EARLY DIAGNOSIS AND DEVELOPMENT OF A NEW GENERATION OF DRUGS FOR PERSONALIZED TREATMENT OF RHEUMATOID ARHTRITIS

Prosjektet knytter molekylær forskning til pasientbehandling, og har som mål å utvikle diagnostiske metoder og individuelt tilpassede medisiner for behandling av den autoimmune sykdommen leddgikt. Leddgikt er en kronisk betennelsessykdom, hvor hvite blodceller anriper og ødelegger fleksible ledd. S Sykdomsårsaken er ikke kjent, og man kjenner ikke til noen kur. Til tross for dette vet man at tidlig og massiv behandling av pasientene er det mest effektivt for å dempe symptomer over tid. Vi har påvist både cellulære og molekylære signaturer som kan benyttes til å diagnostisere RA parsienter bedre. Vi har identifisert molekyler som hemmer omsetningen av nærinstoffer i aktive immunceller. Disse hemmerene blir optimalisert slik at de kan brukes I behandlingen av RA pasienter mtp å dempe symptomer og bedre livskvalitet.

Autoimmunity is with cancer and cardiovascular disease the most common causes of morbidity in the world and is a feature of many different diseases including rheumatoid arthritis (RA). RA affects about 1% of the world's population and is gender-biased tow ards the female. RA is a chronic and systemic inflammatory disorder associated with harmful proliferation of white blood cells (lymphocytes) that attack and destroy flexible joints. Early detection and aggressive therapy is crucial to successfully treat a nd dampen symptoms of RA. At an early stage RA patients normally receive the anti-cancer drug methotrexate (MTX), which inhibits all forms of cell proliferation. This together with the fact that some RA patients do not respond to MTX and that medication i s life-lasting may explain the severe side effects and the low life quality associated with RA-medication. A method to diagnose MTX-none-responders and to develop more specific drugs to treat RA patients are greatly needed. Proliferating lymphocytes requ ire large amounts of the carbohydrat glucose and the amino acid glutamine to support proliferation. Interestingly, proliferating but not quiescent lymphocytes over-produce lactate and alanine when combusting glucose and glutamine, respectively, demonstrat ing a major metabolic difference between the two cell populations. Lactate dehydrogenase (LDH) catalyse the formation of lactate and our preliminary results demonstrate a 30-40 forld induction of the A form of LDH (LDHA) in proliferating lymphocytes. This together with the fact that glutaminase (GLS) converts glutamine to glutamate, make LDHA and GLS promising therapeutic targets of RA patients responsive to MTX. Moreover, the fact that lactate and alanine are over-produced by proliferating lymphocytes ma ke these molecules promising biomarkers for RA which may provide early diagnosis of MTX responsive RA patients. Results from the present project will open for new and personalized treatment of RA patients.