The CXC chemokine receptor 3 (CXCR3) is predominantly expressed on T helper type 1 (Th1) cells that are involved in inflammatory diseases. The three CXCR3 ligands CXCL9, CXCL10, and CXCL11 are produced at sites of inflammation and elicit migration of pathological Th1 cells. Here, we are the first to characterize the pharmacological potencies and specificity of a CXCR3 antagonist, N-1R- [3-(4-ethoxy-phenyl of 7 to 18 nM). NBI-74330 was selective for CXCR3 because it showed no significant inhibition of chemotactic responses to other chemokines and did not inhibit radioligand binding to a panel of nonchemokine G-protein coupled receptors. There was a striking difference in potencies among the three CXCR3 ligands, with CXCL11 Ͼ Ͼ CXCL10 Ͼ CXCL9. A comparison of the rank order of K i values with the rank order of monocyte production levels of these three ligands revealed a precise inverse correlation, suggesting that the weaker receptor affinities of CXCL9 and CXCL10 were physiologically compensated for by an elevated expression, perhaps to maintain effectiveness of each ligand under physiological conditions.

APCs of the nonobese diabetic (NOD) mouse have a genetically programmed capacity to overexpress IL-12p40, a cytokine critical for development of pathogenic autoreactive Th1 cells. To determine whether a diabetes-associated NOD chromosomal locus (i.e., Idd) was responsible for this defect, LPS-stimulated macrophages from several recombinant congenic inbred mice with Idd loci on a C57BL/6 background or with different combinations of NOD and CBA genomic segments were screened for IL-12p40 production. Only macrophages from the congenic strains containing the Idd4 locus showed IL-12p40 overproduction/expression. Moreover, analysis of IL-12p40 sequence polymorphisms demonstrated that the Idd4 intervals in these strains contained the IL-12p40 allele of the NOD, although further analysis is required to determine whether the IL-12p40 allele itself is responsible for its overexpression. Thus, the non-MHC-associated Idd4 locus appears responsible for IL-12p40 overexpression, which may be a predisposing factor for type 1 diabetes in NOD mice.

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