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Mechanisms of T Cell Reconstitution Following Lymphoablation in Transplantation And Description of a Novel Protective Role for T Cells in Epilepsy

Ayasoufi, Katayoun
http://rave.ohiolink.edu/etdc/view?acc_num=case1481213939247414

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
The ultimate goal of transplantation is to prevent organ rejection by the immune system, while leaving protective immunity against pathogens intact. To achieve this, T cell- depleting therapies have been developed. “Anti-Thymocyte-Globulin,” or, ATG is clinically used to deplete T cells. While theoretical benefits of lymphoablation in sensitized transplant patients is the rationale for the use of depletion-therapy, memory T cells are resistant to depletion. Resistance of memory T cells to deletion is a barrier to successful transplantation. The goal of our study was to understand the role of depletion-resistant memory CD4 T cells in T cell reconstitution following lymphoablation in a fully MHC-mismatched model of heart transplantation. We found that both residual memory CD4 T cells and a functional thymus was required for optimal T cell reconstitution following depletion. Residual memory CD4 T cells enhanced reconstitution of CD8 T cells through B cells and CD40-CD40L interactions. Depletion-resistant CD4 T cells were capable of infiltrating the thymus and enhancing thymopoiesis, as well. Inhibiting helper functions of CD4 T cells during depletion improved allograft outcomes in naive and sensitized recipients, but did not decrease T cell responses against other antigens. Our studies will help devise new strategies to improve graft survival, improve the efficacy of current lymphoablative therapies, and benefit sensitized transplant patients. With the help of immunological advances, the adaptive immune system may be manipulated in many diseases to yield beneficial results. Epilepsy is a heterogeneous disease with many causes and no cure. The role of the adaptive immune system in epilepsy is not known. We directly tested the role of brain-infiltrating T cells in epilepsy in a model of cortical dysplasia; a brain malformation causing medically intractable epilepsy. We report that T cells infiltrate the brain in rats following a seizure and accumulate in rats with cortical dysplasia. Intraventricular transfer of T cells from brains or spleens into naive rats decreases the epileptic activity. Understanding the complex contribution of T cells in epilepsy and investigating the mechanisms of such protection by T cells will help us devise novel strategies to help improve the lives of patients with epilepsy.
Anna Valujskikh (Advisor)
272 p.
Immunology; Neurobiology
Lymphoablation; T cells; Transplantation; Immunological memory; CD4 T cells; T cell reconstitution; Transplant Rejection; Sensitized transplant recipients; Epilepsy; Cortical Dysplasia; Seizures

Recommended Citations

Citations

  • Ayasoufi, K. (2017). Mechanisms of T Cell Reconstitution Following Lymphoablation in Transplantation And Description of a Novel Protective Role for T Cells in Epilepsy [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1481213939247414

    APA Style (7th edition)

  • Ayasoufi, Katayoun. Mechanisms of T Cell Reconstitution Following Lymphoablation in Transplantation And Description of a Novel Protective Role for T Cells in Epilepsy. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1481213939247414.

    MLA Style (8th edition)

  • Ayasoufi, Katayoun. "Mechanisms of T Cell Reconstitution Following Lymphoablation in Transplantation And Description of a Novel Protective Role for T Cells in Epilepsy." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481213939247414

    Chicago Manual of Style (17th edition)

case1481213939247414
341
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.