Sarcoidosis is a multisystem granulomatous disorder that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. With an incidence of -10-40 per 100,000 people, predominant in African Americans and women in the U.S., sarcoidosis represents a significant health problem and health disparity concern. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. There are no diagnostic tests for sarcoidosis except for biopsy of affected tissues that carry considerable expense and risk. Sarcoidosis is widely believed to be underdiagnosed, in part due to a lack of diagnostic tools. There are no safe, effective treatments for sarcoidosis. The goals of this application are first to develop a safe, standardized diagnostic skin test for sarcoidosis, and second, to establish an immunotherapeutic approach for treatment of sarcoidosis. Our specific approach capitalizes on our recent discovery that IVIycobacterium tuberculosis catalase-peroxidase (mKatG) is a prototypic pathogenic tissue antigen in sarcoidosis. This discovery was based on a novel proteomic approach in which mKatG was isolated based on the biophysical properties of the Kveim reaction, an established diagnostic skin test for sarcoidosis which was discontinued for safety concerns since it uses allogeneic sarcoidosis tissues. Our hypotheses are 1. mKatG induces a local granulomatous response in the skin of sarcoidosis patients characteristic of disease related granulomas and Kveim reactions that can serve as a diagnostic tool, and 2. oral vaccination with mKatG suppresses experimental mKatG driven granulomatous lung inflammation in a preclinical model of sarcoidosis.
In Aim 1 studies, we will manufacture recombinant mKatG under Good Manufacturing Practices suitable for use as an intradermal skin test reagent and test the safety and effect of intradermal administration in sarcoidosis patients and control subjects.
In Aim 2 studies, we will test the hypothesis that oral vaccination with mKatG suppresses experimental granulomatous lung inflammation by upregulating mKatG specific regulatory T cells, thereby establishing the immunologic framework for treating sarcoidosis with oral vaccines using prototypic pathogenic antigens such as mKatG.
Our proposed studies may lead to the development of a safe, simple diagnostic skin test for sarcoidosis that could reduce risk, health care expenses and misdiagnosis. Furthermore, our studies would test whether an oral vaccine based on disease-related microbial proteins is able to suppress the characteristic inflammation seen in sarcoidosis, offering a novel, and possibly, far safer treatment strategy for sarcoidosis.
