Encapsulation in hollow fibres of xenogeneic cells engineered to secrete IL-4 or IL-13 ameliorates murine collagen-induced arthritis (CIA)

Abstract

SUMMARYA strategy of gene therapy using IL-4 or IL-13 xenogeneic transfected cells encapsulated into permeable hollow fibres (HF) was used to treat CIA. Hydrogel-based hollow fibres were obtained from AN-69 copolymer, already known for its biocompatibility and tolerance in rodents. Permeability to IL-4 and lack of cell leakage from the fibres were ascertained in vitro and in vivo. Chinese hamster ovary (CHO) fibroblasts transfected with mouse IL-4 gene were encapsulated in HF (6·25 × 10 5 cells/HF). IL-4 was detected in vitro in the culture supernatant of filled fibres for at least 19 days. IL-4 or IL-13 transfected CHO cells encapsulated in HF were implanted in the peritoneum of mice on days 11-13 after immunization with type II collagen. Control mice were treated with fibre containing CHO cells transfected with b-galactosidase (bgal) gene; a positive control group consisted of mice treated by subcutaneous injection of 10 6 cells on days 10 and 25. Mice were monitored for signs of arthritis by observers unaware of the status of animals. Results of these experiments indicate that severity of the articular disease was significantly reduced in the groups of mice treated with CHO/IL-4 or CHO/IL-13 cells encapsulated in HF, compared with control groups receiving CHO/bgal cells encapsulated in HF. Histological analysis confirmed these data and extended them to a better inhibitory effect of encapsulated cells compared with free cells on inflammatory and destructive joint disease. Moreover, such long-term treatment with HF was well tolerated; macroscopic and histological aspects of peritoneal cavity were moderately inflammatory. Thus, our results may have important implications for clinical use of gene transfected cells as therapeutic agents in the treatment of autoimmune diseases.

Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis

“…19,20 More importantly, we and others have shown that administration of IL-4, IL-13, or IL-10 ameliorates CIA, as well as other models of RA. 16,17,[21][22][23][24] To overcome the short half-life of cytokines in vivo, gene transfer has been investigated in various models of RA. 25 Adenoviral and retroviral vectors have been used successfully in several RA models to deliver genes encoding anti-inflammatory compounds such as IL-1ra, 8,9,26 TNF soluble receptor 7 or IL-10.…”

“…Furthermore, we have shown in an earlier study that cell vector systems such as cells transfected in vitro, although cumbersome, can be used successfully in experimental arthritis. 16,17,21 Nonviral vectors are not immunogenic but until now have not allowed effective delivery and prolonged expression of transgenes. The adeno-associated virus (AAV) exhibits a number of advantages over these vectors.…”

Vectors for the treatment of autoimmune disease

“…The safest ex vivo strategy is to re-introduce cells in an encapsulated form, which will permit secretion of therapeutic protein, but also provide the means to remove all transduced cells should termination of the treatment be required. 183 Alternatively, cells transduced ex vivo can be directly re-injected at the disease site. This approach has been applied in a phase I clinical trial in RA where retrovirally transduced synoviocytes were injected into metacarpophalangeal joints.…”

Circadian renal rhythms influenced by implanted encapsulated hANP-producing cells in Goldblatt hypertensive rats

“…10,11 Another approach of gene therapy developed to overcome these obstacles consists of implanting microencapsulated gene-transfection cells. [12][13][14][15] The engineered cells are encapsulated to prevent them from having contact with host tissues. We used a technique based on local delivery of hANP from genetically engineered Chinese hamster ovary (CHO) cells, using capsules that can be implanted in the body for therapeutic protein or peptide release in the treatment of cardiovascular diseases.…”