Monocytes play a major role in the cellular defence against Aspergillus fumigatus in immunocompromised patients. To obtain a better understanding of the mechanisms involved in this interaction, phagocytosis and gene expression profiling of human monocytes was carried out after incubation with A. fumigatus resting, swollen and germinating conidia and hyphae (for 3, 6 and 9 h). The majority of monocytes phagocytosed up to three conidia during the first 3 h of incubation. Microarray analysis showed an increased expression level of immune-relevant genes, which was dependent on the germination state of the fungus and the incubation period. Among these genes, those encoding interleukin-8, macrophage inflammatory protein 3-α (CCL20) and monocyte chemotactic protein-1 (CCL2) were found to be potential key regulators involved in the A. fumigatus-induced immune response. In addition, A. fumigatus was found to be an inducer of the genes encoding urokinase type plasminogen activator (uPA), urokinase type plasminogen activator receptor (uPAR),plasminogen activator inhibitor (PAI), pentraxin-3 (PTX3) and intercellular adhesion molecule-1 (ICAM-1), which, in combination, may contribute to thrombosis and local lung tissue injury.

Invasive aspergillosis is a significant cause of morbidity and mortality in patients after stem cell transplantation, in solid organ transplant recipients, and in patients with hematological malignancies. The interactions between human immature dendritic cells (iDCs) and Aspergillus fumigatus antigens are widely uncharacterized. We analyzed the immune response of iDCs to different recombinant A. fumigatus antigens (Aspf1 and Crf1). One of these antigens, the 18-kDa RNase Aspf1, triggered the increased level of expression of genes encoding proinflammatory cytokines and chemokines, and augmented the activation of NFB and the apoptosis of iDCs. Furthermore, by fluorescence microscopy, we could demonstrate that in the first 3 h a major portion of Aspf1 accumulates on the cell surface. Finally, we could show an increased segregation of cytokines and chemokines after the stimulation of iDCs by an Aspf1 deletion mutant strain of A. fumigatus.

Allogeneic stem cell transplant is indicated for patients with refractory or relapsed acute myeloid leukemia (AML). Since elimination of the leukemic load is thought to be a prerequisite for treatment success, we here investigate toxicity and anti-leukemic activity of a clofarabine-AraC salvage protocol preceding transplant. In this retrospective analysis, we observed induction of objective remissions in 86% of patients receiving clofarabine-AraC as compared to 83% with sequential high dose AraC/mitoxantrone (S-HAM) and 50% after mitoxantrone/topotecane/AraC (MTC) salvage strategies. In addition, clofarabine conferred anti-leukemic activity to some patients who failed initial MTC or S-HAM therapy. For overall and leukemia-free survival, we identified cytogenetically defined adverse risk markers but not response to therapy to be a strong predictor. In summary, the clofarabine-AraC salvage strategy combines pronounced anti-leukemic activity with an acceptable toxicity profile and allows the majority of patients with relapsed or refractory AML to proceed to allo-SCT, even in cytogenetically defined high risk situations.