Mucosal and systemic immune response to sublingual or intranasal immunization with phosphorylcholine

Objective

Phosphorylcholine (PC) is a structural component of a wide variety of pathogens including Streptococcus pneumoniae and Haemophilus influenzae. Here, the immune response in mice to PC immunization via the sublingual (SL) route versus the intranasal (IN) route was investigated in terms of efficacy and safety.

Protection of liver sinusoids by intravenous administration of human Muse cells in a rat extra-small partial liver transplantation model

Small-for-size syndrome (SFSS) has a poor prognosis due to excessive shear stress and sinusoidal microcirculatory disturbances in the acute phase after living-donor liver transplantation (LDLT). Multilineage-differentiating stress enduring (Muse) cells are reparative stem cells found in various tissues and currently under clinical trials. These cells selectively home to damaged sites via the sphingosine-1-phosphate (S1P)–S1P receptor 2 system and repair damaged tissue by pleiotropic effects, including tissue protection and damaged/apoptotic cell replacement by differentiating into tissue-constituent cells. The effects of intravenously administered human bone marrow-Muse cells and -mesenchymal stem cells (MSCs) (4 × 10⁵) on liver sinusoidal endothelial cells (LSECs) were examined in a rat SFSS model without immunosuppression. Compared with MSCs, Muse cells intensively homed to the grafted liver, distributed to the sinusoids and vessels, and delivered improved blood chemistry and Ki-67(+) proliferative hepatocytes and -LSECs within 3 days. Tissue clearing and three-dimensional imaging by multiphoton laser confocal microscopy revealed maintenance of the sinusoid continuity, organization, and surface area, as well as decreased sinusoid interruption in the Muse group. Small-interfering RNA-induced knockdown of hepatocyte growth factor and vascular endothelial growth factor-A impaired the protective effect of Muse cells on LSECs. Intravenous injection of Muse cells might be a feasible approach for LDLT with less recipient burden.     

Optimal stimulation for CD70 induction on human monocyte‐derived dendritic cells and the importance of CD70 in naive CD4+ T‐cell differentiation

Studies in mice have shown that CD70 on dendritic cells (DCs) is sufficient to convert T‐cell tolerance into immunity and hence induce anti‐tumour immune responses. Therefore, it is important to investigate (i) optimal stimuli to induce CD70 on human monocyte‐derived DCs (MoDCs), which are widely used for tumour immunotherapy, and (ii) the role of CD70 in functional differentiation of naive CD4⁺ and CD8⁺ T cells stimulated with MoDCs. We show that interferon‐α (IFN‐α) is a key cytokine to differentiate monocytes into DCs with the capacity to express CD70 upon maturation. CD70 expression on IFN‐α‐induced MoDCs was elicited by different categories of maturation‐inducing factors (Toll‐like receptor ligands, CD40 ligand and pro‐inflammatory mediators), among which prostaglandin E₂ was most effective. Naive T cells stimulated with MoDCs also expressed CD70. Stimulation with MoDCs promoted naive CD4⁺ T cells to acquire the ability to produce T helper type 1 and 2 cytokines in a CD70‐dependent manner. In contrast, the CD70–CD27 interaction diminished the production of an immunoregulatory cytokine IL‐10. The CD27 signal did not play a dominant role in the induction of effector molecules in naive CD8⁺ T cells during the stimulation with MoDCs. This study adds a novel function to the versatile cytokines, type I IFNs, that is, the induction of CD70 on MoDCs. CD70 promotes naive CD4⁺ T cells to acquire immunostimulatory activity through the DC–T‐cell and T‐cell–T‐cell interactions during the stimulation with MoDCs. Hence, the CD70–CD27 interaction may play an important role in inducing effective immune responses in DC‐based immunotherapy.     

Nonsteroidal anti-inflammatory drugs potentiate 1-methyl-4-phenylpyridinium (MPP+)-induced cell death by promoting the intracellular accumulation of MPP+ in PC12 cells

In this study, we investigated the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in PC12 cells. Coincubation of PC12 cells with indomethacin, ibuprofen, ketoprofen, or diclofenac, but not aspirin or N-[2-(cyclohexyloxy)-4-nitrophenyl]methanosulfonamide (NS-398), significantly potentiated the MPP(+)-induced cell death. In contrast, these NSAIDs had no effect on rotenone-induced cell death. The potentiating actions of these NSAIDs were not suppressed by treatment with phenyl-N-butyl-nitrone, a radical scavenger; N-acetyl-l-cysteine, an antioxidant; Ac-DEVD-CHO, a selective caspase-3 inhibitor; or 2-chloro-5-nitro-N-phenylbenzamide (GW9662), a selective antagonist of peroxisome proliferator-activated receptor gamma. Furthermore, we observed that DNA fragmentation, which is one of the hallmarks of apoptosis, was not induced by coincubation with MPP(+) and NSAIDs. We confirmed that coincubation of PC12 cells with 30 microM MPP(+) and 100 microM indomethacin, ibuprofen, ketoprofen, or diclofenac led to a significant increase in the accumulation of intracellular MPP(+) compared with incubation with 30 microM MPP(+) alone. In addition, these NSAIDs markedly reduced the efflux of MPP(+) from PC12 cells. (3-(3-(2-(7-Chloro-2-quinolinyl) ethenyl) phenyl ((3-dimethyl amino-3oxo-propyl) thio) methyl) propanoic acid (MK 571), which is an inhibitor of multidrug resistance proteins (MRPs), mimicked the NSAIDs-induced effects, increasing cell toxicity and promoting the accumulation of MPP(+). Moreover, some types of MRPs' mRNA were detected in PC12 cells. These results suggest that some NSAIDs might cause a significant increase in the intracellular accumulation of MPP(+) via the suppression of reverse transport by the blockade of MRP, resulting in the potentiation of MPP(+)-induced cell death.     

Historical trends in human serum levels of perfluorooctanoate and perfluorooctane sulfonate in Shenyang, China

Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are widespread contaminants in the environment, as well as in wildlife and in humans. The PFOS and PFOA concentrations were determined in historical human serum samples collected in Shenyang, China, in 1987 (n=15), 1990 (n=33), 1999 (n=68) and 2002 (n=119). The serum donors were students, faculty members and university workers. Since the serum PFOA and PFOS levels did not follow a normal or log-normal distribution, a nonparametric method was applied to analyze the historical trends. For the total male and female subjects, the median level of serum PFOA increased significantly from 0.08 microg/l in 1987 to 4.3 microg/l in 2002 (p<0.05), while the median level of serum PFOS also increased significantly from 0.03 microg/l in 1987 to 22.4 microg/l in 2002 (p<0.05). Both the serum PFOA and PFOS levels continued to increase from 1999 to 2002, with remarkable increases observed in females: 6.3-fold increase for PFOA and 13-fold increase for PFOS. In 2002, serum PFOA and PFOS concentrations of female subjects have increased to 4.9 microg/l and 22.4 microg/l in median, respectively, which are comparable to those in U.S.A. and Japan. For male subjects, serum PFOA and PFOS concentrations (1.6 microg/l and 8.3 microg/l in median, respectively) are comparable to those in Italy. The data from this study indicate that females are likely to experience higher exposure to these chemicals.     

Disappearance of CD 20 after treatment with rituximab of mantle cell lymphoma

A 60-year-old female visited our hospital in May 2001 because of systemic lymphadenopathy. Her white blood cell count was 25,510/microliters with 93% of lymphocytes. Bone marrow aspiration revealed that 86% of nucleated cells were lymphocytes. Lymphocytes in the peripheral blood and bone marrow were positive for CD 5, 19, 20, and sIgx and negative for CD 23. FISH analysis detected the chimeric bcl 1/IgH fusion gene. Immunohistochemistry of a biopsied lymph node revealed that lymphoma cells were positive for cyclin D 1. Mantle cell lymphoma (MCL) was diagnosed at clinical stage IV A. Although a partial remission was obtained after CHOP plus rituximab therapy, the patient's disease recurred in March 2002 and she died in spite of salvage therapy including rituximab. Immunohistochemistry of the bone marrow cells after salvage rituximab therapy revealed that lymphoma cells were still positive for CD 5 and cyclin D 1, but negative for CD 20 and sIgx. We could not exactly determine how frequently CD 20 expression becomes negative in B-cell lymphomas after treatment with rituximab. We found only two reported cases that suggested rituximab down-regulated CD 20 expression in MCL. We herein describe a case of MCL with very notable clinical features.