The hyperplastic and highly vascular synovial tissue that characterises the synovitis of juvenile idiopathic arthritis (JIA) has a dense infiltrate of activated inflammatory T cells, as well as B cells, macrophages and dendritic cells [1
]. To enter the inflamed site, these cells migrate across an endothelial barrier, a complex process that involves molecular interactions between several receptor-ligand pairs [4
]. Chemokines are small secreted chemo-attractant molecules involved in such leukocyte trafficking, as well as playing important roles in lymphoid homeostasis and development [6
]. Functionally distinct subsets of leukocytes express different chemokine receptors: thus, recently activated, effector and memory T cells express high levels of the receptors that bind inflammatory chemokines, thought to facilitate their accumulation at inflammatory sites, compared to naïve cells. Similarly, chemokine receptor expression can be used to distinguish Th-1 T cells (which typically express CXCR3 and CCR5) from Th-2 populations (typically CCR3 positive) [9
], or 'central' from 'effector' memory T cell populations [12
As well as mediating chemoattraction, chemokines may also play a direct role in the activation of leukocytes. For example, the chemokine CCL5 (also known as 'regulated upon activation, normally T cell expressed and secreted' (RANTES)) activates T cells when in high concentration through a tyrosine kinase pathway [13
], leads to production of IFNγ by T cells [15
] and may induce maturation of dendritic cells [16
]. Thus, migration of T cells under a chemokine gradient into an inflamed site such as the joint in JIA may itself lead to further T cell activation. Furthermore, several of the inflammatory chemokines have recently been shown to be able to increase T cell activation during T cell-antigen presenting cell interaction through their recruitment to the immunological synapse [17
We have previously shown that inflammatory T cells in the joint in JIA are predominantly of an activated memory phenotype and express high levels of the chemokine receptors CCR5 and CXCR3, and that this correlates with the highly Th-1 skewed phenotype of synovial T cells, which make high levels of IFNγ [18
]. A recent study has extended these data by showing that the CCR5+IFNγ+CD4+ synovial cells were enriched within the CCR7- effector memory population, while CXCR3 was also highly expressed in CCR7+ cells, and that these two receptors may be differentially expressed in different areas of synovial tissue [19
A reduction in T cell migration to the joint in rheumatoid arthritis (RA) has been observed after treatment with anti-tumour necrosis factor therapy or cyclophosphamide [20
], and the number of peripheral blood T cells expressing CXCR3 has been shown to rise after anti-tumour necrosis factor therapy for RA, an observation that may be explained by reduced recruitment to the joint [23
]. A recent phase 1b trial of CCR1 blockade in RA showed clinical benefit at 15 days in those treated with a CCR1 antagonist compared to controls, and a significant decrease in cellularity in synovial biopsies was seen in the treated group [24
]. Thus, chemokines and their receptors represent potential targets for new therapeutics [25
] and drugs that block chemokine-mediated processes might provide synergy with the cytokine blocking biological agents that are now available.
In animal models of arthritis and inflammation, some chemokine blocking agents have been shown to ameliorate or inhibit disease. Thus, antibody to block RANTES inhibited adjuvant-induced arthritis in rats, [27
] and anti-CXCR3 antibody can block inflammation in a mouse model of peritonitis [28
]. The amino-terminal methionylated RANTES antagonist, met-RANTES, has been shown to block disease in both collagen-induced arthritis and recently adjuvant-induced arthritis [29
]. Thus, evidence for the use of chemokine blockade is encouraging. For some chemokine receptors expressed on inflammatory cells, however, data from animal models have provided conflicting results. Blockade of CCR2 in collagen-induced arthritis produced varying results, with the effect being critically dependent on the timing of blockade, suggesting that in the late phase of disease, other populations of cells, perhaps with a regulatory function, may express CCR2 [31
]. Therefore, to design and direct therapies based upon chemokine blockade accurately, it is important to understand the relative contribution of the various chemokines to inflammation, as well as the triggers for, and sites of, their production in human arthritis.
In this study, we have investigated the expression in JIA patients of three of the ligands for the receptors CCR5 or CXCR3. We demonstrate that the chemokines CCL5 (RANTES) and CCL3 (also known as macrophage inflammatory protein (MIP)-1α), ligands for CCR5, and CXCL10 (also known as IFNγ-induced protein (IP)-10), a ligand for CXCR3, are expressed in the inflamed joint in JIA at higher levels than in peripheral blood. High levels of CCL5 protein is demonstrated in synovial CD8+ T cells, from which it is rapidly released on T cell receptor triggering, a response that does not require new protein synthesis. Our data suggest that the chemokines under investigation here are differentially regulated in the inflamed joint compared to healthy tissues. Inhibition of chemokine release, or blockade of their action, may be important pathways to consider in the search for novel therapies to block inflammation in JIA.