Abstract
Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease characterised by periods of flare and remission. Today’s treatment is based on continuous immunosuppression irrespective of the patient’s inflammatory status. When the disease is in remission the therapy is withdrawn but withdrawal attempts often results in inflammatory flares, and re-start of the therapy is commenced when the inflammation again is prominent which leads both to suffering and increased risk of tissue destruction. An attractive alternative treatment would provide a disease-regulated therapy that offers increased anti-inflammatory effect during flares and is inactive during periods of remission. To explore this concept we expressed the immunoregulatory cytokine interleukin (IL)-10 gene under the control of an inflammation dependent promoter in a mouse model of RA - collagen type II (CII) induced arthritis (CIA). Haematopoetic stem cells (HSCs) were transduced with lentiviral particles encoding the IL-10 gene (LNT-IL-10), or a green fluorescence protein (GFP) as control gene (LNT-GFP), driven by the inflammation-dependent IL-1/IL-6 promoter. Twelve weeks after transplantation of transduced HSCs into DBA/1 mice, CIA was induced. We found that LNT-IL-10 mice developed a reduced severity of arthritis compared to controls. The LNT-IL-10 mice exhibited both increased mRNA expression levels of IL-10 as well as increased amount of IL-10 produced by B cells and non-B APCs locally in the lymph nodes compared to controls. These findings were accompanied by increased mRNA expression of the IL-10 induced suppressor of cytokine signalling 1 (SOCS1) in lymph nodes and a decrease in the serum protein levels of IL-6. We also found a decrease in both frequency and number of B cells and serum levels of anti-CII antibodies. Thus, inflammation-dependent IL-10 therapy suppresses experimental autoimmune arthritis and is a promising candidate in the development of novel treatments for RA.
Highlights
Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that mainly affects the joints and leads to severe bone and cartilage destruction
Arthritis is Ameliorated in LNT-IL-10 Mice To investigate whether an inflammation-dependent increase in IL-10 production would change disease status in the CIA mouse model, the promoter of the human cytokine gene interleukin-6 (IL6) in combination with the IL-1 enhancer region [13] were used to drive the expression of the IL-10 (LNT-IL-10) or a green fluorescent (LNT-green fluorescence protein (GFP)) control gene (Figure 1A)
The integration of the lentiviral construct was successful (Suppl 1B) and, almost all mice in both groups developed arthritis, those transplanted with the LNT-IL-10 transduced Haematopoetic stem cells (HSCs) showed a significant reduction in the severity of clinical arthritis (Figure 1B)
Summary
Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that mainly affects the joints and leads to severe bone and cartilage destruction. Todays treatment is based on continuous immunosuppression either by conventional disease modifying anti-rheumatic drugs such as methotrexate and/ or by biological agents targeting specific proteins e.g. TNF These treatment modalities can cause side effects such as severe infections and, in addition, attempts to withdraw therapies in established RA often leads to flares [1]. To overcome these hurdles, disease-regulated therapy appears ideally suited, as it would allow intrinsic expression of the immunosuppressive therapy only during inflammatory conditions i.e. during disease flares but not during periods of remissions. It has been shown that disease-regulated IL-4 expression achieved via the IL-1/IL-6 promoter can protect against cartilage destruction in CIA [3]
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