Analytical Processing of Binary Mixture Information by Olfactory Bulb Glomeruli

Odors are rarely composed of a single compound, but rather contain a large and complex variety of chemical components. Often, these mixtures are perceived as having unique qualities that can be quite different than the combination of their components. In many cases, a majority of the components of a mixture cannot be individually identified. This synthetic processing of odor information suggests that individual component representations of the mixture must interact somewhere along the olfactory pathway. The anatomical nature of sensory neuron input into segregated glomeruli with the bulb suggests that initial input of odor information into the bulb is analytic. However, a large network of interneurons within the olfactory bulb could allow for mixture interactions via mechanisms such as lateral inhibition. Currently in mammals, it is unclear if postsynaptic mitral/tufted cell glomerular mixture responses reflect the analytical mixture input, or provide the initial basis for synthetic processing with the olfactory system. To address this, olfactory bulb glomerular binary mixture representations were compared to representations of each component using transgenic mice expressing the calcium indicator G-CaMP2 in olfactory bulb mitral/tufted cells. Overall, dorsal surface mixture representations showed little mixture interaction and often appeared as a simple combination of the component representations. Based on this, it is concluded that dorsal surface glomerular mixture representations remain largely analytical with nearly all component information preserved

Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities

The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2–3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFNγ expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections

Intratumoral IL-12 and TNF-α–Loaded Microspheres Lead To Regression of Breast Cancer and Systemic Antitumor Immunity

Background: Local, sustained delivery of cytokines at a tumor can enhance induction of antitumor immunity and may be a feasible neoadjuvant immunotherapy for breast cancer. We evaluated the ability of intratumoral poly-lactic-acid-encapsulated microspheres (PLAM) containing interleukin 12 (IL-12), tumor necrosis factor α (TNF-α), and granulocyte-macrophage colony stimulating factor (GM-CSF) in a murine model of breast cancer to generate a specific antitumor response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41401/1/10434_2004_Article_147.pd

Renal cell carcinoma : recent progress and future directions

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Reactivity of anti-asialo GM1 serum with tumoricidal and non-tumoricidal mouse macrophages

All peritoneal macrophage (pMΦ) populations studied exhibited some binding of the anti-asGM1 serum as assessed by flow cytometry. The levels of reactivity varied quantitatively among populations, depending on the combination of eliciting and activating agents employed prior to the harvest of pMΦ. Resident pMΦ contained a very small percentage (4%) of cells that were strongly asGM1 +. Any treatment of these cells that induced them to become stimulated or activated increased the percentage of highly asGM1 + cells. Treatments that enhanced anti-asGM1 binding including eliciting pMΦ with proteose peptone (16% asGM1 +) or Brewer's thioglycollate medium (66% asGM1 +), treatment with the activating biological response modifiers (BRMs) MVE-2 (12% asGM1 +) and P acnes (18% asGM1 +), or treatment with both peptone + MVE-2 (37% asGM1 +) or peptone + poly IC/LC (33%). Increased expression of anti-asGM1 was accompanied by some increase in the reactivity of the various pMΦ populations to treatment with anti-asGM1 serum. This conclusion was based on the reduced viabilities of cells treated with both an eliciting agent and an activating agent prior to in vitro treatment with anti-asGM1 + C, as well as by reductions in cytolytic activity of pMΦ elicited with peptone and activated by MVE-2, following anti-asGM1 treatment in vitro or administration in vivo. Conversely, the cytolytic activity of resident pMΦ activated in vivo by MVE-2 or heat-killed P acnes, agents that induced relatively small increases in the percentage of asGM1 + cells, was resistant to the effects of in vivo and/or in vitro treatment with doses of anti-asGM1 serum that inhibit NK activity. These results indicate that stimulation of pMΦ by eliciting or activating agents can increase the level of expression of asGM1. This increased expression of asGM1 may be a useful marker for some aspects of macrophage heterogeneity, but increased expression is not necessarily directly related to expression of tumoricidal activity. In fact, the results of this study demonstrate that anti-asGM1 serum can be used for specific depletion of NK activity in vivo in normal mice and in mice treated with at least some BRMs. However, the results also demonstrate that the use of eliciting agents, particularly thioglycollate, or eliciting agents in conjunction with activating agents can cause pMΦ to become reactive with anti-asGM1 serum