Rat Anti-Human CCR8 monoclonal antibody, clone 202815 [PE]

Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a "benign'' disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell-or immunoglobulin-related (Fc-gamma receptor-mediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.

Background: Such CC chemokines as eotaxin and RANTES induce preferential eosinophil recruitment in allergic inflammation. They also elicit proinflammatory effector functions of eosinophils, such as enhanced adhesion and superoxide generation. Eosinophil degranulation by chemokines, however, has not been studied in detail. Objective: The purpose of this study was to identify chemokines and their corresponding receptors that induce eosinophil degranulation by using a panel of chemokines and blocking antibodies to candidate receptors. Methods: Highly purified eosinophils were preloaded with Fura-2 and stimulated with a panel of chemokine ligands for 14 known chemokine receptors: CCR1 to CCR8, CXCR1 to CXCR4 CX3CR1, and XCR1. Calcium influx was measured with fluorescence spectrometry. Eosinophils were also stimulated with the chemokines in the presence or absence of IL-5, and levels of eosinophil-derived neurotoxin were measured in the supernatant with RIA. Specific antibodies to chemokine receptors were used to block degranulation. Results: Calcium influx was induced by monocyte chemotactic protein (MCP) 1, MCP3, MCP-4, RANTES, eotaxin, IL-8, and stromal cell-derived factor 1 alpha, which are chemokines that bind several chemokine receptors. However, degranulation was induced only by CCR3 ligands, including MCP3, MCP-4, RANTES, and eotaxin. Priming of eosinophils with IL-5 enhanced CCR3 ligand-induced degranulation but did not cause non-CCR3 ligands to induce eosinophil-derived neurotoxin release. An antibody against CCR3 significantly inhibited degranulation induced by CCR3 ligands, eotaxin, or RANTES. Conclusion: These results suggest that chemokine-induced eosinophil degranulation, a major effector of eosinophil functions, is mediated through only CCR3, although some non-CCR3 ligands induce calcium influx in eosinophils. CCR3 may be an important target in the treatment of eosinophilic inflammation.