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Forum on Immunopathological Diseases and Therapeutics

Mark A Underwood
Premature infants are at increased risk for morbidity and mortality due to necrotizing enterocolitis (NEC) and sepsis. Probiotics decrease the risk of NEC and death in premature infants; however, mechanisms of action are unclear. A wide variety of probiotic species have been evaluated for potential beneficial properties in vitro, in animal models, and in clinical trials of premature infants. Although there is variation by species and even strain, common mechanisms of protection include attenuation of intestinal inflammation, apoptosis, dysmotility, permeability, supplanting other gut microbes through production of bacteriocins, and more effective use of available nutrients...
2016: Forum on Immunopathological Diseases and Therapeutics
Nabil Aziz, Benjamin Bonavida
During the last decade, probiotics have been established to be important mediators of host immunity. Their effects on both innate and adaptive immunity have been documented in the literature. Although several reports have correlated different strains of bacteria as probiotics, their effects on immunity vary. Clearly, there is a complex interplay between various constituents of probiotics and the immune response in humans. The role of probiotics on natural killer (NK) cells in the gut has been the subject of a few reports...
2016: Forum on Immunopathological Diseases and Therapeutics
Swapan K Ray
The Krüppel-like factor 4 (KLF4) gene is located on chromosome 9q31. All of the currently known 17 KLF transcription regulators that have similarity with members of the specificity protein family are distinctly characterized by the Cys2/His2 zinc finger motifs at their carboxyl terminals for preferential binding to the GC/GT box or the CACCC element of the gene promoter and enhancer regions. KLF4 is a transcriptional regulator of cell proliferation, differentiation, apoptosis, migration, and invasion, emphasizing its importance in diagnosis and prognosis of particular tumors...
2016: Forum on Immunopathological Diseases and Therapeutics
John Phair, Roger Detels, Joseph Margolick, Charles Rinaldo, Lisa Jacobson, Otoniel Martínez-Maza, Steven Wolinsky, Alvaro Muñoz
John Fahey was an integral member of the small group of investigators who developed the Multicenter AIDS Cohort Study (MACS) in the early 1980s. A major research theme in the MACS was defining immune system changes in men at risk for developing AIDS. John's experience and expertise provided a solid grounding for the immunologic investigations conducted in the MACS. Additionally, he contributed enormously to the science of the MACS and pioneered the critical evaluation of serologic methods of documenting infection with HIV and T cell phenotyping...
2015: Forum on Immunopathological Diseases and Therapeutics
Marta Epeldegui, Otoniel Martínez-Maza
HIV infection is associated with a greatly elevated risk for the development of non-Hodgkin lymphoma (NHL), which while diminished, remains elevated in the highly active antiretroviral therapy (HAART) era. Chronic B cell activation, driven by contact with HIV virions, B cell-stimulatory cytokines, viruses (EBV, HPV, HCV), and by high levels of antigenic stimulation occurs in HIV infected persons, and it is seen at even higher levels in those who go on to develop AIDS-NHL. Evidence from multiple studies indicates that elevated serum levels of several B cell-stimulatory cytokines and biomarkers are seen preceding AIDS-NHL, as well as in immunocompetent persons that develop NHL...
2015: Forum on Immunopathological Diseases and Therapeutics
Rachel S Resop, Christel H Uittenbogaart
Emigration of mature naïve CD4 SP T cells from the human thymus to the periphery is not fully understood, although elucidation of the mechanisms that govern egress of T cells is crucial to understanding both basic immunology and the immune response in diseases such as HIV infection. Recent work has brought to light the requirement for sphingosine-1-phosphate (S1P) and its receptors in a variety of fields including mature naïve T-cell egress from the thymus of mice. We are examining the expression and function of this novel requisite T-cell egress receptor within the human thymus, characterizing changes observed in the expression and function of this receptor in infectious diseases...
2015: Forum on Immunopathological Diseases and Therapeutics
Stergios Katsiougiannis
Extracellular vesicles, including microvesicles, exosomes and apoptotic bodies are recognized as carriers of pathogen-associated molecules with direct involvement in immune signaling and inflammation. Those observations have enforced the way these membranous vesicles are being considered as promising immunotherapeutic targets. In this review, we discuss the emerging roles of extracellular vesicles in autoimmunity and highlights their potential use as disease biomarkers as well as targets for the treatment and prevention of autoimmune diseases...
2015: Forum on Immunopathological Diseases and Therapeutics
Hannah Akuffo, Sven Britton, Thomas Schön
Chronic asymptomatic worm infection, often in combination with tuberculosis (TB), is common in low-income countries. Indeed, a life without worm infestation, as is now the case in most high-income countries, is a recent condition for humankind. Worms and Mycobacterium tuberculosis give rise to different immune response patterns (Th2 vs. Th1 driven), and we have studied whether chronic worm infection affects the susceptibility to and control of TB in the low income country of Ethiopia. Our results, as well of those in the general literature, are inconclusive, although we have some rather strong data in support of adult deworming in relation to vaccination with bacillus Calmette-Guérin (BCG) against TB...
2015: Forum on Immunopathological Diseases and Therapeutics
Kellie N Smith, Robbie B Mailliard, Charles R Rinaldo
Despite the success of combination antiretroviral therapy (cART), a latent viral reservoir persists in HIV-1-infected persons. Unfortunately, endogenous cytotoxic T lymphocytes (CTLs) are unable to control viral rebound when patients are removed from cART. A "kick and kill" strategy has been proposed to eradicate this reservoir, whereby infected T cells are induced to express viral proteins via latency-inducing drugs followed by their elimination by CTLs. It has yet to be determined if stimulation of existing HIV-1-specific CTL will be sufficient, or if new CTLs should be primed from naïve T cells...
2015: Forum on Immunopathological Diseases and Therapeutics
Najib Aziz
Measurement of circulating cytokine levels can provide important information in the study of the pathogenesis of disease. John L. Fahey was a pioneer in the measurement of circulating cytokines and immune-activation markers and a leader in the quality assessment/control of assays for measurement of circulating cytokines. Insights into the measurement of circulating cytokines, including consideration of multiplex assays, are presented here.
2015: Forum on Immunopathological Diseases and Therapeutics
Junghwa Lee, Eunseon Ahn, Haydn T Kissick, Rafi Ahmed
T-cell exhaustion due to persistent antigen stimulation is a key feature of chronic viral infections and cancer. Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. Recently, antibodies blocking PD-1 have been approved for use in cancer patients. In this review, we summarize the role of the PD-1 pathway in chronic infection and cancer and the therapeutic potential of PD-1-directed immunotherapy in patients with chronic infection or cancer...
2015: Forum on Immunopathological Diseases and Therapeutics
Roger Detels
John Fahey was one of the first investigators to study the then-new acquired immune deficiency syndrome (AIDS). He made major contributions to the design of the Multicenter AIDS Cohort Study (MACS), and vigorously promoted novel and high-quality science as the MACS evolved. His contributions are highly valued.
2015: Forum on Immunopathological Diseases and Therapeutics
Matthew D Marsden, Jerome A Zack
Antiretroviral therapy (ART) can reduce HIV viral loads to undetectable levels and prevent disease progression. However, HIV persists in rare cellular reservoirs within ART-treated patients and rapidly reemerges if ART is stopped. Latently infected CD4(+) T cells represent a major reservoir of HIV that persists during ART. Therefore, a cure for HIV must include methods that either permanently inactivate or eliminate latent virus. Experimental methods under investigation for eliminating latently infected cells include transplantation/gene therapy approaches intended to deplete the infected cells and replace them with HIV-resistant ones, and DNA editing strategies that are capable of damaging or excising non-expressing HIV proviruses...
2015: Forum on Immunopathological Diseases and Therapeutics
Jonathan M Kagan, Ana M Sanchez, Alan Landay, Thomas N Denny
Foundational cellular immunology research of the 1960s and 1970s, together with the advent of monoclonal antibodies and flow cytometry, provided the knowledge base and the technological capability that enabled the elucidation of the role of CD4 T cells in HIV infection. Research identifying the sources and magnitude of variation in CD4 measurements, standardized reagents and protocols, and the development of clinical flow cytometers all contributed to the feasibility of widespread CD4 testing. Cohort studies and clinical trials provided the context for establishing the utility of CD4 for prognosis in HIV-infected persons, initial assessment of in vivo antiretroviral drug activity, and as a surrogate marker for clinical outcome in antiretroviral therapeutic trials...
2015: Forum on Immunopathological Diseases and Therapeutics
Robert Scheinman
NF-κB has long been known to play an important role in autoimmune diseases such as rheumatoid arthritis (RA). Indeed, as our understanding of how NF-κB is utilized has increased, we have been hard put to find a process not associated with this transcription factor family in some way. However, new data originating, in part, from genome-wide association studies have demonstrated that very specific alterations in components of the NF-κB pathway are sufficient to confer increased risk of developing disease. Here we review the data which have identified specific components of the NF-κB pathway, and consider what is known of their mechanisms of action and how these mechanisms might play into the disease process...
April 1, 2013: Forum on Immunopathological Diseases and Therapeutics
Benjamin Bonavida, Ali Jazirehi, Mario I Vega, Sara Huerta-Yepez, Stavroula Baritaki
The current anti-cancer therapeutic armamentarium consists of surgery, chemotherapy, radiation, hormonal therapy, immunotherapy, and combinations thereof. Initial treatments usually result in objective clinical responses with prolongation of overall survival (OS) and progression-free survival (PFS) in a large subset of the treated patients. However, at the onset, there is a subset of patients who does not respond and another subset that initially responded but experiences relapses and recurrences. These latter subsets of patients develop a state of cross-resistance to a variety of unrelated therapies...
2013: Forum on Immunopathological Diseases and Therapeutics
Benjamin Bonavida, Stavroula Baritaki
Treatment of cancer cell lines with high levels of nitric oxide (NO) via NO donors, such as DETANONOate, inhibits cell growth and survival pathways and sensitizes resistant tumor cells to apoptosis by chemoimmunotherapeutic drugs. In addition, we recently have reported that NO also inhibits the epithelial-to-mesenchymal transition (EMT) phenotype in metastatic cancer cell lines via dysregulation of the nuclear factor (NF)-κB/Snail/Yin Yang 1 (YY1)/Raf kinase inhibitor protein circuitry. The mechanism underlying NO-mediated dysregulation of this circuit was investigated, namely, NO-mediated inhibition of the activity of the transcription factors NF-κB, Snail, and YY1...
2012: Forum on Immunopathological Diseases and Therapeutics
Khosrow Kashfi
Nitric oxide (NO)-releasing agents such as JS-K and NO-releasing hybrids such as NO- and NONO-nonsteroidal anti-inflammatory drugs are novel agents with great potential for controlling cancer. Although studied extensively, a key question pertaining to their molecular targets and mechanism of action remains unclear: the role of NO in the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S-nitrosylation and induce apoptosis. We showed that 3 structurally diverse NO-nonsteroidal anti-inflammatory drugs S-nitrosylated nuclear factor-κB p65 in vitro and in vivo and also showed that these agents S-nitrosylated caspase-3 in vivo...
2012: Forum on Immunopathological Diseases and Therapeutics
Naveena B Janakiram, Chinthalapally V Rao
Nitric oxide (NO) is a short-lived pleiotropic regulator and is required for numerous pathophysiological functions, including macrophage-mediated immunity and cancer. It is a highly reactive free radical produced from l-arginine by different isoforms of NO synthases (NOSs). Sustained induction of inducible NOS (iNOS) during chronic inflammatory conditions leads to the formation of reactive intermediates of NO, which are mutagenic and cause DNA damage or impairment of DNA repair, alter cell signaling, and promote proinflammatory and angiogenic properties of the cell, thus contributing to carcinogenesis...
January 1, 2012: Forum on Immunopathological Diseases and Therapeutics
Anna E Maciag, Ryan J Holland, Joseph E Saavedra, Harinath Chakrapani, Paul J Shami, Larry K Keefer
Promising drug candidates of the diazeniumdiolate (NONOate) chemical family include several types of thiol modification among their mechanisms of action: 1) drugs designed to release nitric oxide (NO) on reaction with the thiol group of glutathione (GSH) arylate the GSH, a step that removes reducing equivalents from the cell; (2) a similar reaction of the drug with the thiol group of a protein changes its structure, leading to potentially impaired function and cell death; (3) the NO generated as a byproduct in the above reactions can undergo oxidation, leading to S-nitrosylation and S-glutathionylation; and (4) diazeniumdiolates can also generate nitroxyl, which reacts with thiol groups to form disulfides or sulfinamides...
2012: Forum on Immunopathological Diseases and Therapeutics
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