This program is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD) AND to using basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include:? ? 1. A study of the mechanism of action of G-CSF in patients with Crohn's disease summarized as follows: ? ? Granulocyte-colony stimulating factor (G-CSF) has proven to be a successful therapy for some patients with Crohns disease. Given the known ability of G-CSF to exert anti-T helper 1 effects and to induce IL-10-secreting regulatory T cells we studied whether clinical benefit from G-CSF therapy in active Crohns disease was associated with decreased inflammatory cytokine production and/or increased regulatory responses. Crohns patients were treated with G-CSF (5ug/kg/day SC) for 4 weeks and changes in cell phenotype, cytokine production, and dendritic cell subsets were measured in the peripheral blood and colonic mucosal biopsies using flow cytometry, ELISA, and immunocytochemistry. Crohns patients who achieved a clinical response or remission based on the decrease in the Crohns Disease Activity Index differed from non-responding patients in several important ways: at the end of treatment, responding patients had significantly increased plasmacytoid to myeloid dendritic cell ratios and significantly more CD4+ memory T cells producing IL-10 in the peripheral blood; they also had a greatly enhanced CD123+ plasmacytoid dendritic cell infiltration of the lamina propria. Interferon-? production capacity was not significantly changed. Additionally, G-CSF treatment did not induce a change in lamina propria cell regulatory (Foxp3+) T cell expression in either responding or non-responding Crohns patients. These data show that clinical benefit from G-CSF treatment in Crohns disease is accompanied by significant induction of IL-10 secreting T cells as well as increases in plasmacytoid dendritic cells in the peripheral blood and in inflamed gut mucosa. ? ? 2. A pilot study of the safety and efficacy of a novel oral agent targeting IL-12p40 in the inflammatory enteropathy affecting a subset of common variable immunodeficiency patients (we reported on this IBD in Gastroenterology 131:748-756, 2006). We enrolled four patients and observed at least one subject who had significant reversal of symptoms including steatorrhea, d-xylose absorption, weight gain, and improvement in cytopenias. ? 3. A Phase II study performed in collaboration with Biogen-Idec in which Avonex (Interferon beta 1a) was evaluated for use in ulcerative colitis. The effect of Avonex on patient immune status and patient clinical response was tested. Using the results of this NIH-based open-label trial of Avonex in UC, we are now moving forward with preparations for a multi-center proof-of-concept placebo-controlled trial to further test the safety and efficacy of this type-I interferon in UC. Patient immune responses to drug treatment with be determined from NIAID patients specimens and specimens obtained from outside of NIH.? 4. A protocol to study the immune abnormalities and response to conventional IBD therapy for Hermansky-Pudlak syndrome patients who develop idiopathic colitis. Hermansky-Pudlak syndrome (HPS) is a model inherited disease for study of IBD etiology because it is caused by a defect in interacting proteins due to single gene mutations on different chromosomes. Patients with HPS have loss of pigment in the skin and eye (oculocutaneous albinism) with reduced vision, a platelet disorder leading to easy bleeding, and may develop pulmonary fibrosis. Patients with HPS also have a risk of IBD over ten-fold greater than the general population; the colitis may be granulomatous and we have shown that it is associated with only two of the known HPS gene defects.? 5. Our purpose was to assess the safety of taking numerous mucosal biopsy specimens during endoscopic procedures (eg, >20/endoscopic procedure) in research subjects. Charts were reviewed for the occurrence of procedure-related major/minor complications. A total of 253 research endoscopies were performed on 133 patients: 169 colonoscopies, 64 sigmoidoscopies, and 20 upper endoscopies. A total of 9,661 biopsy specimens were obtained for research and histopathologic examination (mean 38.2 15.6 per procedure). No major complications were identified. Minor complications occurred with 13 (5.1%) lower endoscopic procedures and included self-limited bleeding (4), pain (5), or both (4). There was no statistically significant association between the number of biopsies, type of procedure, location of research biopsies, operator, polypectomy, or the use of nonsteroidal anti-inflammatory drugs and the risk of complications. This is the first report on the safety of performing large numbers of endoscopic biopsies in research subjects. This practice is well tolerated and appears to have no more than minimal risk without appreciably increasing the risk of otherwise routine endoscopy
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