A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

<p>Abstract</p> <p>Background</p> <p>The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.</p> <p>Results</p> <p>In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC₅₀ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC₉₀about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.</p> <p>Conclusions</p> <p>SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.</p

Income Composition and Redistribution in Germany: The Role of Ethnic Origin and Assimilation

This paper deals with the relative economic performance of immigrants compared to the native born population in Germany. We compare pre and post-government income, using data from the German Socio-Economic Panel from 1995 to 1997. We categorize six population subgroups by the ethnicity of the adult household members: native-born West Germans, East Germans, "pure" Aussiedler (ethnic German immigrants), "pure" non-ethnic German foreign immigrants, and "mixed" immigrants, either Aussiedler or foreign, living with an adult native-born German. Our results show that immigrants are quite heterogeneous with respect to their economic performance but, overall, non-ethnic German immigrants are net payers to the social security system. The two subgroups substantially benefiting from the income redistribution are "pure" Aussiedler and East Germans. By this measure, immigrants of non-German nationality are not an economic burden to the native-born population.

The Role of Cultural Clustering in Attracting New Immigrants

This paper argues that new immigrants cluster in culturally homogeneous groups in the host country because of imperfect information. However, a pulling effect exists provided that the cultural communities are not too large. With a panel of migration flows to the major O.E.C.D. countries from the mid 1980s to the mid 1990s, it is shown that the existence of similar cultural communities attracts new immigrants. However, the effect is not homogeneous for all types of source and destination countries. Furthermore, the pulling effect is shown to fall to zero for cultural communities above a certain threshold size. Copyright Blackwell Publishing, Inc 2003