- Paper Report
- Open Access
Targeted arthritis gene therapy with T cells
- David Gould1
© Biomed Central Ltd 2001
- Received: 16 August 2001
- Accepted: 4 September 2001
- Published: 4 September 2001
- gene therapy
- IL-12 p40
- T cells
CD4+ T cells have tissue-specific homing properties and are observed in target organs in autoimmunity. As such, these cells could be utilised as carrier cells to achieve local expression of immunoregulatory genes at disease sites. IL-12 is a heterodimeric cytokine that promotes Th1 differentiation of T cells. The p40 subunit of IL-12 expressed by itself, however, is an antagonist of IL-12 function and therefore has potential therapeutic benefit in arthritis. To provide direct evidence of T cell homing to disease sites in the mouse collagen-induced arthritis (CIA) model, the authors have utilised collagen type II (CII)-specific primary T cells and hybridomas derived from CII-specific TCR transgenic mice. Cells engineered to express reporter genes enabled analysis of in vivo localisation, and cells transduced to express IL-12 p40 were assessed for therapeutic effect.
Adoptively transferred CII-specific T-cell hybridomas localised to, and remained within, both asymptomatic and arthritic joints in CIA, whilst localisation in the joints of naive animals was only transient. Hybridomas with antigen specificity for myelin basic protein (MBP) also localised to normal and diseased joints but only transiently. When CII-specific hybridomas were engineered to express IL-12 p40 they inhibited disease development when delivered before disease onset, whilst MBP-specific hybridomas expressing IL-12 p40 were not effective. Hybridomas with dual antigenic specificities modulated cytokine balance (IFN?, IL-4) in draining lymph nodes but did not alter T-cell proliferation or systemic antibody production. Therefore, the therapeutic effect observed with CII-specific cells was postulated to be due to their unique ability to localise to and express IL-12 p40 within joints. In addition, primary CD4+ lymphocytes isolated from CII transgenic mice were also therapeutic when transduced to express IL-12 p40.
Setoguchi K, Misaki Y, Araki Y, Fujio K, Kawahata K, Kitamura T, Yamamoto K: Antigen-specific T cells transduced with IL-10 ameliorate experimentally induced arthritis without impairing the systemic immune response. J Immunol 2000, 165:5980-5986 (PubMed abstract).
Chernajovsky Y, Adams G, Podhajcer OL, Mueller GM, Robbins PD, Feldmann M: Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. Gene Therapy 1995, 2:731-735 (PubMed abstract).
Chernajovsky Y, Adams G, Triantaphyllopoulos K, Ledda MF, Podhajcer OL: Pathogenic lymphoid cells engineered to express TGF b1 ameliorated disease in a collagen-induced arthritis model. Gene Therapy 1997, 4:553-559 (PubMed abstract).