New research provides a novel model for rheumatoid arthritis research. The report by LaBranche is titled, "Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse".
Rheumatoid arthritis is characterized by chronic inflammation of the distal joints and is mediated in part by emigration and activation of immune cells. The restrictions of present animal models, which either mimic chronic disease or a synchronized version of early disease (but not both), have hampered scientific understanding of the specific roles immune cells and their mediators play in disease initiation and maintenance.
In this regard, Dr. Paul Allen and colleagues at the Washington University in St. Louis School of Medicine, in collaboration with Dr. Timothy LaBranche and colleagues at Pfizer Global Research & Development developed and characterized a chronic yet synchronized animal model of rheumatoid arthritis (KRN-CTM).
Disease in these animals developed with a uniform onset of 7 days post-initiation and was maintained chronically (through Day 42). These mice revealed a time course of rheumatoid arthritis characteristics including edema, immune cell infiltration, cartilage damage and osteoclast-mediated bone resorption.
According to Dr. LaBranche, "the main benefit of the KRN-CTM is its utility, which adds significant logistical and platform advantages to study T cell targets since the model is T cell-dependent and engages both early and late stages of innate and adaptive immune responses (a drawback of the antibody-dependent K/BxN serum transfer model).
In addition, by polarizing T helper (Th) cells and/or knocking down genes prior to transfer, the KRN-CTM may enable investigators to ask how specific Th subsets and/or specific T cell genes contribute to disease. Lastly, incidence, onset, and severity of disease are highly synchronized without requiring adjuvant. The KRN-CTM presents a novel opportunity for investigators to study specific pathways and mechanisms involved in both the early and chronic phases of disease, thereby enabling the validation of targets and biopharmaceuticals for rheumatoid arthritis patients."
In future studies Dr.'s Allen and LaBranche aim to demonstrate the utility of the KRN-CTM, illustrating the roles Th subsets and particular genes have in both the model and people.
There are approximately 1.3 million rheumatoid arthritis sufferers in the United States, about 75 percent of whom are women. Rheumatoid arthritis damages the joints, most commonly in the hands, feet, and cervical spine. Inflammation can also affects other organs and systems in the body such as the skin, lungs (fibrosis), kidneys (amyloid protein deposits), and cardiovascular system (increased risk for heart attack and stroke, as well as fibrosis and pericarditis). A clinical diagnosis can be made on the basis of symptoms, physical exam, radiographs, x-rays and lab tests. There are many prescription medications used to treat rheumatoid arthritis such as hydroxychloroquine (Plaquenil®), chloroquine (Aralen®), leflunomide (Arava®), and methotrexate (Rheumatrex ®). Non-pharmacological treatment includes psychical therapy, orthoses, and nutritional therapy but these do not stop progression of joint destruction. Analgesia (painkillers) and anti-inflammatory drugs, including steroids, are used to suppress the symptoms, while disease-modifying antirheumatic drugs (DMARDs) are required to inhibit or halt the underlying immune process and prevent long-term damage. Recently the newer group of biologics, such as abatacept (Orencia®), adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®), and rituximab (Rituxan®) have increased treatment options.
Although the course of disease varies greatly, daily living activities are impaired in most affected individuals and after 5 years approximately 33% of sufferers are no longer able to work.
This work was funded by Pfizer, Inc. Timothy LaBranche is employed by and has stock options in Pfizer, Inc. None of the other authors declared any relevant financial relationships.
LaBranche TP, Hickman-Brecks CL, Meyer DM, Storer CE, Jesson MI, Shevlin KM, Happa FA, Barve RA, Weiss DJ, Minnerly JC, Racz JL, Allen PM: Characterization of the KRN cell transfer model of rheumatoid arthritis (KRN-CTM), a chronic yet synchronized version of the K/BxN mouse. Am J Pathol 2010, 177: 1388-1396
For more information on Dr Timothy LaBranche, please contact Anne Wilson Senior Director, Media & Public Relations Pfizer, Inc.(212)733-5017 [email protected]
For press copies of the articles, please contact Dr. Angela Colmone at 301-634-7953 or [email protected]
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.