Therefore, today’s primary therapy for GO are anti-inflammatory immunosuppressives. by G-protein receptor kinases, which enables -arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R conversation. In this review, novel pharmacological strategies with allosteric small-molecule modulators to TPOR treat GO and GD on the level of the TSHR and/or the Promethazine HCl TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients. Keywords: Insulin-like growth factor 1 receptor, Thyroid-stimulating hormone receptor, Crosstalk, Graves’ orbitopathy, Graves’ disease Introduction TSH-Receptor, Graves’ Disease and Graves’ Orbitopathy The thyrotropin receptor or thyroid-stimulating hormone (TSH) receptor (TSHR) is mainly expressed in follicular epithelial cells of the thyroid gland [1]. TSHR activation by TSH leads to stimulation of secondary messenger pathways involving predominantly cAMP but also inositol 1,4,5-trisphosphate (IP3) [2, 3]. Activation of the ERK pathway by TSHR via -arrestin 1 is usually involved in osteoblast homeostasis [4]. Pathological activation of the TSHR by TSHR-stimulating autoimmune antibodies (TSAb) leads to the uncontrolled production of thyroid hormones T3 and T4 in the thyroid causing hyperthyroidism in Graves’ disease (GD) [5]. The TSAb binds to the TSHR at a similar extracellular site as TSH itself and causes deregulated TSHR hyperactivation [6]. To date, antithyroid drugs are used to reduce hyperthyroidism by correcting the clinically evident consequences. Here, the activity of the enzyme thyroid peroxidase is usually inhibited, thereby impairing thyroid hormone synthesis and release. However, pathological activation of the TSHR by TSAbs is not causally resolved. To date, there is no therapy available targeting the activated TSHR itself. Therefore, if the pathological antibody production does not calm down during the course of antithyroid drug treatment (remission), the thyroid will be removed either by radioiodine therapy or by surgical thyroidectomy and, as a consequence, L-thyroxin has to be substituted lifelong in these patients (summary in [7]). In addition to follicular epithelial cells of the thyroid gland and osteoblasts, the TSHR is also expressed in retro-orbital fibroblasts [1]. Thus, autoimmune TSAbs also activate the TSHR in the orbit causing Graves’ orbitopathy (GO), a quality of life-reducing, appearance-changing, and sight-threatening disease. It is characterized by inflammatory symptoms, extraocular muscle fibrosis, Promethazine HCl and adipose tissue growth leading to protrusion of the Promethazine HCl eyes, diplopia, and blurred vision. About half of GD patients develop GO and 3C5% develop a severe sight-threatening course of disease [8]. Of note, while autoimmune TSAbs are activating the TSHR in both the thyroid and orbit, different molecular mechanisms are activated in the orbit. The therapy using antithyroid drugs decreasing thyroid hormone synthesis does not target the TSHR itself and has, thus, only an indirect and very limited effect on GO (poor control of thyroid function is usually a risk for more severe course of GO). The autoimmune reaction in the orbit leads finally to the infiltration of orbital tissues with predominantly macrophages and T cells and to the release of several potent mediators of inflammation. Therefore, today’s primary therapy for GO are anti-inflammatory immunosuppressives. Steroids are the first-line therapy, followed by immunosuppressive drugs if the therapy effect is not or not sufficiently achieved. A careful look at the outcome measures in all treatment studies discloses that all these.