Tuesday 30 March 2010
Adenoviral infections in the immunocompromised host;
Towards tailor-made therapy
Promotor: Prof.dr B.J. Prakken and prof.dr W. Kuis
Defence: 30 March 2010
In this thesis we study HAdV infections in the immunocompromised host, especially in pediatric patients after allogeneic stem cell transplantation (SCT). To get a more tailor-made treatment to improve the outcome of HAdV infected patients after SCT we studied at least three questions: which patients are at risk for HAdV infection, when to start treatment and how to optimize the treatment of HAdV infection in the SCT patient. We found that HAdV DNA positivity in nasopharyngeal aspirate before SCT is a very strong risk factor for getting an invasive HAdV infection after SCT. We also found that children with a localized HAdV infection have a different cytokine profile as patients with an invasive HAdV infection. Because no effective medication for HAdV infection exists, the focus of this thesis is the development of cellular immunotherapy. The adoptive transfer of HAdV-specific T-cells seems a promising therapeutic option. In this thesis we describe the identification of HAdV pan-DR binding epitopes by using a computer algorithm. Culturing peripheral blood mononuclear cells (PBMCs) of healthy donors with the identified HAdV epitopes results in the generation of CD4+ HAdV specific T-cells. With artificial antigen presenting cells (aAPCs) it is possible to select and isolate these cells.
Umbilical cord blood (UCB) transplants emerge as an alternative stem cell source for SCT. However, immune reconstitution is severely hampered in patients receiving UCB and patients have a higher risk of viral infections. Also from naive UCB it was possible to generate HAdV specific T-cells in response to HAdV peptides. In conclusion, the generation of HAdV-specific T-cells in response to peptides from peripheral blood and from cord blood and the isolation of these cells by using aAPCs, is an important step towards a more tailor-made therapy for HAdV infections in the immunocompromised host.