Background and aim HLA-B27/human β2m transgenic rats (B27-rats), a model of spondylarthritis (SpA) develop spontaneous colitis and arthritis. Recently, we demonstrated that altered DCs function could be critical for triggering SpA since DCs from B27 rats promote a biassed expansion of pro-inflammatory Th17 cells, which might have a pathogenic role. Furthermore, the altered interaction of DC/T cell induces a modification of regulatory T cells function, resulting in decreased IL-10 and enhanced IL-17 production by those cells. Interestingly, in vitro blockade of ICOS-ICOSL interaction demonstrated that ICOS signalling plays a key role in generation and maintenance of IL-10/IL-17 imbalance production by regulatory T cells, and biassed-Th17 cells expansion. Thus, we hypothesised that in vivo modulation of ICOS-ICOSL pathway may have therapeutic utility in this model. To investigate this hypothesis we used a genetic approach producing B27. ICOS (B27. ICOS-KO) knockout rats.
Material and methods Using TALEN technology for disrupt the ICOS locus, Dr Anegon and colleagues produced the ICOS. Kcnockout rats that were backcrossed onto the B27 transgenic background. B27 and B27. ICOS-KO rats were weekly weighted, examined and scored for clinical symptoms, including colitis (intensity of diarrhoea), arthritis (severity of swelling), alopecia, orchitis and nail dystrophy
Results As expected, chronic diarrhoea was the most common and persistent finding, being present in all B27 rats. Arthritis and alopecia developed only in some B27 rats. The clinical disease score progressively worsened in B27 rats. In contrast, the B27. ICOS-KO rats did not develop any symptom of disease until age of 16 weeks. Attenuated symptoms were observed in B27. ICOS-KO animals until 24 weeks compared to B27 rats.
Conclusions Our preliminary clinical results suggest a protective role of Icos deletion in onset and severity of the disease in B27 rats.