Targeted Delivery of BZLF1 to DEC205 Drives EBV-Protective Immunity in a Spontaneous Model of EBV-Driven Lymphoproliferative Disease
| Autor: | Alexander Prouty, Tamrat Abebe, Eric McLaughlin, Frankie Jeney, Shelby Sloan, Sarah Schlotter, Charlene Mao, Admasu Tenna Mamuye, Gerard Lozanski, Eric Brooks, Salma Shire, Polina Shindiapina, Robert A. Baiocchi, Manjusri Das, Claire Hale, Xiaoli Zhang, Elshafa H. Ahmed, Lapo Alinari, Michael A. Caligiuri |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Immunology Population medicine.disease_cause BZLF1 Virus Article 03 medical and health sciences 0302 clinical medicine Immune system Immunity hemic and lymphatic diseases vaccine Drug Discovery Cytotoxic T cell Medicine Epstein-Barr virus Pharmacology (medical) education Pharmacology Hu-PBL-SCID model education.field_of_study business.industry BZLF1-specific cytotoxic T-cells biochemical phenomena metabolism and nutrition Epstein–Barr virus Vaccination 030104 developmental biology Infectious Diseases 030220 oncology & carcinogenesis business post-transplant lymphoproliferative disease (PTLD) |
| Zdroj: | Vaccines Volume 9 Issue 6 Vaccines, Vol 9, Iss 555, p 555 (2021) |
| ISSN: | 2076-393X |
| DOI: | 10.3390/vaccines9060555 |
| Popis: | Epstein-Barr virus (EBV) is a human herpes virus that infects over 90% of the world’s population and is linked to development of cancer. In immune-competent individuals, EBV infection is mitigated by a highly efficient virus-specific memory T-cell response. Risk of EBV-driven cancers increases with immune suppression (IS). EBV-seronegative recipients of solid organ transplants are at high risk of developing post-transplant lymphoproliferative disease (PTLD) due to iatrogenic IS. While reducing the level of IS may improve EBV-specific immunity and regression of PTLD, patients are at high risk for allograft rejection and need for immune-chemotherapy. Strategies to prevent PTLD in this vulnerable patient population represents an unmet need. We have previously shown that BZLF1-specific cytotoxic T-cell (CTL) expansion following reduced IS correlated with immune-mediated PTLD regression and improved patient survival. We have developed a vaccine to bolster EBV-specific immunity to the BZLF1 protein and show that co-culture of dendritic cells (DCs) loaded with a αDEC205-BZLF1 fusion protein with peripheral blood mononuclear cells (PMBCs) leads to expansion and increased cytotoxic activity of central-effector memory CTLs against EBV-transformed B-cells. Human–murine chimeric Hu-PBL-SCID mice were vaccinated with DCs loaded with αDEC205-BZLF1 or control to assess prevention of fatal human EBV lymphoproliferative disease. Despite a profoundly immunosuppressive environment, vaccination with αDEC205-BZLF1 stimulated clonal expansion of antigen-specific T-cells that produced abundant IFNγ and significantly prolonged survival. These results support preclinical and clinical development of vaccine approaches using BZLF1 as an immunogen to harness adaptive cellular responses and prevent PTLD in vulnerable patient populations. |
| Databáze: | OpenAIRE |
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