Humanized Transgenic Mice Reproduce the Disease Evolution in Severe RA

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DESCRIPTION (provided by applicant): Humanized transgenic mice reproduce the disease evolution in severe RA Rheumatoid arthritis (RA) is a common autoimmune disease in humans genetically associated with specific HLA class II alleles. Although several mouse models of RA develop symptoms and clinical arthritis with similar joint distribution as RA in humans, none of these models accurately replicates the slow, chronic disease progression with extra-articular symptoms seen in humans. In the recently reported D1CC transgenic mice that express the class II transactivator (CIITA) under the rat collagen II promoter, we presented an inducible disease syndrome, which very closely reproduces the late stages of RA with severe chronic progressive erosive disease, nodules, and, in some mice autoimmune pneumonitis. The proposed research will further advance this mouse model by introducing the RA-susceptible HLA- DR*0401 gene and a luciferase transgene (controlled by a minimal Drosophila promoter activated by 3 NF:B binding sites), which will facilitate continuous in vivo monitoring of the disease process. The first aim will be to complete the selection of the best founder lines from new transgenic mouse production. The second aim will be to trigger arthritis using Zymosan (a non-specific stimulator of the innate immune system), collagen II/CFA or HCgp39/CFA (two joint-related autoantigens in RA) that activate the adaptive immune system, and to develop in vivo monitoring protocols using a combination of clinical arthritis scoring, X-rays, X-ray tomography, and luciferase imaging. The third aim will be to test the effects of 1) anti-TNF1 blockade (an already well- established treatment in humans with RA), and 2) anti-IL17 blockade on arthritis progression in the new model. IL-17 seems to have special significance in the erosive process in RA and anti-IL17 blockade may therefore open a new alley for attacking this process. PUBLIC HEALTH RELEVANCE. Humanized transgenic mice reproduce the disease evolution in severe RA This application describes a new mouse model of inflammatory arthritis, which develops a disease syndrome that very closely reproduce the natural history of chronic rheumatoid arthritis (RA) with progressive development of erosive bone disease and extra articular disease manifestation characteristic of severe RA in humans. By expressing, as a transgene, the human Class II transactivator, CIITA, in the synovial joints, it was found that mice attain a much higher sensitivity to develop inflammatory arthritis and this feature is here included in the application's humanized HLA-DR4, CIITA transgenic mice. Since the expression of the CIITA transgene is contingent upon continuous inflammation in the joints, the arthritis syndrome can presumably be turned off and controlled by treatment making the mice ideal for evaluation of new treatments for RA.