Ceramide-enriched membrane domains.

Cellular activation involves the re-organization of receptor molecules and the intracellular signalosom in the cell membrane. Recent studies indicate that specialized domains of the cell membrane, termed rafts, are central for the spatial organization of receptors and signaling molecules. Rafts are converted into larger membrane platforms by activity of the acid sphingomyelinase, which hydrolyses raft-sphingomyelin to ceramide. Ceramide molecules spontaneously associate to form ceramide-enriched microdomains, which fuse to large ceramide-enriched membrane platforms. The acid sphingomyelinase is activated by multiple stimuli including CD95, CD40, DR5/TRAIL, CD20, FcgammaRII, CD5, LFA-1, CD28, TNF, the Interleukin-1 receptor, the PAF-receptor, CD14, infection with P. aeruginosa, S. aureus, N. gonorrhoeae, Sindbis-Virus, Rhinovirus, treatment with gamma-irradiation, UV-light, doxorubicin, cisplatin, disruption of integrin-signaling and under some conditions of developmental death. Ceramide-enriched membrane platforms serve the clustering of receptors, the recruitment of intracellular signaling molecules and the exclusion of inhibitory signaling factors and, thus, facilitate signal transduction initiated by the specific stimulus.

Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies.

Invasive aspergillosis has become a major cause of infection-related mortality in nonneutropenic patients after allogeneic stem cell transplantation (SCT). To assess the potential role of Aspergillus-specific T-cell responses for the successful control of invasive aspergillosis, lymphoproliferative responses to Aspergillus fumigatus antigens were studied in healthy individuals, patients with evidence of invasive aspergillosis, and patients late after allogeneic SCT. In healthy individuals, a positive lymphoproliferative response was documented to cellular extracts of A fumigatus (14 of 16), the 88-kDa dipeptidylpeptidase (4 of 16), and the 90-kDa catalase (8 of 11). A predominant release of interferon gamma (IFN-gamma) in culture supernatants on stimulation with A fumigatus antigens was demonstrated in 13 of 17 healthy individuals, indicating a T(H)1 response. In patients with clinical evidence of invasive aspergillosis, a favorable response to antifungal therapy was found to correlate with a higher IFN-gamma/interleukin 10 (IL-10) ratio in culture supernatants (n = 7; median ratio, IFN-gamma/IL-10 = 1.0; range, 0.09-24.8) compared to 10 patients with progressive or stable disease (median ratio, IFN-gamma/IL-10 = 0.1; range, 0.002-2.1; P =.04). Steroid treatment was found to suppress Aspergillus-specific lymphoproliferation (P =.037) and release of IFN-gamma in culture supernatants (P =.017). In contrast to cytomegalovirus- and tetanus toxoid-specific T-cell responses, Aspergillus-specific T-cell reconstitution late after allogeneic SCT was characterized by low stimulation indices and a low IFN-gamma/IL-10 ratio. In addition, phosphoantigen-reactive V(gamma)9/V(delta)2 T-cell clones from healthy individuals were found to produce significant amounts of tumor necrosis factor in response to A fumigatus antigens. In conclusion, these results further support the hypothesis that T cells contribute to the host defense against A fumigatus.