Dynorphin and related subfragments augment splenic effector cell lytic function against YAC-1 tumor cells in vitro

Regulation of the immune system by the neuroendocrine system is a relatively new concept. We have investigated the influence of the opioid peptide dynorphin (DYN) and its subfragments on murine splenic natural killer (NK) cell cytotoxicity against YAC-1 cells in vitro. Addition of DYN or a/B interferon (IFN) significantly augmented NK lytic function in a 4 hour chromium release assay. Dynorphin added to effector cells previously incubated with a/B IFN showed an augmentation over a/B IFN priming alone. Dynorphin exerted its effects on NK cytotoxicity over a range of 10-8M to 1010M, with 10-9M having the optimal augmentation effect. Leucine-enkephalin and other DYN subfragments exerted similar patterns of augmentation. The opioid peptide-induced augmentation was blocked by the general opiate antagonist naloxone. Verapamil, a calcium channel blocker, also suppressed the effect of DYN and its subfragments on NK cells, indicating calcium dependence in augmentation. Thus, it appears that the neuroendocrine opioid peptide DYN and its subfragments act as regulatory molecules to augment murine NK cell lytic functions. This effect is mediated by functional opiate receptors on the NK cell surface, which can be blocked by naloxone. This study provides further evidence for the concept of a neuro-immuno regulatory axis in tumor surveillance models

Opioid peptides and opiate alkaloids in immunoregulatory processes

Among the various non-neuronal cell types known to express and utilize neuropeptides, those of the immune system have received much attention in recent years. In particular, comparative studies in vertebrates and invertebrates have shown that endogenous opioid peptides are engaged in receptor mediated autoregulatory immune and neuroendocrine processes. The majority of these immune processes are stimulatory, as determined by their effects on conformational changes indicative of immunocyte activation, cellular motility, and phagocytosis. Endogenous opioid peptides form an effective network of messenger molecules in cooperation with cytokines, opiate alkaloids, and certain regulatory enzymes (neutral endopeptidase 24.11). Peptide-mediated immunostimulatory effects observed in this system are operationally counteracted by the inhibitory effects of morphine and related opiates. Opioid/opiate signaling processes are mediated by several types of receptors with different degrees of selectivity. Among them the recently identified, opioid insensitive µ3 receptor deserves attention on account of its specificity for opiate alkaloids

Effects of Syndyphalin-33 on appetite, endocrine, and immune parameters in the recently weaned pig

This thesis discusses the background information regarding the physiological effects the pig encounters during weaning as well as a potential factor that can be used to assist the pig during this time. Specifically, the research focus is to assess the ability of the tri-peptide opioid agonist, Syndyphalin-33 (SD-33), to increase feed intake and body weight and modulate immune responses during the post-weaning period. The results of this research have demonstrated that SD-33 increases feed intake, transiently increases growth hormone and cortisol levels, and increases total white blood cell counts while selectively increasing monocyte numbers in healthy weaned pigs. This research also demonstrates that, although co-treatment with SD-33 during an immune challenge of Salmonella enterica did not result in increased feed intake, SD-33 exerted effects relating to increasing the circulating populations of immune cells at 48 h postinjections, selectively increasing monocyte numbers. Based on these results, SD-33 may have the potential to be used as an agent to decrease the negative effects of stress during weaning in pigs. However, further investigation is needed to better understand the timing of effect, and to rule out any immunosuppressive effects, which would be detrimental to the animal’s well-being

A “Drug-Dependent” Immune System Can Compromise Protection against Infection: The Relationships between Psychostimulants and HIV

Psychostimulant use is a major comorbidity in people living with HIV, which was initially explained by them adopting risky behaviors that facilitate HIV transmission. However, the effects of drug use on the immune system might also influence this phenomenon. Psychostimulants act on peripheral immune cells even before they reach the central nervous system (CNS) and their effects on immunity are likely to influence HIV infection. Beyond their canonical activities, classic neurotransmitters and neuromodulators are expressed by peripheral immune cells (e.g., dopamine and enkephalins), which display immunomodulatory properties and could be influenced by psychostimulants. Immune receptors, like Toll-like receptors (TLRs) on microglia, are modulated by cocaine and amphetamine exposure. Since peripheral immunocytes also express TLRs, they may be similarly affected by psychostimulants. In this review, we will summarize how psychostimulants are currently thought to influence peripheral immunity, mainly focusing on catecholamines, enkephalins and TLR4, and shed light on how these drugs might affect HIV infection. We will try to shift from the classic CNS perspective and adopt a more holistic view, addressing the potential impact of psychostimulants on the peripheral immune system and how their systemic effects could influence HIV infection.Fil: Assis, Maria Amparo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet Noa Sur. Instituto Multidisciplinario de Salud, Tecnologia y Desarrollo. - Universidad Nacional de Santiago del Estero. Instituto Multidisciplinario de Salud, Tecnologia y Desarrollo.; Argentina. Universidad Nacional de Educación a Distancia; España. Universidad Nacional de Santiago del Estero. Facultad de Ciencias Medicas.; ArgentinaFil: Carranza, Pedro Gabriel. Universidad Nacional de Santiago del Estero. Facultad de Agronomía y Agroindustrias; Argentina. Universidad Nacional de Santiago del Estero. Facultad de Ciencias Medicas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto Multidisciplinario de Salud, Tecnología y Desarrollo. - Universidad Nacional de Santiago del Estero. Instituto Multidisciplinario de Salud, Tecnología y Desarrollo; ArgentinaFil: Ambrosio, Emilio. Universidad Nacional de Educación a Distancia; Españ

Modulation of Macrophage Chemiluminescence by Biological Response Modifiers and Neuroendocrine Hormones

Neuroendocrine mediators have been shown to influence a broad spectrum of immune functions suggesting the existence of a neuroimmune regulatory axis effecting feedback control of the immune response. Most studies in support of this paradigm have employed either intact animals or immune cells derived from blood and other tissues. Under these conditions it becomes difficult to cope with numerous variables associated with the complex milieu of the immune system and the interpretation of data. An in vitro model using a murine macrophage cell line, J774, was developed to circumvent these problems. Using this model, macrophages activated by exposure to the biological response modifiers lipopolysaccharide bacillus Calmettc-Guerin, Corynebacterium parvum, α + ß interferon and γ-interferon exhibited a readily observed and quantitated chemiluminescent oxidative burst. This activity was modulated by the neuropeptides ß-endorphin, dynorphin A, neurotensin and tuftsin as well as the neuroendocrine hormones norepinephrine γ-aminobutyric acid and the pineal hormone melatonin. In the case of norepinephrine, the mechanism of action may involve hormone-mediated hyperpolarization of the macrophage membrane potential

Immunomodulation and immunopharmacology in heart failure

The immune system is intimately involved in the pathophysiology of heart failure. However, it is currently underused as a therapeutic target in the clinical setting. Moreover, the development of novel immunomodulatory therapies and their investigation for the treatment of patients with heart failure are hampered by the fact that currently used, evidence-based treatments for heart failure exert multiple immunomodulatory effects. In this Review, we discuss current knowledge on how evidence-based treatments for heart failure affect the immune system in addition to their primary mechanism of action, both to inform practising physicians about these pleiotropic actions and to create a framework for the development and application of future immunomodulatory therapies. We also delineate which subpopulations of patients with heart failure might benefit from immunomodulatory treatments. Furthermore, we summarize completed and ongoing clinical trials that assess immunomodulatory treatments in heart failure and present several therapeutic targets that could be investigated in the future. Lastly, we provide future directions to leverage the immunomodulatory potential of existing treatments and to foster the investigation of novel immunomodulatory therapeutics.</p

Opioids and the immune system: implications for clinical practice

Już ponad 100 lat temu obserwowano niekorzystny wpływ opioidów na układ immmunologiczny. Od tego czasu zgromadzono wiele dowodów na to, że opioidy oddziałują na różne elementy tego układu, takie jak makrofagi, granulocyty, komórki NK czy cytokiny. Jednakże większość wniosków oparta jest na badaniach in vitro albo na modelach zwierzęcych. Prawdopodobnie istnieją trzy mechanizmy immunosupresji wywołanej opioidami, a mianowicie bezpośrednie działanie na receptory opioidowe na komórkach immunologicznych oraz działanie pośrednie - poprzez wpływ na układ adrenergiczny i uwalnianie steroidów. Nadal nie wiadomo, jakie znaczenie w praktyce klinicznej mają wszystkie te obserwacje. W artykule omówiono między innymi różne kontrowersyjne problemy dotyczące wpływu leczenia opioidami na rozwój infekcji, przebieg zakażenia HIV-1 czy oddziaływania na chorobę nowotworową. Nadal istnieje potrzeba przeprowadzenia badań klinicznych, które pozwoliłyby na wyjaśnienie tych wątpliwości.The first observations of the adverse effects of opiods on the immune system were made more than a century ago. Since then there have been many reports that show that opioids have immunomodulating effects on different parts of the immune system such as macrophages, granulocytes, NK-cells, or different cytokines. However, most conclusions are based on observations from in vitro or animal studies. There are 3 proposed mechanisms of immunosuppression by opioids, including a direct impact on opioid receptors on immune cells and an indirect effect on the adrenergic system and opioid-induced steroid release. Nevertheless, it is unclear whether these findings have any clinical relevance. This article will present the controversies concerning the impact of opioid therapy on different clinical concerns such as infections, HIV-1 promotion and cancer. There is still an urgent need for studies in clinical settings with clinical parameters

Principles and Applications of Cardio-immunology in Heart Failure

Cardio-immunology is an emerging field at the intersection of cardiology and immunology, focusing on the role of the immune system in cardiovascular disease. Heart failure (HF), in particular, is considered an immunologic phenomenon. However, attempts to modulate the immune system for treating HF have been largely unsuccessful. In this thesis we examined various aspects of immune activation in HF.In Chapter 2 we summarized the immunomodulatory properties of current treatments for HF, we summarized previous and ongoing clinical studies of immunomodulatory treatments for HF and discussed potential future applications. In Chapters 3 and 4, the association between circulating interleukin-6 and clinical characteristics and prognosis in patients with HF was evaluated. Elevated interleukin-6 levels were associated with a worse prognosis, as well as specific clinical characteristics and blood measurements. In Chapter 5, biomarker analyses identified processes related to interferon-γ signaling and T cell co-stimulation as having the most consistent associations with all-cause mortality in patients with HF. Chapter 6 revealed that autoantibodies against autonomic nervous system receptors had limited prognostic value in patients with HF, although anti-β1 seropositivity was independently associated with a higher likelihood of hospitalization for HF. In Chapter 7, white blood cell profiling in patients with HF provided prognostic and pathophysiologic information, suggesting its potential use for risk stratification and patient selection for immunomodulatory treatments.Overall, this thesis contributes to the understanding of immune activation in HF and lays the foundation for further research in cardio-immunology for preventive, diagnostic/prognostic, and therapeutic applications

Tsütokiinide ja neuroendokriinse süsteemi osalemine vitiliigo patogeneesis

Väitekirja elekrooniline versioon ei sisalda publikatsioone.Vitiliigo on elu jooksul omandatud haigus, kus seni veel täpselt teadmata põhjustel hävinevad melanotsüüdid ja selle tagajärjel tekivad nahale pigmenditud laigud. Patsiendid kannatavad psühholoogilise stressi all ja neil on suurenenud risk saada nahavähk. On teada, et vitiliigohaigetel on muutunud ekspressioonimuster paljudel geenidel, mis osalevad ühe olulisima stressivastuse andja hüpotaalamuse-hüpofüüsi-neerupealise telje (HPA telg) töös. HPA telg koosneb klassikaliselt CRH-POMC-glükokortikoidide signaalirajast ja selle regulatsioonis osalevad erinevad tsütokiinid ja neuromediaatorid. Meie töö eesmärk oli saada lisainformatsiooni närvi- ja immuunsüsteemi interaktsioonidest vitiliigohaigetes. Selleks mõõtsime CRH-POMC-MCH süsteemi, melanogeneesiga seotud tsütokiinide ning dopamiini raja geenide mRNA ja valgu taset vitiliigohaigete ja tervete indiviidide nahas ja veres. Lisaks juba varasemalt näidatud POMC süsteemi geenide (olulised melanogeneesi aktiveerijad) ekspressiooni langusele leidsime, et kasvanud on endogeense opioidi PNOC ja selle retseptori ekspressioon kahjustatud nahas, samuti on suurenenud POMC süsteemi inhibeeriva MCH süsteemi geenide ekspressioon. Näitasime muutusi HPA telje aktiivsust reguleerivate interleukiin-10 perekonna tsütokiinide ja nende retseptorite ekspressioonis ning teiste melanogeneesi ja melanotsüütide kasvu ja arengut reguleerivate tsütokiinide ja muude mediaatorite ekspressioonis. Andsime lisakinnitust neuromediaatori dopamiini raja võimalikule osalusele vitiliigo patogeneesis – lisaks tasakaalu mõjutamisele läbi melanokortiini raja võib dopamiin olukorda nahas ka otseselt muuta. Kokkuvõteks, leidsime, et lokaalse HPA telje funktsioneerimine on vitiliigohaigete nahas oma normaalsest olekust kõrvale kaldunud. Peamiseks põhjuseks näivad olevat muutused melanokortiini rajas, samuti HPA telje tööd aktiveerivate tsütokiinide ja inhibeeriva dopamiini süsteemi muutused võivad tuleneda katsest taastada normaalne olukord ja tasakaal.Vitiligo is an acquired disease, where melanocytes are destroyed and white patches appear on skin. The reasons are not jet fully understood. Patients are suffering from psychological stress and the risk for skin cancer increases. In vitiligo patients, the expression pattern has changed for genes that are involved in functioning of the hypothalamic-pituitary-adrenal axis (HPA axis) – the major pathway for stress response. Classically the HPA axis consists of CRH-POMC and glucocorticoid signaling pathways and is regulated by various cytokines and neurotransmitters. Our aim was to get more information about the nervous and immune system interactions in vitiligo patients. We measured mRNA and protein levels in skin and blood of vitiligo patients and healthy individuals; studied genes were associated to CRH-POMC-MCH system, melanogenesis regulating cytokines and dopamine pathway. In addition to our previous findings (decreased expression level of POMC system genes; essential activators of melanogenesis), we found that expression of endogenous opioid PNOC and its receptor has grown in lesional skin, also the MCH system (inhibits POMC system) expression has increased in patients. We showed changes in the expression pattern of interleukin-10 family cytokines and their receptors (regulating HPA axis) expression and other cytokines connected to melanogenesis and melanocyte growth and development. We provided supplemental confirmation that the neurotransmitter dopamine pathway may be involved in the pathogenesis of vitiligo - in addition to influencing the melanogenesis through the melanocortin pathway; dopamine may influence the skin homeostasis directly. In conclusion, in vitiligo patients, the functioning of cutaneous HPA axis has deviated from its normal state. The main inducer appears to be the changes in melanocortin system and the activating (cytokines) and inhibiting (dopamine) agents may attempt to restore the normal state of skin homeostasis