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

The mechanism of action of cyclosporin A and FK506

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

CYCLOSPORINA and FK506 inhibit T- and B-cell activation and other processes essential to an effective immune response1–3. In T lymphocytes these drugs disrupt an unknown step in the trans-mission of signals from the T-cell antigen receptor to cytokine genes that coordinate the immune response4–6. The putative intracellular receptors for FK506 and cyclosporin arecis-trans prolyl isomerases7–11. Binding of the drug inhibits isomerase activity8,10,11, but studies with other prolyl isomerase inhibitors12 and analysis of cyclosporin-resistant mutants in yeast suggest that the effects of the drug result from the formation of an inhibitory complex between the drug and isomerase13,14, and not from inhibi-tion of isomerase activity. A transcription factor, NF-AT, which is essential for early T-cell gene activation, seems to be a specific target of cyclosporin A and FK506 action because transcription directed by this protein is blocked in T cells treated with these drugs, with little or no effect on other transcription factors such as AP-1 and NF-κB (refs 15–17). Here we demonstrate that NF-AT is formed when a signal from the antigen receptor induces a pre-existing cytoplasmic subunit to translocate to the nucleus and combine with a newly synthesized nuclear subunit of NF-AT. FK506 and cyclosporin A block translocation of the cytoplasmic component without affecting synthesis of the nuclear subunit.

Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A.

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

/pdf/the-chemical-and-biological-route-from-podophyllotoxin-22n0kaczzy.pdf

The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain memorial Award lecture.

Synthesis and antimitotic activity of glycosidic lignan derivatives related to podophyllotoxin.

The immunosuppressant cyclosporin A (Sandimmune®) has become the first line treatment for preventing rejection of transplanted organs and for certain, autoimmune diseases. The discovery of that drug and its preclinical development are described, and it is shown that most earlier accounts of the history of this compound are, in important respects, incorrect and misleading.

The history of cyclosporin A (Sandimmune ® ) revisited: Another point of view

As a basis for studies on the interaction of phagocytes and tubercle bacilli experiments were carried out to obtain information on some biochemical characteristics of exudate leucocytes from guinea pigs.

It was found that total cellular phosphorus was the most suitable measure of protoplasm. Cell counts were less reliable because of unavoidable clumping in the suspension, and dry weight measurements were less specific when contamination with erythrocytes occurred. The utility of phosphorus measurements in this connection depends upon the fact that an erythrocyte contains only 4 per cent of the phosphorus present in a leucocyte.

From measurements on mixed suspensions consisting of varying known proportions of polymorphonuclear and mononuclear leucocytes as determined by differential counting, it was possible to compute true values for these two cell types with respect to oxygen consumption and lactic acid production. Thus it was found that monocytes consumed considerably more oxygen and produced more lactate than polymorphonuclear leucocytes. From the data obtained it is suggested that differences in metabolic activity found when comparing cell suspensions obtained by the use of different irritants are due to different proportions of the two cell types.

In particular, the effects of oxygen tension and pH on the activities of the cells were studied. It was found that decreasing the proportion of oxygen in the atmosphere from that of air to 1 per cent reduced oxygen consumption by about 80 per cent, whereas lactic acid production was increased by about 45 per cent. It was also found that decreasing the pH of the medium below pH 7.5 caused a considerable reduction in the respiration, lactate production, and viability of polymorphonuclear leucocytes. The monocytes proved less sensitive to similar changes in pH, especially with regard to lactic acid production and viability.

Observations were made of oxygen consumption and lactate production during phagocytosis. During the hour following the addition of heat-killed tubercle bacilli to the phagocytes, the oxygen consumption of suspensions rich in polymorphonuclear leucocytes rose by 60 per cent, and that of suspensions rich in monocytes rose by nearly 100 per cent. Lactic acid production was unchanged during phagocytosis.

/pdf/studies-on-the-interaction-between-phagocytes-and-tubercle-58timg05qw.pdf

Studies on the interaction between phagocytes and tubercle bacilli : i. observations on the metabolism of guinea pig leucocytes and the influence of phagocytosis

Hartmann Stähelin

Papers

Biological effects of cyclosporin A: A new antilymphocytic agent

The chemical and biological route from podophyllotoxin glucoside to etoposide: ninth Cain memorial Award lecture.

Synthesis and antimitotic activity of glycosidic lignan derivatives related to podophyllotoxin.

The history of cyclosporin A (Sandimmune ® ) revisited: Another point of view

Studies on the interaction between phagocytes and tubercle bacilli : i. observations on the metabolism of guinea pig leucocytes and the influence of phagocytosis