Human Autologous Dendritic Cell–Glioma Fusions: Feasibility and Capacity to Stimulate T cells with Proliferative and Cytolytic Activity

Gliomas are the most common primary neoplasm of the central nervous system. The failure of conventional treatment modalities to improve outcome over the last two decades has led to interest in alternative treatment modalities. Dendritic cell (DC)-based immunotherapy has utilized DC pulsed with tumor lysate or peptide to induce an anti-tumor immune response mediated largely by CD8 T cells. While this has been effective in preclinical studies, clinical efficacy remains unproven. Recently, hybrid cells produced by fusions of tumor and autologous DC have demonstrated remarkable efficacy for stimulating an anti-tumor immune response in both preclinical and clinical studies of extra-cranial neoplasms. The advantage of generating such hybrid cells is that the entire cellular material of the tumor is processed and presented in both endogenous and exogenous pathways. This leads to activation of both MHC class I restricted CD8 cells as well as MHC class II restricted CD4 T cells.Here, we examined in vitro T cell stimulatory capacity of autologous human DC–glioma fusion in comparison to DC loaded with apoptotic glioma. DC fused with autologous tumor or loaded with apoptotic tumor cells (DC/apo) were first used to stimulate autologous non-adherent peripheral blood mononuclear cells (PBMC), in vitro. The PBMC were then examined for phenotype (CD3, CD4, CD8) and intracellular IFN- using flow cytometry. Lymphocyte proliferation and cytolytic responses were also assessed. Lymphocytes stimulated in vitro with fusion or DC/apo cells showed significantly enhanced cytotoxicity and proliferation against autologous tumor cells compared with PBMC stimulated with tumor cells or DC alone. Both strategies had similar efficacy. Tumor-cytolytic responses were enhanced by the addition of CD40 ligand (CD40L), and partially blocked by anti-MHC class I antibody. Flow cytometric analysis detected CD3⁺CD8⁺ T cells, which also stained positive for intracellular IFN-. The study suggests that DC/glioma fusion and DC/apo have comparable efficacy for stimulation of CTL with cytolytic and proliferative activity against human malignant gliomas. These findings may have implications for future studies of DC-based immunotherapy in malignant gliomas.     

Choroidal metastasis from primary adenocarcinoma of the esophagus

Primary adenocarcinoma of the esophagus is uncommon and the incidence in the middle third of the esophagus is rare, accounting for about 0.7%-1.5% of cases. Metastasis of carcinoma to the eye is a rare occurrence. We report here a case of primary adenocarcinoma of the middle third of the esophagus with choroidal metastasis. © 1993 Wiley-Liss, Inc.     

Flt3 ligand and conjugation to IL-1beta peptide as adjuvants for a type 1, T-cell response to an HIV p17 gag vaccine

The adjuvant activity of Flt3 ligand (Flt3L) and conjugation to an interleukin (IL)-1beta bioactive fragment were compared, either alone or in combination, for their ability to induce T- and B-cell responses to the HGP-30 peptide sequence (amino acids 86-115 of human immunodeficiency virus (HIV) gag p17). The efficiency of HGP-30/IL-1beta conjugation, Flt3L administration or both as adjuvants was examined and all were found to augment similar levels of delayed type hypersensitivity (DTH) responses. In contrast, significant antigen (Ag)-specific types 1 and 2 T-cell ELISPOT responses were induced only by the combination of adjuvants. Further, in vitro sensitization with HGP-30 selectively increased Ag-specific, type 1 T-cell and cytotoxic T lymphocyte (CTL) responses to HGP-30-derived nonapeptide epitopes, while type 2 responses declined as measured in the ELISPOT assay. No serum antibodies to HGP-30 were induced unless HGP-30 was conjugated to keyhole-limpet hemocyanin. This suggests that a combination adjuvant strategy using Flt3L and conjugation to a biologically active IL-1beta fragment may be used to preferentially increase type 1 T-cell and CTL responses to HIV-1 gag antigenic epitopes.     

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes

OBJECTIVEEnvironmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.RESEARCH DESIGN AND METHODSAssociation between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes (n = 271) or multiple diabetes-associated islet autoantibodies (n = 384) and children without diabetes who are negative for diabetes autoantibodies.RESULTSAgricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16–0.87, P = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, P = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, P = 0.001) compared with an urban environment known to have lower environmental microbial diversity.CONCLUSIONSThe study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.     

Delayed kidney graft function in simultaneous pancreas‐kidney transplant recipients is associated with early pancreas allograft failure

Delayed graft function (DGF) is a common complication associated with significant untoward effects in kidney‐alone transplantation. The incidence and outcomes following kidney delayed graft function (K‐DGF) among patients undergoing simultaneous pancreas‐kidney (SPK) transplantation are less certain. We analyzed SPK recipients transplanted at our center between January 1994 and December 2017. A total of 632 recipients fulfilled the selection criteria, including 69 (11%) with K‐DGF and 563 without. The incidence of K‐DGF was significantly higher in recipients of organs from older donors and donation after circulatory death (DCD). The presence of K‐DGF was significantly associated with an increased risk of pancreas graft failure during the first 90 days (n = 9, incidence rate [IR] 2.45/100 person‐months), but not with late pancreas failure (n = 32, IR 0.84/100 person‐months), kidney graft failure, or patient death. Although DCD was associated with K‐DGF, it was not associated with either pancreas (hazard ratio [HR] 0.91, 95% CI 0.58‐1.44, P = .69) or kidney (HR 1.09, 95% CI 0.66‐1.82, P = .74) graft failure after adjustment for potential confounders. We found K‐DGF to be a significant risk factor for pancreas graft failure but not kidney graft failure, with the major risk period being early (<90 days) posttransplant, and the major donor risk factor being older donor age.     

Meiosis‐specific cohesin component,Rec8, promotes the localization of Mps3 SUN domain protein on the nuclear envelope

Proteins in the nuclear envelope (NE) play a role in the dynamics and functions of the nucleus and of chromosomes during mitosis and meiosis. Mps3, a yeast NE protein with a conserved SUN domain, predominantly localizes on a yeast centrosome equivalent, spindle pole body (SPB), in mitotic cells. During meiosis, Mps3, together with SPB, forms a distinct multiple ensemble on NE. How meiosis‐specific NE localization of Mps3 is regulated remains largely unknown. In this study, we found that a meiosis‐specific component of the protein complex essential for sister chromatid cohesion, Rec8, binds to Mps3 during meiosis and controls Mps3 localization and proper dynamics on NE. Ectopic expression of Rec8 in mitotic yeast cells induced the formation of Mps3 patches/foci on NE. This required the cohesin regulator, WAPL ortholog, Rad61/Wpl1, suggesting that a meiosis‐specific cohesin complex with Rec8 controls NE localization of Mps3. We also observed that two domains of the nucleoplasmic region of Mps3 are essential for NE localization of Mps3 in mitotic as well as meiotic cells. We speculate that the interaction of Mps3 with the meiosis‐specific cohesin in the nucleoplasm is a key determinant for NE localization/function of Mps3.     

Phytochemical and Morphological Traits of Ginger Cultivars are Modulated by Agro-Climatic Conditions

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - In the present work, three promising ginger cultivars, Suprabha, Suravi and Varada, were cultivated in nine...     

Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10

Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia-reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice were exposed to lower limb RIPC or sham ischemia. After 24?h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120). These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased phosphorylation of the protein kinase Akt and limited infarct size after I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein levels and caused activation of Akt and endothelial nitric oxide synthase in the heart at 24?h, which was also blocked by anti-IL-10 receptor antibodies. In the gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase PTEN and activation of Stat3, with increased IL-10 expression?24?h later. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury.