Inflammatory Bowel Disease

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The gut has been proposed as a target for gene delivery for a variety of diseases including both metabolic diseases and primary diseases affecting the intestine, including the inflammatory bowel diseases, Chron's disease and ulcerative colitis [42, 43], Toward this end Hogaboam and colleagues have shown that intraperitoneal delivery of adenovirus encoding interleukin-4 (AdIL-4), a prototypic TH2 cytokine, attenuates colitis induced by trinitroben-zene sulfonic acid (TNB) [44], TNB-induced colitis is associated with an acute phase followed by an immunologically mediated phase, which is thought to be hapten-induced [45], The attenuation as a result of AdIL-4 in colitis was associated with a reduction in colonic IFN levels and less induction of inducible nitric oxide synthase [44]. The same group has shown similar data for another TH2 cytokine, interleukin-10 in a similar model of colitis [46].

Adenovirus IL-10 treatment was again done by the intraperitoneal route and associated with a significant reduction in colonic myeloperoxidase activity and leukotriene levels, both markers of acute inflammation. What remains unclear from these studies is whether T-cell activation is modified and whether there is protection against a second bout of colitis. Last, the intraperitoneal approach is essentially a systemic form of therapy since IL-4 and IL-10 can be detected in the serum of these mice. Since the gut can be transduced directly with adenovirus vectors, this raises the possibility that local administration of vectors to inflamed intestine could be used to compartmentally upregulate an immunomodulatory gene that would prevent or attenuate existing colitis.

Toward this end, Wirtz and colleagues have investigated adenovirus-mediated gene transfer to the inflamed colon using intrarectal administration of Ad5-based vectors. These investigators observed significant gene transfer to colonic epithelium, whereas no colonic gene transfer was observed when the vector was given systemically (intravenous or intraperitoneally). Moreover, gene transfer was enhanced in the setting of TNB-induced inflammation. Last, the investigators investigated an Ad5-based vector with a lysine repeat engineered in the fiber gene, the protein responsible for initial interactions with the Coxsackie-adenovirus receptor. With this genetically modified vector, the investigators observed enhanced gene transfer to cells in the lamina propria and spleen, suggesting that antigen-specific T cells could be modified with this vector approach.

B. Arthritis

Like inflammatory bowel disease, rheumatoid arthritis (RA) is thought to be dominated by THl-like inflammation (Fig. 5) [47, 48]. Among chronic inflammatory diseases, more has been published on gene therapy for arthritis than any other disease. This is likely due to the fact that (1) it is a common disease entity, (2) current treatment, although effective in many cases, can be improved upon, (3) there is a readily accessible site for gene transfer, (4) there are relevant clinical models of the disease, particularly RA, and (5) gene transfer can be accomplished locally to the synovial lining cells using adenovirus-based vectors [49]. The pathogenesis of RA is complex but data to date suggest that there exist alloreactive T cells that secrete TH-l-like cytokines such as TNFa, TNFp, IL-2, and IFN, which drives inflammation. Accessory cells can also secrete TNF, IL-ip, and IL-18, which are also proinflammatory and can drive TH1 inflammation. This leads to an inflammatory synovial pannus, which mediates destruction of cartilage and joint erosion, which results in loss of joint function over time. A novel T-cell-derived cytokine, IL-17, has also been implicated in the pathogenesis of RA [50].

Since TH-1 inflammation can be downregulated by TH-2 cytokines, such as IL-4 or IL-10, these cytokines have been investigated as candidate genes

Figure 5 Schematic diagram of the pathogenesis of RA.

to modify RA inflammation. Woods and colleagues investigated adenoviral-mediated gene transfer of the human IL-4 gene into synovial explants from RA patients and demonstrated a significant reduction in IL-ip, TNFa, and IL-8 elaboration in the explant cultures treated with AdIL-4 [51]. In follow-up to this work, the same group demonstrated in vivo efficacy of intraarticular AdIL-4 treatment in adjuvant-induced arthritis in a rat model [52]. Of note was that AdIL-4 was effective in both a pretreatment and a posttreatment paradigm [52]. Similar to the in vitro findings in human explants, the in vivo treatment with AdIL-4 in the rat model was associated with lower TNFa and IL-ip levels [52]. Lubberts and colleagues have also shown efficacy of AdIL-4 in a murine model of collagen-induced arthritis (CIA) [53, 54]. Interestingly, in these studies IL-4 had less effect on the joint inflammation than it appeared to have on preservation of cartilage and in preventing bone erosion [53]. These later effects were associated with a reduction of mRNAs for IL-17, TNF, and IL-lp, as well as a decrease in metalloproteinase activity [53, 54]. These investigators also demonstrated that IL-4 can increase type I procollagen synthesis and thus this may explain the joint-sparing/repair effect of IL-4 [53]. Last, Kim and colleagues demonstrated that both periarticular and systemic AdIL-4 were effective in a model of CIA [55].

Whalen and colleagues have investigated another TH2 cytokine, viral IL-10, encoded by an adenoviral vector (AdvIL-10) given by periarticular injection in the same model of CIA and found significant benefit in terms of development of arthritis and arthritis score. Moreover, the investigators showed that the injection of AdvIL-10 into one joint prevented arthritis in a second joint [56], This may be due to in vivo T-cell immunomodulation by viral IL-10. In further support of a role for TH2 cytokine gene therapy in RA, Woods and colleagues have recently demonstrated that adenovirus-mediated gene transfer of interleukin-13, another TH2 cytokine, also suppresses TNF and IL-ip production in RA explant cultures [57].

In addition to the TH2 cytokine approach, the other approach of adenoviral gene transfer for arthritis has largely focused on the proinflammatory cytokines TNFa and IL-ip. Toward this end, our laboratory has created soluble type-1 receptors for both IL-1 [58] and TNFa [59] (Fig. 6). Both these molecules are dimerized by the addition of murine IgG Fc fragment and in the case of the TNF inhibitor, this molecule has been found to be more potent in TNF inhibition than monoclonal antibodies that only bind to one epitope [60]. Moreover, the proteins have longer half-lives in vivo than the monomeric soluble receptors [59]. Adenoviral-mediated gene transfer of either one of these constructs into the joint space in a rabbit model of arthritis showed less white blood cell infiltration as well as less joint swelling. However, the IL-1 inhibitor showed a better effect in preventing a reduction in cartilage matrix

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