Progressive destruction of articular cartilage and bone is the pivotal problem of rheumatoid arthritis (RA). Joint destruction is the cause of severe disability and determines the long-term outcome of disease. Conventional therapy does not control this destructive process sufficiently and the anti-rheumatic drugs available today can cause severe systemic adverse effects. Local application of chondroprotective and osteoprotective agents by means of gene therapy would be an attractive alternative to conventional therapy of RA and could provide long-term expression of the therapeutic agents and minimize systemic adverse effects. For this purpose, we have developed the concept of adoptive cellular gene therapy. This treatment strategy is based on using genetically engineered cells that home specifically to sites of autoimmune inflammation and thus allow local delivery of therapeutic gene products. Ex vivo transduction of these cells avoids systemic exposure of the host to the transgene-encoding vector and thus adds to the safety of this approach. In this article of the CIS Spring School in Autoimmune Diseases 2005 proceedings, we review our work on developing the strategy of adoptive cellular gene therapy and summarize recent advances in the evaluation of therapeutic effects and the identification of novel therapeutic targets.
"Local and systemic approaches have both been successful for delivery of therapeutic genes, where each can be accomplished via an in vivo or ex vivo manner. This topic has been covered thoroughly in several recent reviews    , and only the basics will be provided here. Local in vivo strategies typically involve gene transfer via an intra-articular (i.a.) injection to cells that comprise the synovial lining, whereas ex vivo strategies involve the removal of synoviocytes from the joint, transduction in vitro, and re-injection of transduced cells into the joints. "
[Show abstract][Hide abstract] ABSTRACT: Chronic autoimmune diseases are driven by cells that respond to tissue components of the body. Inflammation in diseases like rheumatoid arthritis, diabetes or multiple sclerosis, can be suppressed by drug therapy. However, the broad range of immunosuppressive action of these drugs often does not restrict to the autoimmune response, but increases the risk of serious infection. Therefore, therapies that restrict to suppression of only the auto-immune response need to be developed. CD4+ T cells that recognize cartilage are responsible for induction of arthritis because they direct their actions to cartilage in the joints. Such T cells are present in the joints of arthritis patients. Therefore, we hypothesized that T cells specific for the cartilage-derived antigen proteoglycan can be used to target arthritis with suppressive agents after introduction of genes that express suppressive agents in these T cells. For our studies we used cartilage proteoglycan-induced arthritis, which is a chronic arthritis in mice. This arthritis represents many features of rheumatoid arthritis, and is mediated by Th1 cells, B cells and antibodies. To enable studies on cartilage-specific T cells, we generated a transgenic mouse expressing a proteoglycan-specific T cell receptor on its T cells. Due to the high number of cartilage-specific T cells, transgenic mice were highly susceptible for arthritis. Moreover, the T cell response of transgenic mice with arthritis shifted to an excessive Th1-phenotype. Therefore, these transgenic mice were useful donors for arthritogenic CD4+ T cells. To explore gene therapy of inflammation with T cells, we provided proteoglycan-specific T cells with different genes encoding immunosuppressive proteins. The genes were isolated from mouse cells and inserted into T cells by retroviruses. Retroviral transduction of T cells resulted in up to 80% of cells expressing the transgenes (IL-4, IL-10, TNF-alpha-Receptor-Ig, IL-1 receptor antagonist). T cells expressing the inserted genes were sorted by flow cytometry and transferred to mice with arthritis. Especially T cells that were manipulated to express IL-10 were able to induce significant suppression of joint inflammation. Moreover, only the IL-10-producing T cells that expressed the cartilage-specific T cell receptor suppressed arthritis, indicating specificity of therapy. In addition, manipulated T cells suppressed production of pro-inflammatory proteins like TNF-alpha, IL-17, IL-2 and PG-specific IgG2a antibodies. Strikingly, we discovered that propagation of IL-10 production in cells of the treated recipient was the mechanism that was used by the transferred IL-10-producing T cells to suppress arthritis. Among the recipient’s cells, T cells and B cells were found to express increased levels of IL-10. Because interleukin-10 is an immunomodulatory cytokine expressed by cells in order to naturally prevent exacerbation of inflammation in healthy individuals, these results indicate that T cells producing IL-10 restore natural immunosuppressive immune responses in arthritis. In conclusion, manipulation of pro-inflammatory T cells that recognize tissue components is a powerful approach to specifically target inflammation in chronic autoimmune diseases. In addition, moving focus from suppression of pro-inflammatory mediators to propagation of immunosuppressive functions of cells may provide a more comprehensive insight in mechanisms that support specific regulatory capacities of the immune system.
[Show abstract][Hide abstract] ABSTRACT: Advances in understanding the biology of rheumatoid arthritis (RA) have opened new therapeutic avenues. One of these, gene therapy, involves the delivery to patients of genes encoding anti-arthritic proteins. This approach has shown efficacy in animal models of RA, and the first human, phase I trial has just been successfully completed. Hand surgery featured prominently in this pioneering study, as a potentially anti-arthritic gene encoding the interleukin-1 receptor antagonist was transferred to the metacarpophalangeal joints of subjects with RA one week before total joint arthroplasty. This study has confirmed that it is possible to transfer genes safely to human joints. It should pave the way for additional application of gene therapy to arthritis and other orthopaedic conditions.
Hand Surgery 01/2002; 6(2):211-9. DOI:10.1007/s11926-001-0054-x
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