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Title: Role of CD 40 in the regulation of anti tumor immune response
Researcher: Murugaiyan, G
Guide(s): Saha, Bhaskar
Keywords: Biotechnology, Tumor
Upload Date: 30-Aug-2011
University: University of Pune
Completed Date: September, 2006
Abstract: Activation of T cells requires signals through antigen-specific T cell receptor and costimulatory molecules such as CD40-ligand (CD40-L). While the use of defined tumor antigens for the induction of protective T cells met with a limited success, CD40-CD40-L interaction that was proposed to induce anti-tumor T cells did not prevent tumor growth completely. Using a model for prostate tumor, a leading cause of tumor-induced mortality in men, it has been shown here that the failure is due to a novel functional dichotomy of CD40 whereby it self-limits its anti-tumor functions by inducing interleukin-10. Interleukin-10 prevents the CD40-induced cytotoxic T cells (CTL) and TNF-α and interleukin-12 production, Th1 skewing and tumor regression. Priming mice with tumor lysate-pulsed interleukin-10-deficient DCs or wild-type DC plus antiinterleukin- 10 antibody establishes anti-tumor memory T cells that can transfer the protection into syngenic nude mice. Infusion of antigen-pulsed interleukin-10-deficient but not wild-type DCs back into syngenic mice results in successful therapeutic autovaccination. Having addressed a novel functional dichotomy of CD40 whereby it induces anti-tumor T cells and a pro-tumor cytokine, interleukin-10, the underlying mechanism for the observed duality in CD40 function has been deciphered using mice expressing different levels of CD40 or CD40-L and different doses of anti-CD40 antibody. Using mice expressing different levels of CD40 or CD40-L and different doses of anti-CD40 antibody, it has been shown that greater the T cell CD40-L expression less is the tumor growth and host-protective is the anti-tumor T cell response. Lower CD40-L expression induced higher IL-10 production, and a parallel IL-4-dominated response, IL- 10-sensitive effector T cells and suppressed tumor-regressing T cells. Thus the results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.
Pagination: 157p.
Appears in Departments:National Centre for Cell Science

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04_acknowledgement.pdf48.28 kBAdobe PDFView/Open
05_index.pdf63.15 kBAdobe PDFView/Open
06_abbreviations.pdf87.83 kBAdobe PDFView/Open
07_abstract.pdf150.88 kBAdobe PDFView/Open
08_chapter 1.pdf1.32 MBAdobe PDFView/Open
09_chapter 2.pdf150.91 kBAdobe PDFView/Open
10_chapter 3.pdf273.15 kBAdobe PDFView/Open
11_chapter 4.pdf591.47 kBAdobe PDFView/Open
12_chapter 5.pdf269.57 kBAdobe PDFView/Open
13_references.pdf325.08 kBAdobe PDFView/Open
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