The purpose of this study was to elucidate the cellular/biochemical pathway(s) by which interleukin-1␤ (IL-1␤) contributes to the pathogenesis of hypoxic-ischemic brain damage. In vivo, IL-1 receptor type I (IL-1RI)-deficient mice showed smaller infarcts and less neurological deficits than wild-type animals after a 90 min reversible middle cerebral artery occlusion.

Interleukin‐1 (IL‐1) is a proinflammatory cytokine released by many cell types that acts in both an autocrine and/or paracrine fashion. While IL‐1 is best described as an important mediator of the peripheral immune response during infection and inflammation, increasing evidence implicates IL‐1 signaling in the pathogenesis of several neurological disorders. The biochemical pathway(s) by which this cytokine contributes to brain injury remain(s) largely unidentified. Herein, we review the evidence that demonstrates the contribution of IL‐1β to the pathogenesis of both acute and chronic neurological disorders. Further, we highlight data that leads us to propose IL‐1β as the missing mechanistic link between a potential beneficial inflammatory response and detrimental glutamate excitotoxicity.

Peri-operative injuries to an allograft exacerbate graft rejection, which, in humans, is primarily mediated by effector memory T cells. IL-6 transcripts are elevated in human coronary artery segments rapidly increase post-transplantation into immunodeficient mouse hosts compared to pre-transplant specimens and fall dramatically by 30 days. Adoptive transfer of human PBMCs allogeneic to the artery two days post-operatively results in T cell infiltrates and intimal expansion four weeks later. Antibody neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration, but increases the relative expression of CD161 while decreasing other Th17 markers. Co-culture of class II MHC-expressing human endothelial cells (ECs) with allogeneic CD4(+) memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC co-cultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures, an effect dependent on CD161(+) T cells, increases expression of FoxP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells.

CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have been identified. Here we describe the lead finding and engineering approach that lead to the identification of BI 655088, a potent biotherapeutic antagonist to CX3CR1. BI 655088 is a potent CX3CR1 antagonist that, upon therapeutic dosing, significantly inhibits plaque progression in the standard mouse model of atherosclerosis. BI 655088 represents a novel and highly selective biotherapeutic that could reduce inflammation in the atherosclerotic plaque when added to standard of care treatment including statins, which could result in a significant decrease in atherothrombotic events in patients with existing cardiovascular disease.

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