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Costimulation and tolerance in T cell immunotherapy

Lute, Kenneth D.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1141850521

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Medical Science.
The results of numerous basic studies support the use of anti-CTLA-4 antibodies in human cancer therapy. To assist in the translation of this concept to the clinic it would be helpful to establish preclinical models to identify anti-human CTLA-4 antibodies that can induce anti-cancer immunity with acceptable autoimmune side effects. To that end we have produced a human CTLA-4 knock-in mouse in which murine CTLA-4 has been replaced with its human homolog. We used our knock-in mouse to screen a panel of anti-human CTLA-4 antibodies to determine whether our model was useful in discriminating the antibodies’ therapeutic effects and autoimmune side-effects. Surprisingly, while all of the antibodies induced protection against cancer and demonstrated some autoimmune side effects, the antibody that induced the strongest protection also induced the least autoimmune side effects. These results suggest that anti-tumor immunity is not necessarily linked to autoimmunity, and that it may be possible to uncouple the two. Studies of neonatal tolerance have suggested that pre-existing antigens are tolerogenic to subsequently generated T cells. However whether the same is true in the adult host is not known. As the effect of tumor on developing T cells has not been tested, we analyzed the impact of resident tumor on the development of tumor-reactive T cells in the thymus and their immune competence in the periphery. Our results suggest that newly produced T cells with specificity for pre-existing tumor cells are activated rather than inactivated by tumor antigens in the host. The importance of B7:CD28 costimulation in Treg development is a widely accepted, yet poorly understood concept. As Treg have been shown to be produced in the periphery as well as intrathymically, it remains unclear as to whether costimulation plays a similar role and produces equivalent effects at each location. To further explore this matter we characterized the expansion of regulatory T cells within Treg-deficient mice following agonistic anti-CD28 antibody treatment. We show here, in the thymus costimulation promotes Treg expansion by licensing developing thymocytes, as Treg are generated de novo, in the absence of proliferation. In the periphery costimulation promotes Treg expansion primarily through enhanced proliferation.
Yang Liu (Advisor)
Health Sciences, Immunology
costimulation; tolerance; T cell; Treg; autoimmune disease; antibody; immunotherapy

Recommended Citations

Citations

  • Lute, K. D. (2006). Costimulation and tolerance in T cell immunotherapy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141850521

    APA Style (7th edition)

  • Lute, Kenneth. Costimulation and tolerance in T cell immunotherapy. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1141850521.

    MLA Style (8th edition)

  • Lute, Kenneth. "Costimulation and tolerance in T cell immunotherapy." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141850521

    Chicago Manual of Style (17th edition)

osu1141850521
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.