Background: Dendritic cell (DC) vaccines can induce antitumor immune responses in patients with malignant diseases, while the most suitable DC culture conditions have not been established yet. In this study we compared monocyte derived human DC from conventional cultures containing GM-CSF and IL-4/TNF-α (IL-4/TNF-DC) with DC generated by the novel protocol using GM-CSF and IFN-α (IFN-DC).
The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. In bone marrow, the level of residual myeloma cells is associated with treatment outcome, but the role of clonotypic cells in the peripheral blood (PB) for the prognosis of patients is not identified yet. In this study, we retrospectively analyzed MRD by quantitative real-time IgH-PCR (IgH-qPCR) in the PB of 42 patients undergoing high-dose therapy followed by autologous PB stem cell transplantation as first-line therapy for multiple myeloma. The MRD level of PB samples was in median 40-fold lower than in bone marrow samples, collected on the same day, with a wide intra- and interindividual variation (range, .4- to 4628-fold). The presence or absence of detectable MRD levels in PB did not correlate with the serological remission status. Still, patients with negative PCR results in PB 3 months after high-dose therapy and PB stem cell transplantation had lower International Staging System stage (P = .01), lower levels of β2-microglobulin (P = .02), higher hemoglobin levels (P = .01), and a prolonged event-free (median, 15 versus 4 months; P = .004) and overall (median, 52 versus 17 months; P = .03) survival. Importantly, by sequential monitoring of clonotypic cells in PB, in 19 of 29 patients (66%) with progressive disease, an increase of the 2IgH/β-actin ratio of at least 1 log step could be detected in median 4 months (range, .8 to 13 months) before the relapse was diagnosed on the basis of the European Group for Blood and Marrow Transplantation criteria. These patients with a molecular relapse in PB before a serological relapse had a significantly shorter overall survival than other patients (median, 17 months versus median not reached, P = .02). In conclusion, IgH-qPCR is a sensitive technique for the detection of clonotypic cells in PB, which precede clinical relapse. Future studies are needed to evaluate whether these circulating tumor cells play a role in promoting disease recurrence.
The outcome of T cell activation is determined by mechanisms that balance Ca2+ influx and clearance. Here we report that murine CD4 T cells lacking Neuroplastin (Nptn
−/−), an immunoglobulin superfamily protein, display elevated cytosolic Ca2+ and impaired post-stimulation Ca2+ clearance, along with increased nuclear levels of NFAT transcription factor and enhanced T cell receptor-induced cytokine production. On the molecular level, we identified plasma membrane Ca2+ ATPases (PMCAs) as the main interaction partners of Neuroplastin. PMCA levels were reduced by over 70% in Nptn
−/− T cells, suggesting an explanation for altered Ca2+ handling. Supporting this, Ca2+ extrusion was impaired while Ca2+ levels in internal stores were increased. T cells heterozygous for PMCA1 mimicked the phenotype of Nptn
−/− T cells. Consistent with sustained Ca2+ levels, differentiation of Nptn
−/− T helper cells was biased towards the Th1 versus Th2 subset. Our study thus establishes Neuroplastin-PMCA modules as important regulators of T cell activation.
The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. We measured MRD levels in bone marrow (BM) samples of 53 patients treated with high-dose therapy (HDT) and autologous peripheral blood stem cell transplantation using real-time quantitative (RQ)-IgH-PCR with allel-specific oligonucleotide probes. We identified a prognostically relevant threshold level of 0.2% 2IgH/β-actin ratio in the BM before HDT. Twenty-six patients with MRD levels below this value were termed as the "low-MRD group," whereas 27 patients with levels above this threshold were allocated to the "high-MRD group." Median event-free-survival (EFS) in the low-MRD group was significantly (P = .001) longer than in the high-MRD group with 35 versus 20 months, respectively. Overall survival (OS) within the low-MRD group was also significantly longer with 70 versus 45 months (P = .04). Using multivariate analysis, we found that the pretransplantation MRD level was an independent prognostic factor for EFS (P = .003) and OS (P = .05). Further, EFS of patients in the high-MRD could be improved (P = .005) when they achieved a low MRD level after HDT. In conclusion, measuring MRD is of prognostic relevance in patients with MM, and low MRD levels should be a goal of treatment.
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