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The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells

McNally, Jonathan P
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Immunology.
The activation and expansion of self-reactive T cells from the immunologic repertoire can lead to detrimental autoimmunity. If these self-reactive T cells are specific for the auto-antigen myelin, the neurodegenerative disease multiple sclerosis can develop. Though it is well known that self-reactive T cells drive the development and persistence of MS, most of the current therapies that are available for the treatment of MS do not specifically target this important cell type. In general, treatments try to suppress the entirety of the immune system, as a means of suppressing self-reactive T cells, rather than directly removing them to prevent CNS damage. However, treatment has a high rate of associated co-morbidities as a result of off-target immunosuppressive effects of these therapies. We have proposed that a more effective approach to the treatment of autoimmune diseases, such as MS, is to directly remove the self-reactive T cells that induce pathology, rather than attempt to and modulate their activities. For this approach to be truly successful the therapy must be highly selective for pathogenic effector T cells with minimal off-target effects. Here we present the use of a series of therapeutic strategies for the treatment of EAE, focused on the manipulation of the DNA damage response pathway. We have utilized drugs that target various stages of the DDR pathway, including directly damaging DNA with etoposide, enhancement of p53 signaling with nutlin, and inhibiting cell cycle arrest with MK-1775 and AZD7762, which can allow for a completely non-genotoxic treatment strategy. These strategies all take advantage of the intrinsic vulnerabilities that rapid division induces in activated T cells, thus allowing for their selective deletion. This results in an amelioration of symptoms in EAE due to the loss of the pathogenic T cells that drive disease. Since only rapidly dividing cells are vulnerable to the effects of our therapies, treatment is highly selective for pathogenic effector T cells. This results in minimal off-target effects, which can positively impact treatment associated side effects. The use of combination DDR-targeting therapy for the treatment of MS has the potential to be a targeted, highly efficacious treatment with minimal side effects that could change the manner in which many autoimmune diseases are treated.
Jonathan Katz, Ph.D. (Committee Chair)
David Hildeman, Ph.D. (Committee Member)
Michael Jordan, M.D. (Committee Member)
William Ridgway, Ph.D. (Committee Member)
Kim Seroogy, Ph.D. (Committee Member)
223 p.
Immunology
T cells; Multiple Sclerosis; DNA Damage Reponse; Autoimmunity; Therapies

Recommended Citations

Citations

  • McNally, J. P. (2015). The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709

    APA Style (7th edition)

  • McNally, Jonathan. The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709.

    MLA Style (8th edition)

  • McNally, Jonathan. "The rational targeting of the DNA damage response pathway for the selective elimination of encephalitogenic T cells." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428652709

    Chicago Manual of Style (17th edition)

ucin1428652709
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© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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