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The roles of leukocyte cell adhesion...

O'Quinn, Darrell B.

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The roles of leukocyte cell adhesion molecules in mucosal inflammation.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The roles of leukocyte cell adhesion molecules in mucosal inflammation./
Author:	O'Quinn, Darrell B.
Description:	112 p.
Notes:	Adviser: Daniel C. Bullard.
Contained By:	Dissertation Abstracts International67-01B.
Subject:	Biology, Animal Physiology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3201173
ISBN:	9780542489334

The roles of leukocyte cell adhesion molecules in mucosal inflammation.
O'Quinn, Darrell B.

The roles of leukocyte cell adhesion molecules in mucosal inflammation. - 112 p.

Adviser: Daniel C. Bullard.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2005.

The process by which leukocytes move from the blood to a site of tissue injury is mediated by cell surface proteins collectively called adhesion molecules. Elucidation of the specific adhesion molecule pathways required for the recruitment of leukocytes to sites of inflammation is essential not only for our understanding of disease pathogenesis, but also for the improved design of therapeutic approaches targeting these proteins. Based on a review of the literature, we hypothesized that there was considerable redundancy in adhesion molecule function, especially in mediating T lymphocyte interactions. Specifically, we proposed that the blocking or removal of multiple adhesion molecules is required to completely prevent all lymphocyte emigration. To test this hypothesis, we performed investigations targeting the adhesion molecules PSGL-1, LFA-1, alpha4beta 7, alphaEbeta7, and VLA-4 using primarily the Citrobacter rodentium infectious model to induce tissue injury in the colon and elicit the recruitment of inflammatory cells. Briefly, our findings showed that the development of colitis in PSGL-1 mutant mice was not significantly altered. In addition, recruitment of CD3+ cells to the lamina propria was only slightly delayed in these mice, despite our previous finding that PSGL-1 was required for T helper cell rolling in an in vitro parallel-plate flow chamber. Conversely, removal of the integrin LFA-1 caused a profound delay in the appearance of C. rodentium-induced colitic lesions that was associated with a significant early reduction of infiltrating CD3+ cells in the lamina propria. When C. rodentium-infected LFA-1 mutant mice were treated with a monoclonal antibody which blocks interactions mediated by VLA-4 and alpha 4beta7, lymphocyte recruitment was effectively blocked and the histologic appearance of the lesions resembled those in comparably infected Rag-2 mutant mice. Finally, resolution of C. rodentium-induced colitis lesions in beta7 mutant mice were significantly delayed at 15 days post-inoculation, and despite additional blocking of VLA-4 interactions in subsequent experiments, significant inflammation and CD3+ cell recruitment were not blocked. Taken together, the overall conclusion of this study is that blocking and/or removal of multiple adhesion molecules, namely LFA-1, VLA-4, and alpha4beta7, is required to completely prevent all lymphocyte recruitment to inflamed colonic lamina propria.

ISBN: 9780542489334Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

The roles of leukocyte cell adhesion molecules in mucosal inflammation.
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100 1 $a O'Quinn, Darrell B. $3 1294660
245 1 4 $a The roles of leukocyte cell adhesion molecules in mucosal inflammation.
300 $a 112 p.
500 $a Adviser: Daniel C. Bullard.
500 $a Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0204.
502 $a Thesis (Ph.D.)--The University of Alabama at Birmingham, 2005.
520 $a The process by which leukocytes move from the blood to a site of tissue injury is mediated by cell surface proteins collectively called adhesion molecules. Elucidation of the specific adhesion molecule pathways required for the recruitment of leukocytes to sites of inflammation is essential not only for our understanding of disease pathogenesis, but also for the improved design of therapeutic approaches targeting these proteins. Based on a review of the literature, we hypothesized that there was considerable redundancy in adhesion molecule function, especially in mediating T lymphocyte interactions. Specifically, we proposed that the blocking or removal of multiple adhesion molecules is required to completely prevent all lymphocyte emigration. To test this hypothesis, we performed investigations targeting the adhesion molecules PSGL-1, LFA-1, alpha4beta 7, alphaEbeta7, and VLA-4 using primarily the Citrobacter rodentium infectious model to induce tissue injury in the colon and elicit the recruitment of inflammatory cells. Briefly, our findings showed that the development of colitis in PSGL-1 mutant mice was not significantly altered. In addition, recruitment of CD3+ cells to the lamina propria was only slightly delayed in these mice, despite our previous finding that PSGL-1 was required for T helper cell rolling in an in vitro parallel-plate flow chamber. Conversely, removal of the integrin LFA-1 caused a profound delay in the appearance of C. rodentium-induced colitic lesions that was associated with a significant early reduction of infiltrating CD3+ cells in the lamina propria. When C. rodentium-infected LFA-1 mutant mice were treated with a monoclonal antibody which blocks interactions mediated by VLA-4 and alpha 4beta7, lymphocyte recruitment was effectively blocked and the histologic appearance of the lesions resembled those in comparably infected Rag-2 mutant mice. Finally, resolution of C. rodentium-induced colitis lesions in beta7 mutant mice were significantly delayed at 15 days post-inoculation, and despite additional blocking of VLA-4 interactions in subsequent experiments, significant inflammation and CD3+ cell recruitment were not blocked. Taken together, the overall conclusion of this study is that blocking and/or removal of multiple adhesion molecules, namely LFA-1, VLA-4, and alpha4beta7, is required to completely prevent all lymphocyte recruitment to inflamed colonic lamina propria.
590 $a School code: 0005.
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650 4 $a Health Sciences, Immunology. $3 1017716
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