ZIA BC 009369 (ZIA) | |||
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Title | Studies of Receptor Interactions and Effects of Alarmins | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Oppenheim, Joost | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $835,806 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Cancer (100.0%) Digestive Diseases (20.0%) |
Breast (20.0%) Melanoma (20.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
We have shown that a variety of antimicrobial peptides (AMPs) and nuclear binding proteins that mimic chemokines also have the capacity to rapidly activate host immune responses. We have proposed calling these early warnings signals alarmins. Alarmins are characterized by having in vitro chemotactic or in vivo recruitment activity for cells expressing GiPCR, together with the capacity to interact with other receptors resulting in the activation of immature dendritic cells (iDC) into mature antigen-presenting capable of interacting with T lymphocytes. These alarmins, if administered together with an antigen result in considerable augmentation of both in vivo cellular and humoral immune responses to the antigen. We previously identified both alpha and beta types of defensins as alarmins with chemotactic and activating effects on immature dendritic cells (iDCs) as having in vivo immunoadjuvant effects. Some of the beta defensins interact with the CCR6 chemokine receptor, others with CCR2, while alpha defensins interact with an as yet unknown G-Protein Coupled Receptors (GiPCR). Defensins by binding to DNA also can activate DC's by triggering TLR-9. Indeed, human neutrophil peptide 1, HNP1 was recently reported by our collaborators to activate pDC's using NF-kappaB and IRF signaling pathways. The resultant IFN production presumably has considerable proinflammatory effects. Another antimicrobial peptide known as cathelicidin (LL37) and its murine homologue CRAMP are chemotactic for FPR2 receptors expressed on monocytes and precursors of iDC. Cathelicidins also induce the maturation iDC and are equally as potent adjuvants in vivo as alum. In addition, we have previously also identified eosinophil derived neurotoxin (EDN, a ribonuclease), granulysin from lymphocytes, lactoferrin from neutrophils and HMGB1, a nuclear binding protein, as functional alarmins. Although alarmins are structurally distinct, they are preformed and constitutively available. Alarmins are rapidly released from granules, cytosol or nucleus of leukocytes and epithelial cells or by necrotic cells. Alarmins can also be induced to be produced in response to proinflammatory stimulants by keratinocytes or epithelial cells lining the GI tract, GU tract and tracheobronchial tree. As such, alarmins probably represent an early warning system to alert the host defense to danger signals. During the past several years, we have also identified a transcription factor, High Mobility Group Nucleosome-binding protein-1 (HMGN-1), as an extracellular alarmin that is chemotactic for DC and an inducer of Toll-like receptor 4 (TLR-4) dependent immune responses. HMGN-1 has the capacity to recruit and induce the maturation of dendritic cells (DC) at sites of injection. HMGN-1 activates NF kappa B and multiple MAP kinases largely in a TLR4 dependent manner. Upon co-administration with antigens, HMGN-1 has potent adjuvant effects favoring Th1 immune responses. Conversely, mice genetically engineered to be deficient in HMGN-1 had greatly reduced antigen specific immune responses even in response to antigens administered together with LPS. This immune deficiency of HMGN-1 knockout mice was associated with deficient recruitment of inflammatory cells and DC to sites of immunization and reduced cytokine production by DC. Thus, HMGN-1 which is largely derived from non-leukocytes (e.g. epithelial cells) plays a non-redundant critical role in the development of innate and adaptive immune responses. In a previous experimental study, we showed that intraperitoneal administration of anthrax vaccine with HMGN1 protein markedly increased the production of both primary and secondary protective IgG antibodies to anthrax toxin. We previously showed that HMGN-1 knockout mice exhibit reduced resistance to tumor (EG-7 or EL-4) challenge. Conversely, tumor cells (EG-7 or EL-4) when transfected to overexpress HMGN1 showed a marked reduction in the rate of growth in normal mice. These observations indicated th |