Sex Steroids Effects on the Molting Process of the Helminth Human Parasite Trichinella spiralis

We evaluated the in vitro effects of estradiol, progesterone, and testosterone on the molting process, which is the initial and crucial step in the development of the muscular larvae (ML or L1) to adult worm. Testosterone had no significative effect on the molting rate of the parasite, however, progesterone decreased the molting rate about a 50% in a concentration- and time-independent pattern, while estradiol had a slight effect (10%). The gene expression of caveolin-1, a specific gene used as a marker of parasite development, showed that progesterone and estradiol downregulated its expression, while protein expression was unaffected. By using flow citometry, a possible protein that is recognized by a commercial antiprogesterone receptor antibody was detected. These findings may have strong implications in the host-parasite coevolution, in the sex-associated susceptibility to this infection and could point out to possibilities to use antihormones to inhibit parasite development

Clinical Study Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator-human dialyzable leukocyte extract (hDLE)-on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1 , IL-2, and IFN-; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro-and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone

Physicochemical Characteristics of Transferonƒ Batches

Transferon, a biotherapeutic agent that has been used for the past 2 decades for diseases with an inflammatory component, has been approved by regulatory authorities in Mexico (COFEPRIS) for the treatment of patients with herpes infection. The active pharmaceutical ingredient (API) of Transferon is based on polydispersion of peptides that have been extracted from lysed human leukocytes by a dialysis process and a subsequent ultrafiltration step to select molecules below 10 kDa. To physicochemically characterize the drug product, we developed chromatographic methods and an SDS-PAGE approach to analyze the composition and the overall variability of Transferon. Reversed-phase chromatographic profiles of peptide populations demonstrated batch-tobatch consistency from 10 representative batches that harbored 4 primary peaks with a relative standard deviation (RSD) of less than 7%. Aminogram profiles exhibited 17 proteinogenic amino acids and showed that glycine was the most abundant amino acid, with a relative content of approximately 18%. Further, based on their electrophoretic migration, the peptide populations exhibited a molecular mass of about 10 kDa. Finally, we determined the Transferon fingerprint using a mass spectrometry tool. Because each batch was produced from independent pooled buffy coat samples from healthy donors, supplied by a local blood bank, our results support the consistency of the production of Transferon and reveal its peptide identity with regard to its physicochemical attributes

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother’s and offspring’s quality of life

Clinical and Experimental Immunomodulation

The inflammatory response is modulated by the concentration of soluble mediators and the coordinated action of different types of immune cells. Furthermore, basic and clinical research has demonstrated that the immune response is regulated by several factors such as: the chemical nature and the concentration of antigen; the route of administration; the cell type involved in the antigen presentation to their specific lymphocytes; and the presence of antibodies and/or immune complexes among other mechanisms. More recently, it has been described that other signaling molecules like neurotransmitters and hormones can also modulate the immune response. Over time, this information has enabled the elucidation of the role of immune cell products in physiological processes like sleep, memory, learning, and pain, or in autoimmune and infective diseases, as well as the mechanisms involved. Such evidence provides the opportunity for the development of novel therapeutic approaches for diseases with deleterious immune and inflammatory components. The papers presented in this special issue focus on the leveraging knowledge of clinical and experimental immunomodulation. First, the reader can find seven experimental approaches that analyze immunomodulation mediated by hormones, neurotransmitters, cytokines, and antigens. The work of M. V. Legorreta-Haquet et al. shows that prolactin in early stages of B cells maturation process may promote the survival of self-reactive clones in a murine model of lupus. T. Schaumann et al. present results of anti-inflammatory effects of glycine in gingival inflammation and encourage further research on the utility of glycine in the prevention therapy of inflammatory periodontitis. B. Dénes et al. share an interesting work on experimental immunotherapy with a multicomponent vaccine containing a cholera toxin B subunit-autoantigen fusion protein for restoration of euglycemia and immunological homeostasis in NOD mice. F. Robledo-Ávila et al. explored a novel therapeutic approach consisting in the administration of murine dialyzable leukocyte extracts plus a reduced, and therefore less toxic, dose of Amphotericin B in a mouse model of systemic candidiasis. The approach proved to be effective in reducing mortality, pathogen burden, and tissue damage at the renal level. S. Mburu et al. evaluated in vitro the modulation of LPS-induced CD4+ T cell activation and apoptosis by antioxidants in cells from untreated asymptomatic HIV infected participants. Their results set the basis for the development of an adjuvant therapy aimed to counteract the harmful effects of chronic immune activation on CD4+ T cells. S. Dang et al. show that LMW-HA modulates papillary thyroid carcinoma (PTC) cell behavior via TLR-4 signaling providing examples of the functional roles of CXCR7 in proliferation and migration. Their data are elegantly complemented with the analysis of TLR4 and CXCR7 expression in PTC clinical samples. Finally, J. M. Calleja-Castillo et al. investigate the effect of deep brain stimulation (DBS) at hypothalamic nucleus in Wistar rats, over the circulating concentrations of corticosterone and proinflammatory cytokines, detecting that the chronic application of this therapy to Wistar rats induces a significant circulatory rise in inflammatory mediators and blocks HPA axis activity. These results suggest that immunity might be altered in patients who are treated with DBS and provide the basis for the development of strategies to prevent immunity-related secondary effects of DBS. Regarding the clinical approaches of immunomodulation, three works are also included. The first one, from N. Valero-Pacheco et al., analyzes the expression of PD-L1 on T cells in patients infected with the influenza virus A(H1N1)pdm09 and its impact on T cell responses. The second one, from J. Galicia-Carreón et al., studies the context of the unbalanced immunological mechanisms underlying the development of allergic conjunctivitis by evaluating the frequency of Tregs as well as cells expressing homing receptors in peripheral blood from patients. The third one, from M. E. Hernández et al., presents the results of a clinical followup of major depressive disorder (MDD) patients treated with a combination of selective serotonin reuptake inhibitors (SSRI) and human dialyzable leukocytes extract (hDLE) as immunomodulator. The latter consists of small weight peptides and has been used successfully as adjuvant therapy in diverse infectious and deficient cell-immunity problems. MDD patients present imbalances in neurotransmitter levels, hormones such as cortisol, and cytokines that contribute to the behavioral and immune disturbances observed in them. This combined treatment efficiently restored the pro- and anti-inflammatory cytokine balance and cortisol levels when compared with patients treated only with SSRI. This study constitutes the first report of a clinical assay that analyzes the effects of immunotherapy in MDD. This special issue also includes two reports of experimental techniques that allow the assessment of immunomodulation. The work of I. Lima Siman et al. evaluated the serum levels of allergen-specific IgG antibodies from atopic patients. The authors conclude that this laboratory test would help specialists to follow up patients under immunotherapy. The report by M. C. Jiménez-Martínez et al. shows an experimental technique to identify NnTreg lymphocytes by staining them with Amaranthus leucocarpus lectin and posterior FACS. Last but not least, this issue presents four revisions on a broad range of topics. N. Deckx et al. focus on multiple sclerosis and discuss the influence of neuroendocrine immune system over the susceptibility and severity of autoimmune diseases, as well as new therapeutic approaches for the treatment of this kind of diseases. R. Cabezón and D. Benitez-Ríbas review the participation of different dendritic cells (DCs) subsets and their role in inflammatory bowel disease and present preclinical studies performed in animal models describing the recent characterization of tol-DCs from Crohn’s disease patients. G. A. Toledo-Ibarra et al. describe some aspects of the immunity of fish and its connections with cholinergic system, highlighting the possibility that bidirectional communication between the nervous and immune systems exists in lower vertebrates as well as during evolution of immune system. G. Hurtado-Alvarado et al. present an extensive review focused on the relationship between inflammation and inflammatory markers as well as sleep and sleep loss

Clinical and Experimental Immunomodulation 2016

Inflammatory response (IR), which is crucial in injuries or infected anatomical regions, also generates systemic effects, regulating multiple physiological processes. Those effects depend on the concentration of soluble mediators likecytokines, chemokines, and other inflammatory molecules. For example, concentrations of soluble mediators around 10nM are enough to induce a neuroendocrine response. The diverse systemic effects triggered by IR are plastic and continuously modified by fluctuations of circulatory levels ofhormones, neurotransmitters, and mediators of inflammation. These feedback loops are possible by the constitutive expression of receptors for hormones, neurotransmitters, and cytokines on leukocytes, which modulate key cellularfunctions like proliferation, differentiation, and the secretion profile.That is the reason whereby the constant research on clinical and experimental parameters that modulate is of great importance. This third special issue on clinical and experimental immunomodulation compiles a selection of high quality works on the field.Fil: Pavón, Lenin. Instituto Nacional de Psiquiatría Ramón de la Fuente; MéxicoFil: Besedosky, Hugo. Universitat Phillips; AlemaniaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Velasco Velázquez, Marco A.. Universidad Nacional Autónoma de México; MéxicoFil: Bauer, Moisés E.. Pontificia Universidade Católica do Rio Grande do Sul; Brasi

Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE)—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone

Effect of A549 neuroendocrine differentiation on cytotoxic immune response

The present study was designed to determine the effects of factors secreted by the lung adenocarcinoma cell line with the neuroendocrine phenotype, A549NED, on cytotoxic T lymphocytes (CTLs) activity in vitro. A perspective that integrates the nervous, endocrine and immune system in cancer research is essential to understand the complexity of dynamic interactions in tumours. Extensive clinical research suggests that neuroendocrine differentiation (NED) is correlated with worse patient outcomes; however, little is known regarding the effects of neuroendocrine factors on the communication between the immune system and neoplastic cells. The human lung cancer cell line A549 was induced to NED (A549NED) using cAMP-elevating agents. The A549NED cells showed changes in cell morphology, an inhibition of proliferation, an overexpression of chromogranin and a differential pattern of biogenic amine production (decreased dopamine and increased serotonin [5-HT] levels). Using co-cultures to determine the cytolytic CTLs activity on target cells, we showed that the acquisition of NED inhibits the decrease in the viability of the target cells and release of fluorescence. Additionally, the conditioned medium of A549NED and 5-HT considerably decreased the viability and proliferation of the Jurkat cells after 24 h. Thus, our study successfully generated a neuroendocrine phenotype from the A549 cell line. In co-cultures with CTLs, the pattern of secretion by A549NED impaired the proliferation and cytotoxic activity of CTLs, which might be partly explained by the increased release of 5-HT