantation.

https://www.nejm.org/doi/pdf/10.1056/NEJMra033540

Immunosuppressive Drugs for Kidney Transplantation

Mycophenolate mofetil and its mechanisms of action.

The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.

Platforms for antibiotic discovery

The fungus metabolite cyclosporin A is a small peptide acting as a novel antilymphocytic agent. It strongly depressed appearance of both direct and indirect plaque-forming cells and produced a clear dose-dependent inhibition of haemagglutinin formation in mice upon oral administration. Skin graft rejection in mice and graft-versus-host disease in mice and rats were considerably delayed by cyclosporin A which also prevented the occurrence of paralysis in rats with experimental allergic encephalomyelitis. This compound was not only highly effective in preventing development of Freund's adjuvant arthritis, but in addition improved the symptoms in rats with established arthritis, although it is inactive in acute inflammation. This new agent contrasts with other immunosuppressives and cytostatic drugs in its weak myelotoxicity. Experimental evidence suggests that cyclosporin A, rather than being cytostatic or lympholytic, affects an early stage of mitogenic triggering of the immunocompetent lymphoid cell.

Biological effects of cyclosporin A: A new antilymphocytic agent

The fungus metabolite cyclosporin A is a small cyclic peptide acting as a novel antilymphocytic agent It is effective following either parenteral or oral administration in mice, rats and guinea-pigs The suppressive effect after short and prolonged treatment on plaque-forming cells, the inhibition of the secondary humoral response and the reversibility of its effect on haemagglutinin formation is demonstrated Cyclosporin A inhibits delayed hypersensitivity skin reaction to oxazolone (primary and secondary responses) in mice and to tuberculin in guinea-pigs Its failure to suppress antibody synthesis to lipopolysaccharide antigens in nude mice suggests a selective effect on T cells High doses of the compound affect the haemopoietic tissues very weakly as shown by the bone marrow and stem cell numbers in mice, which finding markedly contrasts with most other immunosuppressive and cytostatic drugs

Effects of the new anti-lymphocytic peptide cyclosporin A in animals.

A kinetic study (0–72 h) was performed on the cellular composition of the exudate in delayed-type hypersensitivity (DTH) induced by the injection of cloned helper T cells into the footpad of C57BL/6J

Mast cell degranulation as a major event in the effector phase of delayed-type hypersensitivity induced by cloned helper T cells.

Aqueous extracts of calf and pig lymphoid organs were prepared and fractionated by means of gel filtration, ion exchange chromatography, and isoelectric focusing. These fractions, which had been previously assessed on mitogen-stimulated mouse spleen lymphocytes and other cells in vitro, were tested for their in vivo activity on humoral (haemolytic PFC in mice) and on cell-mediated immunity (skin allograft survival in mice, lymph node weight assay in rats, and systemic GvH-reaction in mice). None of these several fractions elicited either biologically significant or reproducible inhibitory effects. In particular, two fractions, a high and a small molecular weight fraction which were strongly inhibitory in vitro, remained without any chalone-like activity in these in vivo assays. Our results therefore failed to support the existence of a lymphocyte chalone.

Camille Feurer

Papers

Biological effects of cyclosporin A: A new antilymphocytic agent

Effects of the new anti-lymphocytic peptide cyclosporin A in animals.

Mast cell degranulation as a major event in the effector phase of delayed-type hypersensitivity induced by cloned helper T cells.

The effects of fractions (chalones) obtained from lymphoid organs on the immune response in vivo.