Effects and mechanisms of actions of cyclosporin, FK506 and 15-deoxyspergualin

Abstract: Immunosuppressive drugs can be used to deal with unwanted or inappropriateimmune reactions, such as the rejection of a transplanted organ. However, treatmentwith these drugs are often associated with serious adverse effects, and therefore lesstoxic immunosuppressants are desired. The aims of the present study were toevaluate the immunologic effects of cyclosporin-sulphate, FK506 and 15-deoxy-spergualin (DSG).CsA-sulphate, a previously unidentified CsA metabolite, is present in highconcentration in the bile and plasma of transplanted patients. In vitro and in vivostudies showed that this metabolite has limited immunosuppressive effects. It islikely that the mother compound is responsible for both the immunosuppressive andadverse effects associated with treatment.FK506 is structurally completely distinct from CsA, but was found to have identicalimmunosuppressive effects in vitro, although at l0-l00 times lower concentrations.Based on studies of combinations of the two drugs, the effects CsA and FK506 arestipulated to be additive. The similar and additive effects of the drugs indicate thatthey share a common mechanism of action. The prevailing theory is that the drugsfirst bind to their respective immunophilin. The drug-immunophilin complexesinhibit the calcineurin-mediated dephosphorylation and thus the translocation to thenucleus of the cytoplasmic component of the transcription factor NF-AT.DSG have immunosuppressive properties that are distinct from CsA and FK506, butits mechanism of action remains elusive. In a safety-study, where DSG was given incombination with methyl-prednisolone as treatmenl of acute graft rejection inkidney transplant recipients, the etfects of DSG on blood mononuclear cells werestudied. DSG decreased the number of leukocytes, and results indicated that DSGmay affect B-cells and perhaps also CD4+ cells. Our in vitro studies confirmed aneffect of DSG on the development of cytotoxic T cells. DSG also suppressed theproliterative responses to S. aureus and PHA, if added within 24 hours afterstimulation. These effects could be explained by a DSG-dependent reduced Il-6production. However, addition of recombinant Il-6 only partly restored thedevelopment of cytotoxic T-cells, and thus, additional Il-6 independent steps shouldbe DSG-sensitive in the differentiation of CTL.In the transplantation of fetal porcine islet cells, reactivity against the graft is likelyto have been induced via the indirect activation pathway of immune recognition.CsA was found to be less efficient in inhibiting the cytotoxicity induced byxenogeneic porcine Iymphocytes via the indirect as compared to the direct pathway.In contrast, DSG inhibited the induction of cytotoxicity equally, irrespective ofactivation pathway. Although DSG did not suppress antibody production to pig PBLin mice completely, it was more efficient than CsA. DSG may act by modulating theactivities of the heat shock proteins Hsc70 and Hsp90.This thesis adds to the knowledge of the effects and mechanisms of action ofcyclosporin, FK506 and DSG, knowledge that may be valuable for the optimaltreatment of transplant recipients, and in the further development of immuno-suppressive drugs.Key words: cyclosporin, FK506, 15-deoxyspergualin, immunosuppressive effects,transplantationISBN 91-628-1770- 1