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Title: The role of OX40-OX40L interactions in experimental colitis
Author: Bachler, Marcus A.
ISNI:       0000 0001 3434 8441
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2003
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Mice with TNBS colitis were treated with OX40 fusion proteins designed to have different effector functions in vivo (human OX40 fused to the constant region of human IgG1, and human OX40 fused to human IgG4 where Leu235 had been mutated to Glu to produce a fusion protein which could no fix complement and is reduced in its ability to mediate ADCC). Each construct was equally effective at reducing the CD4 cell infiltrate and TNFα transcript numbers in the colon of mice with TNBS colitis. In addition the efficacy of adenoviruses expressing soluble OX40 and OX40-IgG1 were also tested, and each were identically efficacious in ameliorating TNBS colitis. To extend this work into other models of colitis, OX40-IgG also reduced inflammation in colitis caused by infection with the bacterium Citrobacter rodentium. Since OX40 is expressed on cells in the gut of mice with TNBS colitis and C. rodentium induced colitis, mice were treated with an OX40L-IgG fusion protein, in an attempt to deliver a co-stimulatory signal in vivo. In both cases, OXj40L-IgG treatment exacerbated inflammation. As part of this work however it was discovered that OX40 was present on T cells in normal colon. When normal mice were repeatedly injected with OX40L-IgG, they developed a mild colitis. In the final part of the thesis, the issue of whether OX40-IgG ameliorates inflammation by blocking extravasation of T cells from the gut into the blood was addressed. When CFSE labelled mesenteric node cells were transferred into mice with TNBS colitis, transferred cells could be recovered from the colon and organised lymphoid tissue 24 hours later. Injection of recipients with OX40-IgG substantially reduced the recovery of labelled cells, strongly suggesting that a blockade of homing to the gut plays a role in the therapeutic effects of OX40 fusion proteins.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available