The overall goal of this project is to functionally and phenotypically characterize gut mucosal T-cells in children with new onset as well as longstanding Crohn's disease (CD), and use this information in guiding the development of new strategies for CD diagnosis, patient substratification and early medical intervention. CD is a devastating lifelong chronic inflammatory destruction of the gastrointestional tract that is most frequently diagnosed in adolescents and young adults. Because the cause of CD remains undefined, diagnosis relies on the identification of destructive mucosal changes identified on x-ray, endoscopy and/or tissue histology. Recent clinical trials suggest that early immunomodulator therapy results in an improved clinical outcome in CD children, but early medical intervention may be hindered by a lag in diagnosis of up to 18 months. Basic investigation also suggests significant differences exist in cellular and molecular mechanisms between """"""""early"""""""" and """"""""late"""""""" phases of chronic inflammation in the intestine, further emphasizing the need for investigation both at the time of diagnosis as well as in longstanding CD. Over the past four years, the investigators have conducted a systematic investigation of mucosal T-cells isolated from endoscopic biopsies in children with CD as well as non-inflammatory bowel disease (IBD) inflammation and normal controls. They have defined unique patterns of in vitro T-cell growth and proliferation in response to interleukin-2 (IL-2), where CD, mucosal T- cells demonstrate significantly enhanced in vitro growth (J. Peds., 133: 675- 81, 1998). Recent flow cytometric analysis of mucosal T-cell phenotype has shown that markers of immunologic memory (CD45RA, CD45RO) and homing (L- selectin) differentiate """"""""early"""""""" and """"""""late"""""""" phases of chronic inflammation in CD children. Thus, the central hypothesis of this proposal is: Characterization of mucosal T-cell function and phenotype will allow for prompt diagnosis as well as substratification into """"""""early"""""""" and """"""""late"""""""" phases of chronic inflammation in pediatric CD. This hypothesis will be tested with the following three specific aims.
Aim 1 is the characterization of mucosal T-cell in vitro growth in the early diagnosis of CD, with cross-sectional validation, longitudinal follow-up, and evaluation of children at risk.
Aim 2 is the characterization of mucosal T-cell phenotype and function during early and late CD with analysis of mucosal T-cell subsets and cytokine production.
Aim 3 is to assess the impact of early immunomodulatory therapy on clinical outcome and correlate with mucosal T-cell phenotype and function in newly diagnosed CD patients over a 24-month longitudinal follow-up. Thus, the K23 Mentored Patient-Oriented Clinical Research Career Development Award will not only define fundamental areas of immunopathogenesis in the under-researched area of pediatric CD, it will also allow the applicant to obtain critical training and expertise required to perform high caliber translational research.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Center for Research Resources Initial Review Group (RIRG)
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Wilde, David B
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Medical College of Wisconsin
Schools of Medicine
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Markowitz, James; Kugathasan, Subra; Dubinsky, Marla et al. (2009) Age of diagnosis influences serologic responses in children with Crohn's disease: a possible clue to etiology? Inflamm Bowel Dis 15:714-9
Dubinsky, Marla C; Kugathasan, Subra; Mei, Ling et al. (2008) Increased immune reactivity predicts aggressive complicating Crohn's disease in children. Clin Gastroenterol Hepatol 6:1105-11
Kugathasan, Subra; Baldassano, Robert N; Bradfield, Jonathan P et al. (2008) Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 40:1211-5
Biank, Vincent; Friedrichs, Frauke; Babusukumar, Umesh et al. (2007) DLG5 R30Q variant is a female-specific protective factor in pediatric onset Crohn's disease. Am J Gastroenterol 102:391-8
Kugathasan, Subra; Loizides, Anthony; Babusukumar, Umesh et al. (2005) Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn's disease. Inflamm Bowel Dis 11:631-8
Kugathasan, Subra; Collins, Nicole; Maresso, Karen et al. (2004) CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn's disease. Clin Gastroenterol Hepatol 2:1003-9
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Kugathasan, Subra; Halabi, Issam; Telega, Grzegorz et al. (2002) Pancreatitis as a presenting manifestation of pediatric Crohn's disease: a report of three cases. J Pediatr Gastroenterol Nutr 35:96-8