Accession Number : AD1034528


Title :   Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis


Descriptive Note : Technical Report,30 Sep 2015,29 Sep 2016


Corporate Author : Tel Aviv University Tel Aviv Israel


Personal Author(s) : Kloog,Yoel ; Goldstein,Itamar ; Zayoud,Morad ; Sfadia,Galit E ; Moshe,Itzhak B ; Vax,Einav


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1034528.pdf


Report Date : 01 Oct 2016


Pagination or Media Count : 37


Abstract : During the first two year of the award, we made several high impact key observations: (I) Prophylactic treatment with Farnesylthiosalicylic acid (FTS), a first-in-class oral selective RAS inhibitor, provides a significant immunomodulatory effect in the rat adjuvant-induced arthritis (AIA) model by all outcome parameters(Clinical assessment and relevant laboratory/immunological/Molecular analyses). (II) Prophylactic dosing of FTS combined with methotrexate (MTX) provides a synergistic protective effect (90% disease inhibition). (III) The FTS derivative, F-FTS, showed superior therapeutic clinical efficacy compared to FTS in the AIA model. (IV) The detailed bioinformatics analysis of the transcriptomes of relevant splenic CD4+ T cells show that FTS/F-FTS are potent suppressors of the in vivo induction of a TH17 immune response. (V) FTS had a non-inferior therapeutic effect as compared to MTX in the collagen type-II induced arthritis (CIA) mouse model. (VI) FTS semi-prophylactic treatment alone or combined with MTX was coupled with significant positive attenuation of multiple relevant immunological and laboratory markers -- all strongly implying that the main biological effect of FTS/F-FTS is inhibition of a pathogenic TH17 autoimmune response to collagen II.


Descriptors :   Arthritis , drugs , immunomodulation , inhibitors , inhibition , mice , models , HISTOPATHOLOGY , cytokines , t lymphocytes , proteins , inflammation


Subject Categories : Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE