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Identifying Risk Profiles and Generating Protective Vaccine for Epstein-Barr Virus-Associated Lymphoproliferative Diseases

Ahmed, Elshafa Hassan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1534540468409883

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Epstein Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus that infects more than 90% of the world’s population. EBV is classified as a lymphocryptovirus that primarily infects B-lymphocytes, but can also infect epithelial cells. In immune-competent individuals, EBV-infected B cells have the capacity to become immortalized, but their proliferation is controlled by a highly efficient EBV-specific cytotoxic T-lymphocyte (CTLs) response. Patients with immunosuppression conditions, including primary or genetic immunosuppression, acquired immunosuppression due to diseases such as human immunodeficiency virus (HIV), or iatrogenic immunosuppression induced by medications are at high risk for developing EBV-associated lymphoproliferative disorders (EBV-LPD). A cohort of solid organ and bone marrow transplant patients treated with immunosuppressive medications to prevent graft rejection are at increased risk of developing EBV-post-transplant lymphoproliferative disease (PTLD). PTLD is associated with a high mortality rate and transplanted allograft loss. Prevention of PTLD would improve overall survival and transplanted organ function in transplant recipients. Currently there is no mechanism to predict who is at highest risk of developing PTLD, and no approach is available to prevent this complication of organ transplantation. In this dissertation, we utilized an in-vivo model of EBV-LPD to develop a genetic risk-prediction profile that may contribute to our ability to identify individuals at risk for developing PTLD. We also describe a promising immunogen to use as an EBV vaccine to prevent EBV-LPDs. Severe combined immune-deficient (SCID) mice engrafted with human peripheral blood monocular cells (PBMCs) from EBV-positive (EBV+) donors spontaneously develop EBV-LPD of human B cell origin that resembles PTLD. CD4+ helper T lymphocytes (Th) are essential for lymphoma development in this model. Immunophenotypic profiles of human lymphocytes recovered from the mice were examined by mass-cytometry and gene expression was evaluated on sorted CD4+ T cells. Two categories of EBV-seropositive donors were identified: donors whose PBMC did not lead to development of EBV-LPD (no incidence donors, NI) and donors whose PBMC generate EBV-LPD in 100% of mice (high incidence donors, HI). When compared NI, HI donors showed significantly higher frequency of follicular T helper (Tfh) and regulatory T cells (Treg) in the peripheral blood and in spleens of engrafted mice. RNA-Seq expression profiles also demonstrated distinct pathways between NI and HI donors on ingenuity pathway analysis. Depletion of these two subsets prolonged survival in engrafted mice, supporting the hypothesis that Tfh and Treg cells act to promote lymphomagenesis and that HI donors may be able to be identified by biomarkers studies. With the intent on preventing EBV-LPD in high-risk individuals, we developed a vaccine strategy targeting the BZLF1 protein. Prior work showed that individuals with high frequency of antigen-specific T cells recognizing BZLF1 showed spontaneous resolution of their PTLD and improved survival. We specifically delivered BZLF1 to dendritic cells (DCs) through its endocytic receptor DEC205. DEC205-BZLF1 fusion protein-loaded DCs were co-cultured with autologous PBMCs. DEC205-BZLF1 in the co-culture led to the significant expansion of EBV-specific CTLs that were capable of potent cytotoxicity and IFN¿ production when compared to controls. SCID mice engrafted with PBMCs from EBV+ individuals were vaccinated with DCs loaded with DEC205-BZLF1 or control viral peptide. DEC205-BZLF1 vaccine provoked robust responsiveness to the recall antigen and enhanced survival compared to control vaccine treated groups. This work reports biomarkers that show potential for identifying individuals that are at high risk for developing EBV-LPD and provides a preventive strategy to reduce the risk of EBV-LPD by vaccination for patients planning to undergo solid organ transplantation.
Robert Baiocchi, MD, PhD (Committee Co-Chair)
Michael Caligiuri, MD (Committee Co-Chair)
Jianhua Yu, PhD (Committee Member)
Mireia Guerau-de-Arellano, Pharm D, PhD (Committee Member)
Immunology
Epstein-Barr Virus; post-transplant lymphoproliferative disease; Lymphoproliferative Diseases; Risk profile for post-transplant lymphoproliferative disease; EBV Vaccine

Recommended Citations

Citations

  • Ahmed, E. H. (2018). Identifying Risk Profiles and Generating Protective Vaccine for Epstein-Barr Virus-Associated Lymphoproliferative Diseases [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1534540468409883

    APA Style (7th edition)

  • Ahmed, Elshafa. Identifying Risk Profiles and Generating Protective Vaccine for Epstein-Barr Virus-Associated Lymphoproliferative Diseases. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1534540468409883.

    MLA Style (8th edition)

  • Ahmed, Elshafa. "Identifying Risk Profiles and Generating Protective Vaccine for Epstein-Barr Virus-Associated Lymphoproliferative Diseases." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1534540468409883

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.