Pan–CC Chemokine Neutralization Restricts Splenocyte Egress and Reduces Inflammation in a Model of Arthritis

Abstract

Chemokines are key regulators of leukocyte trafficking and play a crucial role under homeostatic and inflammatory conditions. Because chemokines are involved in multiple pathologies, they represent an attractive class of therapeutic targets. However, because of the redundancy of this system, neutralizing a single chemokine may be insufficient to achieve therapeutic benefit. Our strategy was to use a Fc-fusion recombinant protein form of the poxvirus-derived viral CC chemokine inhibitor protein (vCCI-Fc) that has the ability to specifically bind to multiple CC chemokines and neutralize their activity. In this study, we demonstrate first that, in vivo, vCCI-Fc prevents CC chemokine-dependent migration of macrophages into inflamed tissue of carageenan-challenged mice. We next studied this effect of inhibiting CC chemokine activity in a model more relevant to human disease, collagen-induced arthritis. Mice receiving vCCI-Fc revealed a striking retention of splenocytes, including activated and IFN-γ–secreting CD4+ and CD8+ T cells, that was associated with a concomitant decrease of cells in the draining lymph nodes. These phenomena resulted in a significant decrease in the incidence of disease and a reduction in clinical score, joint inflammation, and cartilage destruction as compared with mice receiving isotype control. Taken together, these results define a role for CC chemokines in the control of disease, as interfering with their function leads to a previously unappreciated role of controlling inflammatory cell trafficking in and out of secondary lymphoid organs.

Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection

“…Migration capacity was further increased in the presence of live pSLC, implying that freshly secreted pSLC factors attracted higher number of macrophages (Figures 5E, F). Although pSLC-CM-induced macrophage migration was slightly decreased (<10%) in the presence of standard dose (200–1000ng) of broader CC-chemokine inhibitor, CCI (recombinant viral CCI-Fc chimera), which has shown to be effective in other studies (Buatois et al, 2010), high dose of non-toxic concentrations of CCI (5000ng) was required to produce a significant inhibition of migration (Figure 5G). Since pSLC produce an array of soluble proteins (Figures 5A, S4), our data suggest that collective effect of immune factors, but not CC-chemokine alone, are required to exert effective macrophage chemotactic ability.…”

Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis

“…However, there has been mechanistic gap between the accumulation of 6DSHbD and reduced homing of effector T cells, which may be explained either by the direct inhibition of T cell adhesion on ECs or by sequestration of chemokines [42, 43]. Actually, neutralization of multiple CC chemokines, which may also achieved by heparin especially via inhibition of oligomerization [44], resulted in a reduction of disease activity in an arthritis model through the retention of effector T cells [43, 45]. The results of the present study may fill this gap by clearly demonstrating that 6DSHbD directly inhibited adhesion of T cells on the endothelium of post-capillary venules by blocking the tethering and adhesion of T cells on 6DSHbD-coated surface of endothelium.…”

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

“…Administration of a recombinant vCCI-Fc protein in a CIA model resulted in reduced infiltration of inflammatory cells into knee joints as well as limited cartilage degradation, possibly as a result of the observed blockade of the egress of IFN-γ-secreting and activated T-cells from the spleen towards the inflamed tissues [36]. Serin protease inhibitors (Serpins) encoded by poxviruses have shown potent anti-inflammatory activity in a number of disease models [37].…”