Preclinical trials with tofacitinib showed significant improvement in experimental models of autoimmunity and organ transplantation (34C36) Currently, tofacitinib is approved in the USA, Japan, Switzerland, Russia, Argentina, Kuwait and the United Arab Emirates for the treatment of patients with RA

Preclinical trials with tofacitinib showed significant improvement in experimental models of autoimmunity and organ transplantation (34C36) Currently, tofacitinib is approved in the USA, Japan, Switzerland, Russia, Argentina, Kuwait and the United Arab Emirates for the treatment of patients with RA. skin diseases. While biologics typically target one single cytokine, these new immunomodulators can inhibit signals from multiple cytokines intracellularly and therefore could be useful when other therapies are ineffective. Thus, Jak inhibitors may replace some traditional immunosuppressive brokers and help patients not responding AZ 23 to previous therapies. Introduction Given the importance that cytokines have in development and homeostasis of the immune system it is not surprising that these soluble factors are crucial players AZ 23 in immune mediated disorders including inflammatory autoimmune diseases. For example, the pathogenesis of psoriasis is usually characterized by the activation of numerous immune cells, which interact with resident tissue cells. In the skin, these cells are primarily composed by keratinocytes and endothelia, in the joints by synoviocytes, fibroblasts and osteoblasts (1, 2). Cellular contact and, more importantly, secreted factors like cytokines, can cause persistent inflammation of skin and joints. The cytokines network in psoriasis pathogenesis is usually well studied (1, 3) and some similarities are found in other pathologies like RA or ulcerative colitis (4, 5). Innate cytokines determining lineage-specification of CD4+ T helper (Th) cells, such as interleukin (IL)-1 and IL-6, AZ 23 and cytokines released by T cells and resident tissue cells like tumor necrosis factor (TNF), interferons (IFNs), IL-17 or IL-23 are indispensable for disease manifestation and perpetuation. Given the role these molecules play in inflammatory pathologies limiting their interaction with their specific receptors has been successfully exploited for therapeutic purposes through the use of biologics. For immunological purposes, biologics such as monoclonal antibodies, recombinant soluble receptors and fusion proteins of receptor moieties with antibodies fragments, block the conversation of AZ 23 a specific cytokine with its receptor. In the past 15 years, biologics have completely revolutionized the clinical approach to the treatment of autoimmunity and inflammatory pathologies. The basis for this success was our better understanding of cellular and molecular players. In psoriasis, clearance was observed after bone marrow transplantation, in those receiving the immunosuppressant cyclosporine or antibodies targeting CD4 suggesting a prominent role for T cells (6, 7) and, in particular, IFN–producing Th1 cells (8, 9). Based on such analysis of disease-associated or tissue-infiltrating Th cells in patients and in animal models, Th1 cells were thought to drive the inflammatory responses in organ-specific autoimmune diseases and inflammatory pathologies like psoriasis. Surprisingly, mice lacking IFN-, the IFN- receptor or its downstream signaling element signal transducer and activator of transcription (STAT)1 exhibit exaggerated autoimmune inflammation (10). Furthermore, the Th1-promoting cytokines IFN- and IFN- both exacerbate psoriasis whereas therapies with recombinant IL-4, IL-10 or IL-11 showed some clinical improvements (9, 11, 12). At the beginning of this millennium, a second CD4+ T cell populace known as Th17, a T cell subset producing IL-17, IL-22 and TNF was recognized to play a major role. Th17 cells with potential to induce inflammatory pathology typically require signals from IL-23 (13, 14). High numbers of IL-17-expressing Th17 cells and IL-23-expressing dendritic cells (DC) are present in psoriatic skin (Physique 1) (15, 16). The knowledge on the underlying cytokine network in AZ 23 psoriasis allowed the establishment of therapies with biologics targeting TNF (17C19) or the IL-12/IL-23 p40 subunit (20). Targeting IL-17 or its receptor is being evaluated in phase III studies for psoriasis (21C23). In RA, biologics targeting TNF, IL-1 or the IL-6 PIK3C2G receptor have been approved (2). Open in a separate window Physique 1 The crucial role of cytokines in the pathogenesis of psoriasis: Targeted therapies inhibiting extracellular cytokine actions and the new approach of blocking intracellular cytokine signalingImmune sensors like dendritic cells release innate cytokines including.