The Study of Molecular Mechanisms of Immunosuppressive Drugs Actions.
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
- MED-DRG/Drug Discovery/Medicine
8 Project completed
Senior Project Manager
Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- FOA National Defence Research Establishment / Department of NBC Defence, Sweden, Umeä\nUniversity of Turku / Finnish-Russian Joint Biotechnology Laboratory, Finland, Turku\nUniversity of Wisconsin-Madison / Medical School, USA, WI, Madison\nLeiras Oy, Finland, Turku\nHealth Protection Agency / CAMR (Centre for Applied Microbiology & Research), UK, Porton Down\nCNRS / Institute de Recherches sur le Cancer, France, Paris\nUmeä University, Sweden, Umeä
Project summaryThe project is devoted to the solution of the actual medical problem - the increase of the efficiency of the immunosuppressive therapy in the course of the tissue or organ transplantation and at the autoimmune disorders therapy. Simultaneously these investigations are directed to the solving of the phenomenon of the immune tolerance and to the further comprehension of the mechanisms of Immunosuppression.
It is proposed to investigate the synergystic action of different immunosuppressive drugs such as cyclosporine A (CsA), alpha-fetopro-tein (AFP), corticosteroid hormones (CS), peptide interleukin-2 inhibitor (piIL-2, author name peptinhll-2), ACTH-like peptides from the H-chain of human immunoglobulin G (author name immunoocorticotropin) peptide from pro-interleukin-I SproIL-1) and peptide IgG-binding factor (pIBF), which were shown to reveal the immunosuppressive activity di rected to the differentiation and activation of the different types of FcR immune cells.
It is proposed to carry out the theoretical calculations of the secondary and tertiary structure of immunosuppressive drugs CsA and FK506, as well as their functional receptors eyelophillines (CyP) and FK506-binding proteins (FKBP). It is also planned to search the active sites of CsA and FK506 responsible for the interactions with phospage 2
phatase calcineurin (CaN) and to suggest the structures of new peptide analogs of CsA and FK506,It is proposed to carry out the chemical synthesis of these peptides and to investigate their biological activity.
It is planned to investigate in vitro and in vivo the biological activity of multidrug compositions of AFP with CsA, corticosteroids and immunoactive synthetic peptides. When receiving the positive results (the synergystic action of different drugs with the essential decrease of the therapeutics dose) it is planned to recommend the medical trials of these multidrug compounds. It is supposed that the suboptimal doses of these drugs would selectively affect the activation of certain Т cell subsets which are able to express AFP receptors. The AFP-CsA multidrug system is proposed to have the selectivity of AFP and high immunosuppressive activity of CsA with minimized unwished side effects in the course of the medical treatment.
It is proposed to investigate also the structural basis of the interaction of these immunosuppressants with their functional cell re-ceptors: immunophllines and cell-surface AFP-receptors.
- theoretical determination of the active sites of CsA and FK506 res-ponsible for the Interaction with cyclophilin, FKBP and phosphatase calcineurin and suggestion and synthesis of peptides with similar activity;
- determination of specific AFP receptor expression on the different types of normal and cancer cells;
- determination of the effect of preparations AFP, CsA, steroids, syntetic peptides derived from IL-2, IL-1 and IgG on the process of immune cell activation and differentiation;
- obtainment of the experimental data on the secondary and tertiary structure of human AFP using biophysical techniques: circular dichroism, microcalorimetry, fluorescence paramagnetic and nuclear magnetic resonance;
- obtainment the experimental data on the synergizm of the immunosuppressive effect of AFP and CsA or corticosteroid hormones;
- obtainment of the experimental data on the immunosuppressive activity of synthetic peptides (ICT, LCT, piIL-2) as well as the pIBF and the middle hinge of IgG;
- elaboration of the combined schemes of the preclynical trials of the multidrug CsA-AFP compounds composed with subobtimal consentrations of both components with the high activity, selectivity and reduced side effects.