Low Dose Cytosine Arabinoside Regimen for Overt Leukemia, Hypoplastic Leukemia and Myelodysplastic Syndromes : Hypoplastic Leukemia Responds Best.

In a series of 38 patients consisting of 13 with overt acute leukemia, 14 with hypoplastic leukemia, and 11 with myelodysplastic asyndromes (MDS), responsiveness to low dose cytosine arabinoside (LDAC) regimen was investigated to clarify the disease type most benefitted. LDAC was continuously administered intravenously at dose 0.2mg/kg/day and continued as long as possible to meet the pre-assigned target point of 5% marrow blasts which was confirmed by weekly marrow aspiration. Overall response rate was 47%; complete remission (CR) being 31% and partial remission (PR) 16%. CR rate was significantly different between the disease types ; 69% in hypoplastic leukemia, 23% in overt leukemia and 0% in MDS (p=0.01). In hypoplastic leukemia the survival time was significantly longer in the LDAC-treated cases compared with 15 historical control cases treated with supportive care only ; median survial being 750 days in the former and 250 days in the latter (p=0.01). In overt leukemia only three M2 AML cases obtained CR ; two of them were treated during hypoplastic phase induced by intensive chemotherapy. All CR cases eventually achieved the target point after 20 to 42 days (median 26) of LDAC administration. Substantial toxicity of LDAC was evident, but most cases tolerated well. The present investigation suggests that hypoplastic leukemia is the disease type most sensitive to LDAC regimen. Stratification of the elderly leukemia patients should be considered for this regimen

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells

Background: Neurotransmitters, including substance P (SP) and neurokinin A (NKA), are widely distributed in both the central and peripheral nervous system and their receptors, neurokinin-1 receptor (NK1R) and neurokinin-2 receptor (NK2R), are expressed on immune cells. However, the role of the NKA-NK2R axis in immune responses relative to the SP-NK1R signaling cascade has not been elucidated. Objective: We sought to examine the effect of neuropeptide signaling through NK1Rand NK2R on antigen presentation by dendritic cells (DCs) and the subsequent activation of effector Th cells. Methods: Expression levels of NK1R, NK2R, HLA-class II and costimulatory molecules of human MoDCs and cytokine production by birch pollen antigen-specific CD4+ T cells cocultured with MoDCs in the presence of NK1R and NK2R antagonists were evaluated by quantitative RT-PCR, flow cytometry or ELISA. NK1R and NK2R expression in the lung of patients with asthma and hypersensitivity pneumonitis was evaluated by immunohistochemistry. Results: Human MoDCs significantly upregulated NK2R and NK1R expression in response to poly I:C stimulation in a STAT1-dependent manner. Both NK2R and NK1R were expressed on alveolar macrophages and lung DCs from patients with asthma and pneumonitis hypersensitivity. Surface expression levels of HLA-class II and costimulatory molecules on DCs were modulated by NK1R or NK2R antagonists. Activation of birch pollen-derived antigen-specific CD4+ T cells and their production of cytokines including IL-4 and IFN-γ as well as IL-12 production by MoDCs, were suppressed by blocking NK1R or NK2R after in vitro antigen stimulation. Conclusions: NK1R- and NK2R-mediated neuropeptide signaling promotes both innate and acquired immune responses through activation of human DCs

一次免疫応答におけるNeuronal leucine-rich repeat protein 3(NLRR3)の機能的役割

Contact between dendritic cells（ DCs） and resting T cells is essential for initiation of the primary immune response. In this study, we examined whether neuronal leucine-rich repeat protein 3 （NLRR3）, a receptor involved in nerve system development, participates in DC-T cell binding and T-cell activation. We confirmed that NLRR3 is expressed on naive T cells. NLRR3 contains an Arg-Gly-Asp （RGD） motif in its amino acid sequence, for which several integrins can be considered as potential ligands. Indeed, monocyte-derived DCs expressed several integrins that can bind to the RGD motif. Functionally, DC-induced resting allogeneic T-cell proliferation was partially inhibited by addition of integrin-specific antibodies and synthetic RGD peptides, indicating that RGD-containing molecules, including NLRR3 and several integrins, at least participate in the events of the initial primary immune response involving naive T cells and DCs. Furthermore, DCs were shown to bind directly to NLRR3-transfected Chinese hamster ovary cells in a NLRR3-dependent manner, and the binding was removed in the presence of integrin-specifi c antibodies. These data suggest that NLRR3 plays an important role in initiation of the primary immune response

Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner

Type-1 immunity plays a crucial role in host defense against various tumors and infectious diseases. Here, we first demonstrated that extract of Larix Leptolepis (ELL), one of the most popular timbers at Hokkaido area in Japan, strongly activated Type-1 immunity. ELL induced production of Type-1 cytokines such as IL-12 and TNF-α from bone marrow-derived dendritic cells (BMDCs) in TLR2- and TLR4-dependent manner and remarkably up-regulated the expression of MHC and co-stimulatory molecules. In addition, antigen-specific CTLs were significantly augmented by the combined administration of ELL, antigen and BMDCs. Finally, we revealed that combination therapy using ELL, antigen and BMDCs significantly inhibited the growth of established tumor in mouse model. Thus, these findings suggested that ELL would be a novel adjuvant for inducing an activation of Type-1-dependent immunity including activation of BMDCs and induction of tumor-specific CTLs, which is applicable to the therapy of cancer and infectious diseases