SP0161 SCID MICE: Models for arthritis and systemic diseases
Authors: U. Müller-Ladner
Journal: Annals of the Rheumatic Diseases (2013)

Regardless of the type of chronic inflammatory immune-system driven disease, the majority of animal models are more or less distant to the respective disease entity in humans and frequently too short-timed because of the severity of the symptoms induced in the animal. To overcome these problems -at least in part- the severe combined immunodeficient (SCID) mouse model has been developed over the past decades to facilitate an experimental setting much closer to clinical reality. At present, this "living culture flask" is currently the only humanized model for RA, which is used routinely in scientific laboratories worldwide to investigate specifically the interactions between human cells and tissue components in rheumatic diseases, especially the "joint-like" interaction between aggressive rheumatoid synovial fibroblasts with healthy cartilage. The primary setting consisted of engrafting human cartilage or even complete synovium together with RA synovial fibroblasts under the kidney capsule for a time-span ranging from 8 weeks up to one year. Based on the easy re-identification of the human tissue after explantation, high-resolution molecular analysis of the interacting human cells and tissues could also be achieved. Owing to the rather difficult implantation under the kidney capsule, the next development was the so called "inverse wrap" technique, in which the human cartilage is embedded in a fibroblast-containing neutral sponge and implanted under the skin at the flank of the mice. To simulate continuous medication, another variant includes the implantation of osmotic minipumps, which release a defined "disease-modifier" on a continuous basis over several weeks. As the human organism consists of more than one joint, the last development was the co-implantation of several fibroblast-cartilage implants to get even closer to the human organism. By using this model, several scientific questions could be addressed, e.g. i) the distinct role of rheumatoid synovial fibroblasts and chondrocytes in cartilage degradation and reparation, the molecular mechanisms, by which these cells are altered and destroy the cartilage, ii) the visualization of these mechanisms, iii) the therapeutic modulation of the cellular activity of the fibroblasts both by drugs used in clinical routine as well as by various gene therapy approaches, and iv) the mode of action, by which rheumatoid arthritis spreads within an organism. The use of the SCID mouse as humanized model, however, is not limited to simulating rheumatoid arthritis. Most recently, it could be shown that also fibroblasts from patients with granulomatosis with polyangiitis show also an aggressive behavior towards human cartilage when implanted into SCID mice. Taken together, the SCID mouse has evolved into one of the most sophisticated humanoid animal models for rheumatic diseases in the past years. <h3>References</h3> Müller-Ladner U, et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 1996;149:1607-1615. Müller-Ladner U, et al. Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum 1999;42:490-497. Judex M, et al. "Inverse wrap" – an improved implantation technique for virus-transduced synovial fibroblasts in the SCID-mouse model for RA. Mod Rheumatol 2001;11:145-150. Knedla A, et al. The therapeutic use of osmotic minipumps in the SCID mouse model for rheumatoid arthritis. Ann Rheum Dis 2009;68:124-129. Lefèvre S, et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 2009;15:1414-1420. Kollias G, et al. Animal models for arthritis: Innovative tools for prevention and treatment. Ann Rheum Dis 2011;70:1357-1362. <h3>Disclosure of Interest</h3> U. Müller-Ladner Grant/Research support from: DFG, BMBF