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Haemopoietic disorders

apoptosis, proliferation and endothelial cell activation/migration have also been reported (reviewed in McInnes et al. 2003). High levels of serum cytokines including IL-15 correlate with T cell responses to type II collagen (CII) in vitro. In addition, CII-driven T cell/synovial fibroblast cross-talk amplified the release of IL-15, IL-17 and IFNy via cell contact and CD40-dependent pathways (Cho et al. 2004). Moreover, IL-15 and TNF together promote expression of NKG2D on CD4+ CD28-RA T cells that in turn were stimulated by synoviocyte expression of MIC ligands of NKG2D. IL-15 thereby opposes the effects of native regulators of this pathway and provides a potential route to enhanced autoreactivity (Groh et al. 2003).

Several approaches are in development to inhibit IL-15 in arthritis including neutralising monoclonal antibody, mutant IL-15:Fc fusion protein and soluble forms of the IL-15Ra (Table 2). A fully human antibody, HuMax-IL15 (Genmab A/C; antibody now termed AMG714) has been developed that is capable of binding not only soluble but also membrane-bound IL-15. AMG714 binds IL-15Ra-bound IL-15 and in vitro, effectively neutralises IL-15-mediated lymphocyte reversal of apoptosis and pro-inflammatory cytokine release. AMG714 is currently in phase I and II clinical trials in patients with active RA. Preliminary data indicate that this agent, administered by sc injection, is well tolerated in patients and when given weekly for 4 weeks produces encouraging ACR20 and ACR50 responses (Baslund et al., 0P0008; EULAR 2003, Ann Rheum Dis 2003). However, the study design did not include a placebo agent throughout and so caution should be exercised in interpreting these data.

Table 2. Agents designed to modify IL-15 function

Enhance immune function Recombinant IL-15

Suppress immune function Anti-IL-15 (AMG714) antibody

Soluble IL-15 receptor a IL-15:Fc mutant (CRB-15) Anti-IL-2/15 receptor P antibody Signalling molecular targets JAK3 STAT3/5

In vivo targeting of IL-15 demonstrates that rodent CIA can be effectively ameliorated using soluble IL-15Ra. Treated DBA/1 mice exhibit reduced inflammation and suppression of histologic articular destruction (Ruchatz et al. 1998). We recently conducted a pilot study in collagen-induced arthritis in cynomolgus monkeys with sIL-15Ra and demonstrated reduction in CRP with suggestive effects on swollen joint count (unpublished data). This approach has not, however, been taken at this stage to human trials. A further intriguing possibility is the use of an IL-15:Fc fusion protein in which the IL-15 component is mutated to form a competitive antagonist. This moiety (designated CRB-15) suppresses delayed-type hypersensitivity in rodent models and delays cardiac transplant rejection (Kim et al. 1998; Ferrari-Lacraz et al. 2001). Thus, IL-15 clearly exhibits a suggestive bioactivity profile, is expressed in RA synovial tissues, is tractable in arthritis models and in early clinical trials shows promise as a target. It is clearly important to test the effect of IL-15 neutralisation in appropriately powered phase II clinical trials -such data will be available in the near future.

IL-15 function has been tested across a range of inflammatory conditions including pulmonary inflammation in which it is unlikely to represent a target in asthmatic conditions, but may offer promise in sarcoidosis or even COPD (reviewed in McInnes and Gracie 2004). Beneficial effects have been reported in models of diabetes and in transplantation across minor and major MHC incompatibility, in the latter utilised with either anti-CD4 or agonistic IL-2 and rapamycin (Zheng et al. 2003).

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