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osu1085004772.pdf (5.51 MB)
ETD Abstract Container
Abstract Header
T cell costimulation in anti-tumor immunity and autoimmunity
Author Info
May, Kenneth F., Jr.
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=osu1085004772
Abstract Details
Year and Degree
2004, Doctor of Philosophy, Ohio State University, Pathology.
Abstract
Costimulatory molecules, including 4-1BB, CTLA-4, and B7, play a critical role in the activation, sustenance, and regulation of T cell immune responses. Manipulation of these pathways holds promise for the development of therapies for cancer and autoimmunity. Anti-4-1BB monoclonal antibody (mAb) has been demonstrated to boost anti-tumor immunity in animal models. Using a model of tumor-specific CD8 T cell adoptive immunotherapy, we demonstrate that anti-4-1BB mAb can mediate the rejection of large established tumors in the absence of CD4 T cell help. Anti-4-1BB mAb increases populations of tumor-specific CD8 T cells in peripheral blood by reduction of activation-induced cell death, but not increased T cell proliferation. The use of anti-CTLA-4 mAb has also been shown to enhance anti-tumor immunity. Here we employ two novel “humanized” mouse models to screen anti-human CTLA-4 mAb for translation to human cancer therapy. Using the hu-PBL-SCID model of Epstein-Barr virus (EBV)-associated lymphoproliferative disease, we show that anti-human CTLA-4 mAb promotes the in vivo expansion of human CD8 and CD4 T cells, and the generation of antigen specific CD8 T cell responses to EBV lymphoma. This correlates with reduced levels of the oncogenic EBV protein LMP-1, and increased survival in these mice. We also characterize the creation of a knock-in mouse model in which mouse T cells express the human CTLA-4 molecule. Preliminary testing in this mouse model supports the use of this model to screen anti-human CTLA-4 mAb for clinical use. Understanding the role of B7/CD28/CTLA-4 interaction in immune activation and tolerance in autoimmune disease is fundamental to successful intervention targeted at costimulatory molecules. We describe the spontaneous development of whole-body alopecia, lymphadenopathy, and skin disease in mice lacking B7 molecules. This disease is mediated by autoimmune CD4 T cells, which induce multi-organ inflammation when transferred to mice expressing B7 molecules. This disease may result from impaired development of CD4+CD25+ regulatory T cells (Treg) in B7-deficient mice. Since provision of Treg can abrogate the multi-organ inflammation despite lack of B7 molecules on the auto-pathogenic T cells, interaction between CTLA-4 on Treg and B7-1/2 on effector T cells is not essential for Treg function.
Committee
Yang Liu (Advisor)
Pages
178 p.
Subject Headings
Health Sciences, Pathology
Keywords
T cell costimulation
;
anti-tumor immunity
;
autoimmunity
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Citations
May, Jr., K. F. (2004).
T cell costimulation in anti-tumor immunity and autoimmunity
[Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1085004772
APA Style (7th edition)
May, Jr., Kenneth.
T cell costimulation in anti-tumor immunity and autoimmunity.
2004. Ohio State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=osu1085004772.
MLA Style (8th edition)
May, Jr., Kenneth. "T cell costimulation in anti-tumor immunity and autoimmunity." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1085004772
Chicago Manual of Style (17th edition)
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Document number:
osu1085004772
Download Count:
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Copyright Info
© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.