Harnessing the autophagy pathway to enhance the immune response to Epstein-Barr-Virus infection and associated tumors
Final Report Abstract
I aimed to improve vaccination strategies for EBV by boosting the virus-specific CD4+ T helper cell-dependent immune response. To this end, I wanted to enhance antigen presentation on MHC II on DCs by transducing them with lentiviral particles encoding a fusion of the EBV antigen EBNA1 to the autophagosome-associated molecule LC3. Mo- DCs expressing the targeted antigen stimulate stronger EBNA1-specific autologous T cell responses than mo-DCs expressing the non-targeted EBNA1. However for mo-DCs from some donors, the positive control, which is a fusion of EBNA1 to the Ii, stimulates stronger immune responses than EBNA1-LC3. Therefore, I cannot conclude whether targeting of antigens into the autophagy pathway is superior to classical MHC II-targeting in vitro. Injection of EBNA1-LC3 encoding lentiviral particles into C57BL/6 mice did not yield a specific immune response in vivo, while injection of Ii-EBNA1 encoding lentiviral particles did. However, this EBNA1-specific immune response was mainly mediated by CD8+ T cells and not by CD4+ T helper cells as would be expected to be the case in the human setting. Injection of Ii-EBNA1 encoding lentiviral particles into hu- NSG mice did not prime specific T cells. This could not be improved by increasing the dose of lentiviral particles, a prime and boost strategy and longer duration of the experiment. Next, I will try to improve the vaccination protocol on the one hand by targeting the lentiviral constructs to DCs in vivo. On the other hand, I will test several adjuvants for activation of DCs in hu-NSG mice and then co-inject the best one with the lentiviral constructs. Then, I can test whether targeting antigens into the autophagy pathway enhances the ensuing immune response in hu-NSG mice. As a result, I hope to define an ideal vaccination strategy to improve the immune response to primary EBV infection and EBV associated malignancies.
Publications
- “Morbus Crohn – a disease of failing macroautophagy in the immune system?”. International Immunology (2009), 21:1205-11
Sonja Meixlsperger and Christian Münz
- “Human NK cells of mice with reconstituted human immune system components require pre-activation to acquire functional competence”. Blood (2010), 116(20):4158-‐4167
Till Strowig, Obinna Chijioke, Paolo Carrega, Frida Arrey, Sonja Meixlsperger, Patrick C. Rämer, Guido Ferlazzo and Christian Münz
- “Mice with human immune system components as in vivo models for infections with human pathogens”. Immunology and Cell Biology (2011), 89(3):408-16
Patrick C. Rämer, Obinna Chijioke, Sonja Meixlsperger, Carol S. Leung and Christian Münz
