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Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints
A.V. Miagkov, … , R.S. Munford, S.S. Makarov
A.V. Miagkov, … , R.S. Munford, S.S. Makarov
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1223-1229. https://doi.org/10.1172/JCI14536.
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Article Genetics

Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints

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Abstract

The treatment of chronic inflammatory diseases is complicated by their unpredictable, relapsing clinical course. Here, we describe a new strategy in which an inflammation-regulated therapeutic transgene is introduced into the joints to prevent recurrence of arthritis. To this end, we designed a recombinant adenoviral vector containing a two-component, inflammation-inducible promoter controlling the expression of human IL-10 (hIL-10) cDNA. When tested in vitro, this system had a low-level basal activity and was activated four to five orders of magnitude by various inflammatory stimuli, including TNF-α, IL-1β, IL-6, and LPS. When introduced in joints of rats with recurrent streptococcal cell wall–induced arthritis, the IL-10 transgene was induced in parallel with disease recurrence and effectively prevented the influx of inflammatory cells and the associated swelling of the joints. Levels of inflammation-inducible hIL-10 protein within the joints correlated closely with the severity of recurrence. An endogenously regulated therapeutic transgene can thus establish negative feedback and restore homeostasis in vivo while minimizing host exposure to the recombinant drug.

Authors

A.V. Miagkov, A.W. Varley, R.S. Munford, S.S. Makarov

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Figure 4

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Gene transfer of inflammation-inducible hIL-10 prevents reactivation of ...
Gene transfer of inflammation-inducible hIL-10 prevents reactivation of SCW arthritis. (a) Inhibition of leukocytosis. On day –42, animals were IA injected with PG-APS in both ankle joints. On day –1, animals were injected in both ankle joints with the indicated Ad, as for Figure 2b. In this experiment there were 12 animals per group on day –1. On day 0, reactivation was induced by intravenous injection of PG-APS. On days 0, 1, 2, 3, 4, and 6 after reactivation, two animals from each group were euthanized, and ankle joints were perfused for determining the numbers of infiltrating white blood cells (WBCs) (21). The time course of leukocytosis is shown. Each bar shows the mean ± SEM of measurements from four joints. Data representative of two experiments are shown. (b) Inhibition of joint swelling. In parallel to measuring leukocytosis, inflammation was assessed by measuring joint swelling. As animals in each group were euthanized in order to obtain joint lavages, the data points represent a diminishing number of joints. Swelling was calculated as (di) – (d0), where (di) and (d0) are mean joint diameters at day i and day 0. Error bars represent SEM. P values for comparisons between groups in a and b were calculated using the unpaired one-tailed Student t test. Data on inhibition of joint swelling in other experiments are presented in Table 1.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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