The involvement and therapeutic potential of lymphotactin (activation-induced, T-cell-derived and chemokine-related cytokine (ATAC)) in Th-cell autoimmune reactions was the subject of a presentation by Professor Richard Kroczek (Berlin, Germany).
ATAC was first cloned in both mice [7
] and humans [8
] more than 15 years ago, and was initially believed to act as a chemoattractant for lymphocytes [7
]. Subsequent studies in humans indicated that ATAC/lymphotactin was primarily produced in the synovium of RA patients and so, given its role as a chemoattractant, might be a key modulator for T-cell trafficking in the pathogenesis of RA [9
]. Studies using murine models suggest that the receptor for ATAC/lymphotactin is only present on CD8+
dendritic cells, such as those found in the spleen, which, given the role of CD8 cells in the development of self-tolerance by the immune system, may be implicated in the development of autoimmunity.
Cartilage destruction and bone erosion are major problems in RA, and studies have shown that these processes may be mediated by cytokines. Murine arthritis models have demonstrated the therapeutic potential of anti-TNFα and anti-IL-1 antibodies [10
]. During this session on cytokines and arthritis, Professor Wim van den Berg (Nijmegen, The Netherlands) postulated that different cytokines may dominate at different stages of the inflammatory process. For example, in early-stage collagen-induced arthritis both anti-TNFα and anti-IL-1 treatments have been shown to be effective [11
]. Moreover, IL-17 - a T-cell cytokine expressed in the synovium and synovial fluid of patients with RA - has been shown to be a potent inducer of TNFα and IL-1, and is involved in both the initiation and progression of murine arthritis models [12
]. IL-17 not only synergizes with TNFα, but also enhances inflammation and destruction independent of IL-1 and TNFα, making it an additional potential target for the treatment of RA. As such, tailor-made treatment is required for the different patient groups.
Professor Stefan Rose-John (Kiel, Germany) discussed the inflammatory properties of IL-6 and the complexity of IL-6 signalling, together with the consequences of and various techniques employed in IL-6 blockade. During his presentation, Professor Rose-John noted that all IL-6 signalling is mediated via binding of the IL-6 receptor to the ubiquitously expressed glycoprotein 130. The IL-6 receptor is normally membrane bound and expressed only on hepatocytes and some leukocytes; however, this receptor can be cleaved, or shed, from the cell via the actions of a metalloprotease (ADAM17), producing a soluble IL-6 receptor that can then bind to cells which do not normally express this receptor. This phenomenon, so-called trans-signalling, enables IL-6 to exert its effects upon a much wider range of cell types, including smooth muscle cells, endothelial cells and neural cells [13
]. Binding of IL-6 to soluble IL-6 receptor has been shown to be proinflammatory, and has thus been implicated in the pathogenesis of RA - making this pathway a target for therapeutic interventions [13
]. Recent studies have revealed that selective blockade of this alternative IL-6 signalling pathway using an engineered variant of soluble glycoprotein 130 (sgp130Fc) led to substantial clinical improvement in a preclinical arthritis model [14
Although TNFα has been implicated in the pathogenesis of RA, it also plays an important role in host defence, with complete TNFα blockade associated with an increased risk of mycobacterial infection [15
]. Professor Sergei Nedospasov (Berlin, Germany and Moscow, Russia) described in detail the development of a novel humanized murine model for the study of TNFα in collagen-induced arthritis [16
]. In this heterozygous model, both alleles are active - producing human and murine TNFα, and thus allowing detailed comparison of human versus mouse regulation of TNFα expression. In the homozygous model, approximately 40 to 50% of humanized mice will develop arthritis (mediated by human TNFα), which can be treated clinically using TNF blockers. Using this, and several other murine models that they have developed, Professor Nedospasov and his team aim to determine the source of TNFα that protects against infection and to develop TNFα inhibitors that target specific cell types or compartments in the body where TNFα is overproduced.
Session 2 continued the theme of cytokines in arthritis and began with an overview of the biological role of IL-1 and its novel homologue IL-33 in inflammatory responses. The original members of the IL-1 superfamily were IL-1α, IL-1β and IL-1Ra; however, several additional molecules with structural homology have been added to this family in recent years, namely IL-1F5, IL-1F6, IL-1F7, IL-1F8, IL-1F9, IL-1F10, IL-18 and IL-33 (Figure ). Professor Cem Gabay (Geneva, Switzerland) discussed how the balance between IL-1and IL-1Ra influences the development and severity of arthritis. Using conditional knockout mice in which the expression of IL-1Ra has been selectively targeted in myeloid cells, Professor Gabay's group showed that these mice had a more rapid onset and severe form of collagen-induced arthritis with lower levels of IL-1Ra in lymph nodes and increased Th1 and Th17 responses [17
]. IL-33 - which binds to a member of the IL-1 receptor family, inducing similar intracellular signals to IL-1 - is also expressed in human synovial fibroblasts with increased expression in arthritic joints of murine models, suggesting a potential role in the pathogenesis of arthritis [18
Figure 3 The IL-1 superfamily. The original members of the IL-1 superfamily were IL-1α, IL-1β and IL-1 receptor antagonist (IL-1Ra). IL-1F5, IL-1F6, IL-1F7, IL-1F8, IL-1F9, IL-1F10, IL-18 and IL-33 have been added to this family in recent years (more ...)
Interferons are a family of naturally secreted proteins with immunomodulatory functions. IFNβ has anti-inflammatory properties and plays a role in bone homeostasis. IFNβ treatment has been shown to reduce the severity of collagen-induced arthritis in mice [19
] and rhesus monkeys [21
]. Conversely, IFNβ deficiency resulted in the development of severe collagen-induced arthritis in mice as a result of increased activation of stromal cells and osteoclasts [22
]. After reviewing the lack of efficacy of subcutaneous injections of IFNβ protein three times weekly for the treatment of RA [23
], Dr Margriet Vervoordeldonk (Amsterdam, The Nether-lands) went on to discuss the potential of intra-articular IFNβ gene therapy for the treatment of RA. In a set of proof-of-principle studies using an adenoviral vector and recombinant adeno-associated virus type 5 for local delivery of the rat IFNβ gene [24
], a beneficial effect has been shown on arthritis development in two different rat models of arthritis.
Local delivery of adenoviral vector or recombinant adeno-associated virus type 5 vectors expressing rat IFNβ after the onset of disease reduced paw swelling impressively in both injected and uninjected joints. Strikingly, IFNβ treatment protected against bone and cartilage erosions. Together, the results provide a rationale for IFNβ as a therapeutic target for intra-articular gene therapy for arthritis.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be produced locally in the synovium of individuals with RA, but not in those with osteoarthritis [26
]. Dr Christine Plater-Zyberk (Munich, Germany) described the validation of an anti-GM-CSF monoclonal antibody (22E9) for the treatment of RA, and noted how administration of this antibody decreased arthritis severity in several experimental models [28
]. Dr Plater-Zyberk went on to discuss the development of MT203, a human anti-GM-CSF antibody with subnanomolar affinity and a very slow off-rate, which has been derived from phage display-guided selection. MT203 has been shown to be stable in human serum and to inhibit the production of IL-8 at subnanomolar concentrations. Preclinical studies suggest that MT203 may be useful for the treatment of RA and other indications, including psoriasis and multiple sclerosis. The first clinical trial application for MT203 was submitted in Europe early in 2009 and the trial has now started.