Immun., Endoc. & Metab. Agents in Med. Chem., 2012, 12, 73-79 73 1875-5844/12 $58.00+.00 © 2012 Bentham Science Publishers Molecular-Targeted and Cell-Based Therapies for Sjögren’s Syndrome Kaori Misuno and Shen Hu* School of Dentistry, University of California, Los Angeles, CA 90095, USA Abstract: Sjögren’s syndrome (SS) is a systemic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands, in particular the salivary and lachrymal glands. The etiology and pathogenic mechanisms of SS remain largely unknown. Accordingly there are no treatments that completely reverse the disease in patients. The purpose of this invited review is not to provide a comprehensive overview of treatment approaches for SS, but rather to comment on emerging molecular targeted therapies and cell-based therapies. Although a number of molecular-targeted therapies are currently available for autoimmune diseases, very few but Rituximab and Epratuzumab appear to be efficacious for pa- tients with SS, suggesting the importance of an enhanced understanding of SS pathogenesis. Cell-based therapy has been demonstrated as a promising approach to treat salivary gland dysfunction in SS mouse models. Further assessment for functional restoration of damaged salivary glands in organotypic culture or in SS patients is necessary to translate the cell- based therapies into the clinic. Keywords: B-cell targeted therapies, bone marrow-derived cells (BMDCs), cell-based therapies, cytokines, epratuzumab, im- munoproteasome, interferons (IFNs), molecular-targeted therapies, rituximab, tumor necrosis factor-alpha (TNF-), sjogren’s syndrome, T-cell targeted therapies. INTRODUCTION Sjögren’s syndrome (SS) is a chronic autoimmune dis- ease, with an estimated prevalence of ~ 4 million in the US [1, 2]. Patients with SS suffer from dry mouth (xerostomia) and eyes (xeropthalmia) caused by lymphocytic infiltration of salivary and lachrymal glands. SS primarily affects women, with a ratio of 9:1 over the occurrence in men. The disease is classified as primary SS when it exists by itself or secondary SS when it is associated with another autoimmune disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis. In addition, pa- tients with SS have a significant higher risk of developing lymphoma than both healthy population and patients with other autoimmune diseases [3]. The most common form is mucosa-associated lymphoid tissue (MALT) lymphoma that remains localized in the affected salivary glands. A typical pathological feature of SS is the presence of progressive lymphocytic infiltrates in the exocrine glands, such as salivary and lachrymal glands, where lymphocytes are not normally found [4]. Histopathological examination of the affected major salivary glands in patients with SS reveals a benign lymphoepithelial lesion, which is characterized by lymphocytic replacement of the salivary epithelium and ac- companied by the formation of epimyoepithelial islands mainly composed of keratin-containing epithelial cells [5, 6]. The predominant cells in the salivary gland infiltrates are T cells, with a ratio of 3–5:1 between CD4+ and CD8+ pheno- types. SS is also associated with B cell hyperactivity as manifested by the production of autoantibodies, hypergam- maglobulinemia, formation of ectopic lymphoid structures *Address correspondence to this author at the School of Dentistry, Univer- sity of California, Los Angeles, CA 90095, USA; Tel: 310-206-8834; E-mail: shenhu@ucla.edu within the inflamed tissues, and enhanced risk of B cell lym- phoma [7]. B cells constitute approximately 20% of the total infiltrating population [6]. Various autoantibodies, such as anti-SS-A (Ro), anti-SS-B (La), anti--fodrin, anti-M3 mus- carinic acetylcholine receptor (anti-M3R), anti-histone and anti-transglutamine are detected in serum or saliva fluids of patients with SS [4, 8-10]. Cytokine Activities Implicated in SS During the formation and proliferation of the lympho- cytic infiltrates, a number of cytokines are aberrantly ex- pressed in the affected glands or circulation system of SS patients. The major pro-inflammatory cytokines found to be important in SS include the interferons (IFNs), tumor necro- sis factor-alpha (TNF-), interleukin-12 (IL-12), IL-18, IL- 1, IL-6 and BAFF (B-cell activating factor; also known as B- lymphocyte stimulator, BLyS). These cytokines play dif- ferent roles in the pathogenesis of SS. IFNs are multifunc- tional cytokines that have anti-viral, anti-proliferative, and immuno-modulatory effects. Type I IFNs (IFN- and -) are secreted by virus-infected cells and plasmacytoid dendritic cells (pDC), whereas type II IFN (IFN-) is mainly secreted by T cells, natural killer (NK) cells and macrophages. Both type I and II IFNs are aberrantly expressed in SS patients, and consequently regulates the expression of many genes such as other cytokines or transcription factors [11-15]. In fact, IFN-, as well as TNF-, induces the expression of apoptotic receptor Fas on the surface of salivary gland cells, leading to Fas-mediated apoptosis and destruction of acini [16-18]. IL-12 and IL-18 are both predominantly secreted by monocytes and macrophages and stimulate the production of IFN- from T and NK cells. These pro-inflammatory cytoki- nes work synergistically with IFN- to drive the Th1- dominated response in SS [19]. IL-1 is produced by acti- vated macrophages as a proprotein, which is then proteolyti-