Abstracts


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The oncogenic potential of mesenchymal stem cells in the treatment of cancer: Directions for future research
Momin E.N., Vela G., Zaidi H.A., Quinones-Hinojosa A.

Mesenchymal stem cells (MSCs) represent a promising new approach to the treatment of several diseases that are associated with dismal outcomes. These include myocardial damage, graft versus host disease, and possibly cancer. Although the potential therapeutic aspects of MSCs continue to be well-researched, the possible hazards of MSCs, and in particular their oncogenic capacity are poorly understood. This review addresses the oncogenic and tumor-supporting potential of MSCs within the context of cancer treatment. The risk for malignant transformation is discussed for each stage of the clinical lifecycle of MSCs. This includes malignant transformation in vitro during production phases, during insertion of potentially therapeutic transgenes, and finally in vivo via interactions with tumor stroma. The immunosuppressive qualities of MSCs, which may facilitate evasion of the immune system by a tumor, are also addressed. Limitations of the methods employed in clinical trials to date are reviewed, including the absence of long term follow-up and lack of adequate screening methods to detect formation of new tumors. Through discussions of the possible oncogenic and tumor-supporting mechanisms of MSCs, directions for future research are identified which may eventually facilitate the future clinical translation of MSCs for the treatment of cancer and other diseases.


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The role of immune system in schizophrenia
Muller N., Schwarz M.J.

Although an immune dysfunction and the involvement of infectious agents in the pathophysiology of schizophrenia are discussed since decades, the field never came into the mainstream of research. In schizophrenia a blunted type-1 immune response seems to be associated with a dysbalance in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia. This is associated with an imbalance in the glutamatergic neurotransmission, leading to an NMDA antagonism in schizophrenia. The immunological effects of antipsychotics rebalance partly the immune imbalance and the overweight of the production of the kynurenic acid. This immunological imbalance results in an inflammatory state combined with increased prostaglandin E2 (PGE2) production and increased cyclo-oxygenase-2 (COX-2) expression. COX-2 inhibitors have been tested in clinical trials, pointing to favourable effects in schizophrenia.


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The concept of depression as a dysfunction of the immune system
Leonard B.E.

Chronic stress, by initiating changes in the hypothalamic-pituitary-adrenal axis and the immune system, acts as a trigger for anxiety and depression. Both experimental and clinical evidence shows that a rise in the concentrations of proinflammatory cytokines and glucocorticoids, as occurs in chronically stressful situations and in depression, contribute to the behavioural changes associated with depression. A defect in serotonergic function is associated with hypercortisolaemia and the increase in proinflammatory cytokines that accompany depression. Glucocorticoids and proinflammatory cytokines enhance the conversion of tryptophan to kynurenine. In addition to the resulting decrease in the synthesis of brain serotonin, this leads to the formation of neurotoxins such as the glutamate agonist quinolinic acid and contributes to the increase in apoptosis of astrocytes, oligodendroglia and neurons. The importance of the inflammation hypothesis of depression lies in raising the possibility which psychotropic drugs that have a central anti-inflammatory action might provide a new generation of antidepressants.


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Immune system modulates the function of adult neural stem cells
Gonzalez-Perez O., Jauregui-Huerta F., Galvez-Contreras A.Y.

New neurons are continuously produced in most, if not all, mammals. This Neurogenesis occurs only in discrete regions of the adult brain: the subventricular zone (SVZ) and the subgranular zone (SGZ). In these areas, there are neural stem cells (NSCs), multipotent and selfrenewing, which are regulated by a number of molecules and signaling pathways that control their cell fate choices, survival and proliferation rates. It was believed that growth and morphogenic factors were the unique mediators that controlled NSCs in vivo. Recently, chemokines and cytokines have been identified as important regulators of NSCs functions. Some of the most studied immunological effectors are leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), interferon-gamma (IFN-γ), insulin-like growth factor-1 (IGF-1), tumor necrosis factor alpha (TNF-α), and the chemokines MCP-1 and SDF-1. These substances exert a considerable regulation on proliferation, cell-fate choices, migration and survival of NSCs. Hence, the immune system is emerging as an important regulator of neurogenic niches in the adult brain, but further studies are necessary to fully establish the biological meaning of these neural effects.


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Microencapsulation of vaccine antigens and adjuvants for mucosal targeting
Rajapaksa T.E., Lo D.D.

Delivery of vaccine antigens that can trigger potent mucosal immune response is one of the effective strategies to overcome a wide array of infectious diseases. Microencapsulation of vaccine antigens with Poly(lactide-co-glycolic acids) (PLGA), an FDA approved biodegradable polymer, has been investigated for targeted M-cell uptake. While PLGA possesses many attractive properties, a successful PLGA based mucosal-targeted vaccine has yet to be introduced. This review focuses on the physiochemical properties important in the preparation of antigen-loaded PLGA microparticles, properties that influence M-cell specific uptake, and the induction of effective immune responses. In addition, a possible role of microparticle properties in immune adjuvant activity is discussed. A careful consideration of these factors may yet lead to the development of an effective needle-free mucosal vaccine using polymer microparticles.


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Aging of the innate immune system: An update
Mahbub S., Brubaker A.L., Kovacs E.J.

The relationship between advanced age and immunologic deficits is becoming an area of rapidly advancing research. Many of the clinical hurdles in the elderly population result from dysregulation of the immune system leading to the inability of the elderly to swiftly combat infection and to the increased incidence of chronic disease states and autoimmune conditions. Herein, we address the crucial alterations in the innate immune system that occur with advancing age. Specifically, we discuss how the effects of advanced age may lead to functional changes in the neutrophil, macrophage, dendritic cell, natural killer cell, and natural killer T cell populations in human and murine models that translate into aberrant innate immune responses. Furthermore, we elucidate how these changes may contribute to documented deficits in adaptive immunity as well as the pathological conditions and the increased morbidity and mortality seen in the elderly population.


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Hypoxia inducible factor-1 in cancer immune suppression
Duechler M., Wilczynski J.R.

Hypoxia is a frequent feature of tumor microenvironment and contributes significantly to tumorigenesis and cancer progression. Furthermore, it is increasingly recognized that the transcription factor called hypoxia inducible factor (HIF)-1 also promotes cancer immunosuppression. HIF-1 is activated during hypoxia by stabilization of the subunit HIF- 1alpha. Alternatively, growth factor stimulation or proinflammatory cytokines can activate HIF-1 also under normoxic conditions. Hypoxia directly converts certain immune effector cells into suppressor cells. Monocytes are recruited into tumors, differentiate into macrophages and accumulate in hypoxic areas where they acquire immunosuppressive characteristics. As a consequence of HIF-1 activation, the production of tolerogenic factors derived from cancer cells as well as from immune suppressor cells is increased. Several of the most important immunosuppressive molecules are under the transcriptional control of HIF-1, including vascular endothelial growth factor, heme oxygenase-1, inducible nitric oxide synthase and cyclooxygenase-2. HIF-1 interacts with several other transcription factors which are crucial for immunosuppression such as Stat3 that is over-activated in many tumor cells and in immune suppressor cells. Some factors which are expressed as a consequence of hypoxia through HIF-1 contribute to HIF-1 stabilization and activation. Hypoxia and HIF-1 facilitate the initiation of the intra- tumoral immunosuppressive state and contribute to its stabilization in regulatory networks.


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Responses of glial cells to stress and glucocorticoids
Jauregui-Huerta F., Ruvalcaba-Delgadillo Y., Gonzalez-Perez O., Gonzalez-Castaneda R., Garcia-Estrada J., Luquin S.

A growing body of evidence suggests that glial cells are involved in practically all aspects of neural function. Glial cells regulate the homeostasis of the brain, influence the development of the nervous system, modulate synaptic activity, and carry out the immune response inside the brain. In addition, they play an important role in the restoration of the nervous system after damage, and they also participate in various neurodegenerative disorders. In a similar way, the importance of stress and glucocorticoids (GCs) on brain function is being increasingly recognized. Within the brain, stress hormones target both neurons and glial cells. Through their actions on these cells, glucocorticoids exert organizational functions on various processes of the developing brain and contribute to neuronal plasticity in the adult brain. Moreover, stress and glucocorticoids have become especially attractive in the study of a number of neurodegenerative disorders. However, studies on the mechanisms behind glucocorticoid-induced regulation of brain function have been classically focused on their effects on neurons. In this review, we start by describing the main functions of glial cells and then proceed to present data highlighting the effects of stress and GCs on brain function. We conclude the review by presenting recent evidence linking stress and glucocorticoids to glial cell function.


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Herpes simplex virus-induced ocular diseases: Detrimental interaction between virus and host
Verjans G.M.G.M., Heiligenhaus A

Herpes simplex virus type 1 (HSV-1) is a common cause of ocular diseases, affecting all parts of the visual axis. HSV-1 keratitis and uveitis represent two prevalent ocular diseases. The outcome of these potentially sightthreatening conditions depends on prompt diagnosis and treatment in order to counteract the detrimental intra-ocular virus-host interaction. This review recapitulates current insights on the diagnosis, pathogenesis, and treatment of HSV-1 keratitis and uveitis in patients and in the respective mouse models.