Lymphocyte and Epithelial Contributions to Crohn's Disease Studied in the SAMP1/YitFc Murine Ileitis Model 539 views

Immunologic mechanisms and etiologic agents that contribute to the development of human Crohn's disease remain poorly understood. SAMP1/YitFc mice spontaneously develop discontinuous, transmural ileitis with histopathologic features strikingly similar to those observed in human Crohn's disease. I first investigated differences in the composition of mesenteric lymph node (MLN) CD4 + T cell populations in SAMP1/YitFc versus wildtype AKR mice in an attempt to differentiate ileitis-producing and nonpathogenic mucosal CD4 + T lymphocyte populations. I identified increases in several SAMP1/YitFc MLN lymphocyte subsets including overlapping populations of α E integrin + and CD25 + CD4 + T cells that express cytokines characteristic of regulatory T cells. These cells block colitis in vivo and effector cell proliferation in vitro, but are incapable of preventing ileitis both in SAMP1/YitFc mice and when adoptively transferred along with effector cells into SCID mice. Based on the observations that the size of the α + E CD4 + cell population correlates with MLN B cell expansion, and that MLN B cell population size is greatly increased in SAMP1/YitFc versus AKR mice, I next determined the phenotype and pathogenicity of SAMP1/YitFc MLN B cells. These B cells produce increased IgA levels, worsen the severity of adoptively transferred ileitis, and promote effector T cell proliferation by inhibiting regulatory T cell function. Finally I determined if SAMP1/YitFc ileitis originates from a primary defect in immune cells or in non-hematopoietic tissues such as the epithelium by generating chimeric mice using bone marrow transplantation. SAMP1/YitFc mice reconstituted with AKR bone marrow developed substantial ileitis, whereas SAMP1/YitFc bone marrow did not confer ileitis to AKR mice. Increased permeability and decreased expression of the peroxisomeproliferator-activated receptor (Ppar)γ by SAMP1/YitFc epithelium suggest that this 3 primary non-hematopoietic susceptibility leading to SAMP1/YitFc ileitis is derived from epithelial cells. Taken together, the results presented herein indicate that SAMP1/YitFc ileitis is likely caused by epithelial dysfunction leading to the initiation of ileal inflammatory responses involving Th1-polarized T cells and pro-inflammatory B cells that cannot be effectively controlled by regulatory T cells. Note: Abstract extracted from PDF text

PHD (Doctor of Philosophy)

English

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2005-01-01