Disease-Dependent Local IL-10 Production Ameliorates Collagen Induced Arthritis in Mice

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 When the disease is in remission the therapy is withdrawn but withdrawal attempts often results in inflammatory flares, and re-start of the therapy is commenced when the inflammation again is prominent which leads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.

Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

“…Concomitantly, these Lenti‐mBiP treated cells up‐regulated IL‐10 in co‐culture with CII primed cells. These data support the counter‐regulation of IL‐10 and T helper type 17 (Th17)/IL‐17A, as reported in both CIA and RA . Of note is the previously reported observation that rhuBiP‐primed cells ameliorate CIA following adoptive transfer, suggesting that BiP‐primed cells have intrinsic regulatory properties .…”

“…Lenti-mBiP treatment caused significant up-regulation of soluble cytotoxic T lymphocyte antigen-S. J. Thompson and V. M. Corrigall are joint senior authors.minimizing unwanted immunosuppression following systemic delivery [2][3][4]. Using a variety of viral and non-viral vectors, gene therapy has already delivered promising results in disease models of inflammatory arthritis [5][6][7] and the rheumatology clinic [8].Binding immunoglobulin protein (BiP/GRP78) is a highly conserved endoplasmic reticulum chaperone that displays potent extracellular anti-inflammatory and immunomodulatory activity in both mouse and man on release from stressed cells [9]. Recombinant human BiP (rhuBiP) binds to an unidentified receptor expressed predominantly on the surface of human peripheral blood bs_bs_banner Clinical and Experimental Immunology ORIGINAL ARTICLE…”

Valproic Acid and Lithium Meditate Anti‐Inflammatory Effects by Differentially Modulating Dendritic Cell Differentiation and Function

“…B). Therefore, the production of IL‐10 triggered by LiCl may play a role in the suppression of CIA (Henningsson et al, ; Ye et al, ). In contrast, in the present study, we showed that VPA significantly increased IL‐6 but decreased IL‐8 and ‐10 and TNF‐α levels during iDC differentiation.…”

Disease-regulated local IL-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis

“…Construction of promoter-luciferase constructs was done as described elsewhere 3. For construction of pRLL-cPPT-PGK-IL10-PRE-SIN, pRLL-cPPT-Saa3-IL10-PRE-SIN and pRLL-cPPT-MMP13-IL10-PRE-SIN, mIL-10 was amplified from pIG1-IL1e-IL6p-IL10, a construct used by Henningsson and collegues,12 using primers FW 5′-tttgctagctccaccatgcctggctc-3′ and RV 5′-aaacatatgttagcttttcattttg-3′ introducing an Nhe I and Nde I site, and ligated into the promoter constructs.…”

“…We previously showed feasibility of the disease-regulated IL-10 therapy by transplantation of lentiviral-transduced haematopoietic stem cells 12. This led to production of IL-10 in B and non-B antigen-presenting cells (APCs) in lymph nodes and clear-cut reduction of CIA.…”