Improvement of a dendritic cell-based tumour vaccine by an influenza virus.

BACKGROUND: Induction of cytotoxic T cells by dendritic cells (DCs) is a promising approach to tumour-immunotherapy. A standardized effective preparation of DCs remains a challenge for clinical application. MATERIAL AND METHODS: We assessed whether influenza A partial NS1 deletion (NS1-124) - or complete NS1 deletion (delNS1) vaccine viruses can be employed to enhance monocyte-derived dendritic cell (MODC)-based T-cell stimulation directed against malignant cells in vitro. RESULTS: Infection of cultures containing human MODCs and CD3(+) T cells with NS1 deletion viruses led to an increased induction of type I interferons and IL-6 compared with infection with wild-type virus. This correlated with the fact that infection of MODCs with NS1 deletion viruses but not with wild type virus led to stimulation of a cytotoxic T-cell (CTL) response against the Panc-1 cells, which were used as cell lysate to prime the MODCs. Moreover, stimulation of MODCs with Panc-1 tumour cell lysate obtained via lysis with the complete deletion virus delNS1, but not with the partial NS1 deletion virus also enhanced the CTL response against the tumour cells. Induction of function CTL response in those assays correlated with an increased proliferation of CD8(+) T cells. CONCLUSIONS: The pro-inflammatory capacity of influenza NS1 deletion vaccine viruses could serve as an adjuvant-like agent to improve preparations of MODC-based anti-cancer vaccines. The complete NS1 deletion virus appears to be more potent as adjuvant when used for production of tumour lysates.

Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations.

Increased blood concentrations of phenylalanine in patients with trauma and sepsis are common but unexplained. We examined the potential relationship between serum concentrations of phenylalanine and the immune activation marker neopterin in 84 specimens of 18 patients (14 males and 4 females) post-trauma during 12-14 days of follow up. Compared to healthy controls, average phenylalanine and neopterin concentrations were elevated in patients, and there existed a positive correlation between concentrations of the two analytes (r (s) = 0.375, p < 0.001). No such association existed between neopterin and tyrosine concentrations (r (s) = -0.018), but neopterin concentrations correlated to the phenylalanine to tyrosine ratio (r (s) = 0.328, p = 0.001). Increased phenylalanine implies insufficient conversion by phenylalanine (4)-hydroxylase (PAH). Oxidative stress due to immune activation and inflammation may destroy cofactor 5,6,7,8-tetrahydrobiopterin and impair PAH activity. This assumption is further supported by the correlation found between higher neopterin concentrations and higher phenylalanine to tyrosine ratio, which estimates efficacy of PAH.

The role of Foxp3+ T cells in long-term efficacy of prophylactic and therapeutic mucosal tolerance induction in mice.

BACKGROUND: Mucosal tolerance induction is suggested as treatment strategy for allergic diseases. Using a murine model of birch pollen (BP) allergy we investigated the long-term efficacy and the underlying mechanisms of mucosal tolerance induction with two structurally different molecules in a prophylactic and in a therapeutic set-up. METHODS: The three-dimensional major BP allergen Bet v 1 or a nonconformational hypoallergenic fragment thereof was intranasally applied before (prophylaxis) or after sensitization (therapy). RESULTS: In the prophylactic application both the Bet v 1 allergen and the fragment prevented allergic sensitization, and this effect lasted for 1 year. In the therapeutic approach established allergic immune responses were also suppressed after treatment with either of the molecules. However, a long-lasting curative effect (6 months) was only achieved with the Bet v 1 allergen but not with the Bet v 1 fragment. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis of splenocytes revealed that tolerance induction with the Bet v 1 allergen was associated with enhanced expression of transforming growth factor (TGF)-beta, interleukin (IL)-10, and Foxp3 mRNA in CD4+ T cells, whereas treatment with the fragment led to the induction of either Foxp3 (prophylaxis) or IL-10 (therapy) alone. CONCLUSION: From these data we concluded (i) that the mechanisms underlying peripheral tolerance are linked to the conformation of the antigen, (ii) that mucosal tolerance is mediated by separate regulatory cell subsets, and (iii) that the long-term efficacy of immunosuppression is associated with the presence of Foxp3+ T cells.