The Digestive Health Center of Excellence

The Cominelli Group
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Research Interest: Cytokine Network and Mucosal Immunity

The focus of our laboratory is on investigation of the role played by the cytokine network in the regulation of mucosal immune responses and its alteration in association with intestinal inflammation. We use a comprehensive approach, including state-of-the-art molecular biology techniques, animal models of inflammation, and cultured human intestinal mucosal cells. A major goal of these studies is to understand the molecular mechanism(s) of intestinal inflammation and to develop novel therapeutic modalities for patients affected by chronic inflammatory diseases.

A significant part of our research currently focuses on the SAMP1/YitFc mouse model of intestinal inflammation. We have demonstrated that these mice develop terminal ileitis (Fig 1) that bears a striking similarity to Crohn's disease in humans. Minimal inflammation is observed at 4 weeks of age, but by 10 weeks of age inflammation is found throughout the ileum (Rivera-Nieves et al, 2003). These mice have proven useful in the elucidation of potential disease mechanisms.


Fig. 1. Ileitis in SAMP1/YitFc mice. Ileal sections from 10, 20 and
 70-week-old mice showing progressively more extensive
 inflammatory disease, with Crohn's-like manifestations.
     
  Recently, we have demonstrated that both TH1 and TH2 cytokines play a role in the Crohn's-like ileitis found in these mice (Bamias et al, 2005). The Th1 cytokines IFN-g and TNF were upregulated during the induction phase of ileitis. However, the TH2 cytokines IL-4, IL-5 and IL-13 were found to be elevated during the chronicity or maintenance phase of ileitis (Fig 2). This challenges the commonly held dogma that Crohn's disease is mediated by TH1 cytokines, while ulcerative colitis is mediated by TH2 cytokines. We are investigating combined manipulation of TH1/TH2, a potential therapeutic strategy for the treatment of Crohn's disease.

Fig 2. TH1 cytokines are upregulated in both the induction and chronicity phases of ileitis in SAMP1/YitFc mice, while TH2 cytokines are upregulated during the chronicity phase.

TL1A is a TNF-like cytokine that stimulates IFN-g through binding to DR3. We have investigated the role that TL1A plays in inflammatory bowel disease in both cultured cells from the inflamed human GI tract and in SAMP1/YitFc mice.


Our group has also demonstrated the critical role of the IL-1ra/IL-1 system in inflammatory diseases, specifically in inflammatory bowel disease (IBD). We demonstrated that specific in vivo blockade of IL-1 effectively reduced the severity of inflammation in an animal model of inflammatory disease. Additionally, we have reported an intrinsic imbalance in the relative concentration of pro-inflammatory IL-1 and anti-inflammatory IL-1ra in patients with IBD, which may be responsible for the chronic, relapsing clinical course of the disease. More recently, our search for the genetic mechanism(s) underlying these findings has involved studies investigating the association and functional significance of novel cytokine polymorphisms, particularly in the IL-1 gene cluster, and chronic inflammatory diseases.

Dr. Cominelli is also a member of the Beirne B. Carter Center for Immunology Research.