Retroviral gene therapy of collagen-induced arthritis by local delivery of IL-4

Objective

Rheumatoid arthritis (RA) is an autoimmune arthritis for which treatment options remain limited. Pathogenic mechanisms of RA and its animal model collagen-induced arthritis (CIA) involve joint infiltration by pro-inflammatory T-helper 1 (Thl) type CD4⁺ T cells. This study investigated the potentiel use of retrovirally transduced collagen type II (CII)-reactive CD4⁺ T cells for local delivery of an anti-inflammatory cytokine, interleukin 4 (IL-4), to inflamed joints.

Method

CII-specific CD4⁺ T-cell hybridomas (made from CII-specific TCR transgenic mouse T cells) were transduced with a retroviral vector encoding IL-4 and the marker yellow fluorescent protein (YFP) in a bicistronic IRES containing construct. Transduced hybridomas were sorted based on YFP expression and injected intravenously into immunized male DBA/lLacJ mice prior to disease onset. For bioluminescence imaging, IL-4 expressing T cell hybridomas were transduced with luciferase expressing retroviral constructs.

Results

Adoptive transfer of transduced hybridomas, that constitutively expressed the transgenes, significantly decreased mean disease severity by reducing the number of inflamed joints. Bioluminescence studies showed that the hybridomas migrated to, accumulated in, and were retained in the inflamed joints. There were no significant changes in the cytokine milieu of the draining lymph nodes nor in the systemic levels of the anti-collagen antibody subtypes IgGl and IgG2a in treated mice.

Conclusion

The beneficial clinical effects observed in our model were most likely based on the local actions of IL-4 in the inflamed joints. The local delivery (and effects) of regulatory cytokines like IL-4 constitute a novel and effective method of treating organ-specific auto-immune diseases and of minimizing the systemic adverse effects of immune-modulating therapy.