Anne Flanigan

A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily originally shown to play a critical role in adipocyte differentiation and glucose homeostasis, has recently been implicated as a regulator of cellular proliferation and inflammatory responses. Colonic epithelial cells, which express high levels of PPAR-gamma protein, have the ability to produce inflammatory cytokines that may play a role in inflammatory bowel disease (IBD). We report here that PPAR-gamma ligands dramatically attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of nuclear factor-kappaB via an IkappaB-alpha-dependent mechanism. Moreover, thiazolidinedione ligands for PPAR-gamma markedly reduce colonic inflammation in a mouse model of IBD. These results suggest that colonic PPAR-gamma may be a therapeutic target in humans suffering from IBD.

Recent developments in inflammatory bowel disease therapy

Inflammatory bowel disease (IBD) is a collective term used to encompass two histologically distinct disorders of the gastrointestinal tract, ulcerative colitis and Crohns disease. Although the exact aetiology of these diseases remains elusive, environmental, genetic and immunological factors appear to have the strongest base for causing the disease. Traditional medical therapy includes corticosteroids, congeners of 5-aminosalicylic acid and immune modulators, such as azathioprine, methotrexate and cyclosporine. The majority of patients can be managed with these therapies; however, IBD does relapse, suggesting that these therapies do not alter the course of disease. An explosion of information and new data has generated a host of pharmacological and immunological strategies to treat IBD. This comprehensive review examines the most recent patented claims that will likely benefit treatment and management of IBD. While some of the claims are not fastidious, a few of the newer claims have tremendous potential...

Inflammatory bowel diseases: a new wave of therapy

This review focuses on recent advances in the pathogenesis of inflammatory bowel diseases (IBDs) and current developments in claimed patents for the management of these diseases. These are developed in the hope of replacing conventional corticosteroids, 5-aminosalicylic acids (5-ASA) and immunosuppressants which have been the mainstay of therapy for decades. These patents represent a change in direction to more specific therapies to block a host of inflammatory mediators, either at their synthesis level or blocking binding to their designated receptors. The changes also represent a shift from synthetic inhibitors to biologicals for which the in vivo efficacy and side-effects need to be evaluated. These advancements represent a new wave of therapy to treat these debilitating diseases.

PParγ Ligands and Intestinal Inflammation

Ulcerative colitis (UC) and Crohn’s disease (CD) comprise a group of inflammatory disorders of the gastrointestinal tract that are collectively termed inflammatory bowel disease (IBD). Both UC and CD are chronic disorders often characterized by exacerbations interposed between variable periods of remission, and are associated with different clinical presentations and histopathological features. Ulcerative colitis is limited to the mucosa of large bowel, whereas Crohn’s diseases is transmural and may affect any portion of the gastrointestinal tract. Although the precise etiology of IBD remains unknown, extensive research in the past decade has led to a greater understanding regarding the pathogenesis of IBD. Application of this knowledge has led to new advances in the treatment of this chronic debilitating condition. In the normal state, the intestinal tract exists in a quiescent inflammatory state presumably to protect the organism from the highly toxic substances and bacteria found in the lumen of the intestinal tract. It is currently believed that inflammatory bowel disease (IBD) constitutes a heterogeneous group of diseases with a common final manifestation of mucosal inflammation resulting from a failure to down-regulate this normal, controlled inflammation that occurs in the gut [1,2].

Lymphotoxin beta receptor-immunoglobulin fusion protein (LTBRFP) ameliorates inflammation and tissue damage in the dextran sulfate (DSS) model of mouse colitis

Lymphotoxin (LT) is a member of the TNF receptor family present on cell surfaces as a LTa/13 heteromeric complex. This ligand binds to the LTI3 receptor (LTBR). This signaling system is important in both the development of lymph nodes and the maintenance of lymphoid architecture in the secondary immune system. To test the role of the LTa/13 complex in the regulation of immunological events associated with inflammatory bowel disease, we used LTBRFP to block LT function. Based on preliminary studies (one, two or three treatments on days 1, 5 and 12), we evaluated the efficacy of this fusion protein in animals with 4% DSS-induced colitis (6 days of DSS followed by 15 days of plain water). Treatments with the LTBRFP and control IgG were done i. p. (0.1 nag/animal) on days 1, 5 and 12. These results were compared to 5-ASA therapy (Dipentum ® 50 mg/kg/day during plain water feeding). Mice were sacrificed on days 14 and 21. Disease activity index (DAI) was measured each day during the study. At the time of sacrifice, blood was drawn for measuring circulating cytokines (IL-6, IL-12 and TNFa) colons were obtained for histological analysis. RESULTS: Preliminary studies showed that a single injection of LTBRFP was marginally effective in reducing the DAI (IgG = 2.13 +/0.13; LTBRFP single injection given on day 1 = 1.58 +/0.50). The effect of multiple treatments of LTBRFP on DAl is shown: