Cyclosporine immunosuppressive action

Kiessig et al. studied the interaction of the immunosuppressant drug cyclosporin A and some derivatives to its cellular receptor protein cyclo-philin (26). The cyclophilin-cyclosporin A complex mediates the immunosuppressive action of cyclosporin A by inhibition of the phosphatase calci-neurin. Using ACE in the equilirium-mixture mode, a separation of the cyclophilin-cyclosporin A complex and the unbound cyclophilin was achieved. The approach allowed a qualitative estimation of the binding affinity of cyclosporin A derivatives compared to cyclosporin A. For the calculation of binding constants, electrophoretically mediated microanalysis was applied. 

The molecular targets of rapamycin inhibitors (mTOR), siroiimus and everoiimus, have a distinct mechanism of immunosuppressive action different from the calcineurin inhibitors cyclosporine and TAC. As such, they are expected to be minimally nephrotoxic per se. 

Tacrolimus, another antibiotic with immunosuppressant actions, does not bind to cyclophilin, but acts similarly to cyclosporine to inhibit caldneurin. 

DOC organ or tissue transplantation (+/- mycophenolate +/- steroids +/- cytotoxic drugs). Tacrolimus has been used alternatively to cyclosporine in renal and liver transplants. Mycophenolate, an inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity. 

FRAP inhibits its function in T lymphocytes, which results in impaired interleukin-2 receptor signaling [31-34], and this is thought to be the basis for the immunosuppressive actions of rapamycin [30]. Another example of an immunosuppressant that acts in this manner is cyclosporin A, which interacts with cyclophilin to form a complex that then binds calcineurin [30]. 

Mycophenolate, an inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity. 

Cyclosporine is effective in organ transplantation. The immunosuppressant action of the drug appears to be due to... 

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

Rapamycin is a macrocyclic lactone produced by Streptomyces hygroscopious. This bacterium was originally cultured from a soil sample collected on Easter Island (known locally as Rapa Nui hence the name rapamycin). Parenthetically, rapamycin shares an interesting mode of action with two other antifungal and immunosuppressive compounds, FK506and cyclosporin A. Inside cells, rapamycin first binds to FKBP12, a small protein receptor known as an immunophilin. FKBP12 is not an essential protein but is an important cofactor required for rapamycin to bind and inhibit TOR. 

A 45-year-old female has a bone marrow transplant for treatment of ovarian cancer Cyclosporine is given as an immunosuppressant What is the mechanism of action of cyclosporine ... 

Echinacea (Echinacea purpurea) Uses immune system stimulant prevention/Rx of colds, flu as supportive th apy for colds chronic infxns of the resp tract lower urinary tract Action Stimulates phagocytosis cytokine production T resp cellular activity topically exerts anesthetic, antimicrobial, anti-inflammatory effects Efficacy Not established may X severity duration of URI Available forms Caps w/ powdered herb equivalent to 300-500 mg, PO, tid pressed juice 6-9 mL, PO, once/d tine 2-4 mL, PO, tid (1 5 dilution) tea 2 tsp (4 g) of powdered herb in 1 cup of boiling water Noles/SE Fever, taste p -version, urticaria, angioedema Contra w/ autoimmune Dz, collagen Dz, progressive systemic Dz (TB, MS, collagen-vascular disorders), HIV, leukemia, may interfere w/ immunosuppressive therapy Interactions t Risk of disulfiram-like reaction W/ disulfiram, metronidazole T risk of exacerbation of HIV or AIDS W/ chinacea amprenavir, other protease inhibitors X effects OF azathioprine, basiliximab, corticosteroids, cyclosporine, daclizumab, econazole vag cream, muromonab-CD3, mycophenolate, prednisone, tacrolimus EMS Possible immunosuppression... 

Sirolimus (Rapamune) is structurally related to tacrolimus. It is approved for use as an adjunctive agent in combination with cyclosporine for prevention of acute renal allograft rejection. It blocks IL-2-dependent T-cell proliferation by inhibiting a cytoplasmic serine-threonine kinase. This mechanism of action is different from those of tacrolimus and cyclosporine. This allows sirolimus to augment the immunosuppressive effects of these drugs. 

Although it is not chemically related to cyclosporine, tacrolimus (6.7) has a similar mechanism of action. Tacrolimus is an immunosuppressant macrolide antibiotic derived from Streptomyces tsukubaenis. Like cyclosporine, tacrolimus inhibits the same cytoplasmic phosphatase, calcineurin, which catalyzes the activation of a T-cell-specific transcription factor (NF-AT) involved in the biosyntheses of interleukins such as IL-2. Sirolimus (6.8) is a natural product produced by Streptomyces hydroscopicus, it blocks the ability of T cells to respond to cytokines. 

The introduction of cyclosporin, a peptide derived from a fungus, revolutionised immunosuppressive therapy, and was one of the major influences in the improvement of early graft survival in transplant surgery when introduced in the 1980s. The main action is a relatively selective inhibition of IL-2 production and consequently a decreased proliferation of T cells. A major advantage of cyclosporin is that it does not cause myelosuppression in therapeutic doses. The major side effect is nephrotoxicity, which occurs in about 20% of patients, and about 50% of patients develop moderate hypertension. The other major side effect is hepatotoxicity with cholestasis and hyperbilirubinaemia. 

Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT. 

---