Back From the Brink: The Uses of Targeting the CXCL10:CXCR3 Axis in Type 1 Diabetes

According to a popular quip, fittingly though incorrectly attributed to the great dyspeptic metaphysicist Arthur Schopenhauer, all truth passes through three stages: first, it is ridiculed; second, it is violently opposed; third, it is accepted as self-evident (1). In the iconoclastic world of biomedical research, however, that is so eager to challenge the old and propose novel paradigms, the evolution of truth may at times take a different path, traveling the route to knowledge almost in the opposite direction: first, a discovery is excitedly embraced; second, it is readily confirmed and expanded upon; and third, it is effectively contested and quietly slips into oblivion. That, or so it seemed, was to be the fate of the chemokine CXCL10 and its receptor CXCR3 as promising therapeutic targets in type 1 diabetes (T1D). Yet in this issue of Diabetes, Lasch et al. (2) pull that concept back from the brink by defining a specific context for effective CXCL10 neutralization, namely, as an adjunct treatment to achieve durable aCD3-induced T1D remission. In the early 2000s, buoyed by a burgeoning interest in the potential contribution of individual chemokine/receptors to diabetes development, two independent groups studying the virus-induced RIP-LCMV-GP model suggested that the CXCL10:CXCR3 axis might constitute a key determinant for T1D pathogenesis (3,4). Transgenic RIP-LCMV-GP mice, in which the rat insulin promoter (RIP) drives expression of the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) specifically in b-cells, are phenotypically normal but readily develop T1D within ;2 weeks after LCMV infection and the generation of a potent LCMV-GP–specific CD8T-cell response. Based on mRNA and protein expression screens of murine islets or pancreata obtained from infected RIP-LCMV-GP mice, CXCL10 was identified as a particularly prominent chemokine (3,4), and corresponding in vivo LCMV challenge experiments demonstrated a substantial delay and/or prevention of T1D in RIP-LCMV-GP mice lacking Cxcr3 (;50% delay, ;50% prevention [3]) or after anti-CXCL10 antibody (aCXCL10) treatment of regular RIP-LCMV-GP mice (;70% prevention [4]). CXCL10: CXCR3–guided pancreatic T-cell trafficking as an essential component for the natural history of T1D and as a suitable therapeutic target proved an attractive concept that was further elaborated in subsequent years, notably by clinical studies of individuals with recent-onset diabetes documenting elevated CXCL10 serum levels (reviewed in [5]) and direct histopathological evidence for islet-associated CXCL10 and CXCR3 expression (summarized in [6]). Indeed, as in the mouse models, CXCL10 appeared to be the major pancreas-expressed chemokine in early human T1D (6). At the same time, however, several publications began to question the precise extent to which CXCL10:CXCR3– dependent T-cell trafficking contributes to T1D. CXCL10 may directly compromise b-cell survival and proliferation possibly through the noncognate Toll-like receptor 4 (7,8), and transgenic overexpression of CXCL10 in b-cells promoted lymphocyte infiltration but not clinical disease (9). After LCMV infection, Cxcl10-transgenic RIP-LCMVGP mice exhibited normal T1D onset kinetics, although accelerated disease development was observed in the related “slow-onset” RIP-LCMV-NP strain (9). These findings were mirrored in work with a small molecule CXCR3 antagonist that did not prevent T1D in RIP-LCMV-GP mice and only slightly delayed diabetes in the RIP-LCMV-NP model (10). In 2013, prompted by the realization that the CXCL10:CXCR3 model in its original conception failed to account for these disparate results, von Herrath and colleagues (11) revisited the foundational studies performed a decade earlier. Using combinations of Cxcr3 and Cxcl10 RIP-LCMV-GP mice, different LCMV isolates and challenge protocols, antibody-mediated CXCL10 blockade and a virus-free T1D induction system, and different strains of RIP-LCMV-GP mice, the authors demonstrated, in contradistinction to the earlier reports, at best a minimal contribution of the CXCL10:CXCR3 pathway to T1D pathogenesis (11). Even more troubling, Cxcr3-deficiency in the NOD