Invasive aspergillosis (IA) caused by the opportunistic pathogenic fungus Aspergillus fumigatus (A.fumigatus) constitutes a serious complication in patients suffering from acute leukaemia and in patients undergoing allogeneic stem cell transplantation (SCT) and is associated with exceedingly high infection-related morbidity and mortality.
Healthy individuals are protected from A. fumigatus by innate and adaptive immunity. In contrast, A. fumigatus can become pathogenic in the immunocompromised host by either a lack or a dysfunction of monocytes/granulocytes/dendritic cells (DC) and antigen-specific Th1 cells resulting in IA or by an imbalance of the adaptive immunity causing immune pathology through excessive tissue damage. In addition, A. fumigatus itself secretes immunosuppressive mycotoxins which either inhibit APC function or induce monocyte death.
Recent data by Luigina Romani showed that mice can be protected from a lethal A. fumigatus challenge by transfer of Th1 T-cells, by DC vaccination as well as by induction of Treg T cells. Our group has identified in human subjects immunodominant A. fumigatus derived T-cell epitopes as well as an A.fumigatus derived protein, which can condition DCs for better inflammatory response.
We are, therefore, proposing to extend our previous work to 1) determine aspergillus derived proteins, which have a proinflammatory action on dendritic cells and, therefore, potentially contribute to efficient recruitment of innate and adaptive immunity 2) identify more immunodominant proteins inducing a Th1 T-cell response for adoptive immunotherapy 3) reprogram aspergillus-specific Th1 T-cells to Treg’s for control of immunopathology of the infection 4) generate an anti-gliotoxin neutralizing antibody 5) translate the results into GMP products as bases for immunotherapy of A. fumigatus infection. 6) conduct a phase I/II trial in patients with probable and proven invasive aspergillosis.