Sj"gren's disease is a common autoimmune disease causing significant morbidity and mortality. Current therapies are inadequate because of poor understanding regarding the pathophysiology of the disorder. Animal models are critical to enhance understanding of this disease. Previous studies have demonstrated a central role for the B cell growth factor Interleukin 14 alpha (IL-14a) in Sj"gren's disease. Increased expression of IL-14a is noted in the lymphocytes of patients with Sj"gren's disease as well in various animal models of Sj"gren's disease. Mice expressing IL-14a at high levels constitutively, IL-14a transgenic mice (IL14aTG), demonstrate all the features of Sj"gren's disease seen in patients in the same relative time frame. In order to understand the role of IL-14a in Sj"gren's disease, we have produced an RNA inhibitor for IL-14a, DRIL14-1. Preliminary data demonstrate that DRIL14-1 inhibits the expression of IL-14a in vitro and in vivo for at least 14 days without notable toxicities or off site effects. The proposed studies will include two specific aims. The first specific aim will study the use of DRIL14-1 for a 6-week period of time in vivo to make sure that there are no toxicities or off site effects in IL14aTG mice. They will then determine the optimal dosing and time interval for the use of DRIL14-1 in vivo. If DRIL14-1 demonstrates untoward side effects, additional DRIL14 will be developed. In the second specific aim, DRIL14 will be utilized in the optimal dose and time interval established in Specific Aim 1 to attempt both prevention and treatment of established Sj"gren's disease in IL14aTG mice and NOD mice, another murine model for Sj"gren's disease. Various manifestations of Sj"gren's disease will be evaluated with and without therapy, including hypergammaglobulinemia, autoantibodies, loss of salivary gland secretions and infiltration of salivary glands and lungs with lymphocytes. We will determine whether IL-14a is critical for all or only some of the manifestations of Sj"gren's disease. We will determine whether IL-14a must be present to initiate the disease and/or to maintain it once it has been established. These studies will provide valuable new information regarding the role of IL-14a in Sj"gren's disease. Future work will be required to extend these findings to human studies. In addition, work to improve the DRIL14 further and to explore the long-term consequences of IL-14a inhibition will be pursued. These studies may lead to new forms of therapy for Sj"gren's disease.
The proposed studies will examine the role of IL-141 in the developing of Sjgren's disease by using specific RNA inhibitor targeted IL-141 to treat two different animal models for Sjgren's disease. These studies may lead to new form of therapy for Sjgren's disease.