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Nathan Goodyear

Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory... - 0 views

jem.rupress.org/...1209.abstract

IL-10 cytokines inflammation Treg cells human

shared by Nathan Goodyear on 18 Apr 12 - No Cached
  • Nathan Goodyear on 18 Apr 12
     
    role of IL-10 cytokine.  IL-10 down regulates  monocyte inflammatory cytokines and class II MHC.  The source of IL-10 is now known to be Treg cells (Th3).  Interesting, viruses can produce a similar IL-10 to suppress the immune reaction.
Nathan Goodyear

Hyperthermia as an immunotherapy strategy for cancer - 1 views

www.ncbi.nlm.nih.gov/...PMC2828267

cancer hyperthermia

shared by Nathan Goodyear on 29 Nov 18 - No Cached
  • the notion of treating human cancers with heat dates back to the writings of Hippocrates
  • enhance the efficiency of standard cancer therapies, such as chemotherapy and radiation treatment
  • After antigen uptake at tumor sites, APCs have the ability to create a robust response by entering lymphoid compartments and programming lymphocytes
  • ...36 more annotations...
  • Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point
  • hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation
  • mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials
  • mild temperature hyperthermia (ie, within the fever-range, 39–41°C)
    • Nathan Goodyear
      Nathan Goodyear on 04 Aug 19
       
      101.2 to 105.8
  • moderate hyperthermia (41°C)
    • Nathan Goodyear
      Nathan Goodyear on 04 Aug 19
       
      105.8 F
  • Hsps are a family of stress-induced proteins
  • they are key regulators of cellular protein activity, turnover and trafficking
  • Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction
  • the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps
  • thermotolerance
  • Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms
  • Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs
  • In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens
  • In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell
  • hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance
  • Fever-range hyperthermia may also induce Hsps
  • Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs
  • thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites
  • specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells
  • Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens
  • It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis
  • tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat
  • Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.
  • support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses
  • whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes
    • Nathan Goodyear
      Nathan Goodyear on 04 Aug 19
       
      This allows for the activation of lymphocytes by the activated dendritic cells.
  • suggest a valuable role of hyperthermia in DC cancer vaccine strategies
  • In mice treated with fever-range whole-body hyperthermia, tumor growth was significantly inhibited and NK-cell infiltration increased
    • Nathan Goodyear
      Nathan Goodyear on 04 Aug 19
       
      Hyperthermia increased NK cell activation, proliferation, and infiltration, which equals increased cytotoxicity.
  • exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types
  • improved activation and function of DCs and NK cells following hyperthermia
  • Hyperthermia increases the expression ICAM-1 a key adhesion molecule,
  • The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.
  • In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.
  • The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment
  • the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical
  • hyperthermia has been shown to improve immune surveillance by T-cell
  • and to increase DC trafficking to lymph nodes
  • Nathan Goodyear on 29 Nov 18
     
    Great review of hyperthermia.
Nathan Goodyear

The Single Nucleotide Polymorphism Gly482Ser in the PGC-1α Gene Impairs Exerc... - 0 views

journals.plos.org/...article

epigenetics exercise training muscle SNPs PGC-1alpha

shared by Nathan Goodyear on 30 Nov 17 - No Cached
  • Oxidative slow-twitch type I fibres (henceforth briefly called ‘slow fibres’) contain MHC-Iβ. They use oxidative phosphorylation (OXPHOS) to generate ATP and are thus highly fatigue resistant and preferentially activated during endurance exercise. Slow fibres comprise high amounts of mitochondria, myoglobin and lipid droplets, and are well supplied by capillaries
  • there are three types of fast-twitch fibres (types IIA, IID/X, IIB, with the corresponding MHC isoforms IIa, IId/x, IIb) which are all used for rapid high-force generation. Oxidative-glycolytic fast-twitch type IIA fibres have intermediate amounts of mitochondria, lipid droplets and capillaries, and are intermediately resistant to fatigue (as compared to type I and types IIB and IID/X). Glycolytic fast-twitch type IID/X fibres are poor in mitochondria, lipids and capillaries and more susceptible to fatique than type IIA. Glycolytic fast-twitch type IIB fibres have the lowest amounts of mitochondria, lipid droplets and capillaries, but generate the highest contraction velocities
  • Several studies have shown that PGC-1α is upregulated after endurance training
  • ...3 more annotations...
  • upregulation of PGC-1α expression enhances and/or maintains mitochondrial biogenesis, eventually leading to an increased mitochondrial content of the muscle fibres.
  • PGC-1α also plays an important role in the pathogenesis of insulin resistance and T2D
  • carriers of the Gly482Ser SNP have a reduced cardiorespiratory fitness and a higher risk for metabolic syndrome and T2D
  • Nathan Goodyear on 30 Nov 17
     
    Those that carry the risk SNP for Gly482Ser for the PGC-1alpha gene dont' transform type II to type I and thus decrease the effectiveness of aeorbic exercise training, decreased oxidative phosphorylation, decreased lipid oxidation, increased lipid accumulaiton in muscle, and increased risk of IR, obesity, and diabetes.
Nathan Goodyear

Activation of NK cells by extracellular heat shock protein 70 through induction of NKG2... - 0 views

www.ncbi.nlm.nih.gov/...PMC2935777

heat shock proteins NK cells natural killer cells cancer

shared by Nathan Goodyear on 29 Sep 18 - No Cached
  • Heat shock proteins (HSPs) are intracellular molecular chaperones that play essential roles in facilitating protein folding
  • their ability to interact with APCs and to chaperone antigenic peptides for cross-presentation to MHC class I and class II molecules on APC
  • vaccination with HSP70 was associated with increased T cell, as well as NK cell, activity in patients with CML
  • ...6 more annotations...
  • HSP70 did not activate NK cells directly. Instead, HSP70 induced the expression of an NKG2D ligand MICA on DCs, which then activated NK cells in an NKG2D-dependent manner.
  • DCs are the most powerful professional antigen presenting cells (APCs) that are instrumental in processing antigens and orchestrating antigen-specific adaptive immunity and tolerance
  • NK cells and DCs can functionally interact with each other both in vitro and in vivo
  • autologous HSP70 could stimulate significant IFN-γ production
  • The magnitude of the IFN-γ response was different from patient to patient and correlated with the number of functional NK cells
  • In addition, 10 out of 14 patients had significantly increased IFN-γ producing cells in the peripheral blood after HSP70 vaccinations, which is again in line with increased NK cell activity as reported in our original study in these patients
  • Nathan Goodyear on 29 Sep 18
     
    great review of the relationship between heat shock proteins and NK cells.
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