Search

Association between vestibular function and immune inflammatory response has garnered increasing interest. Immune responses can lead to anatomical or functional alterations of the vestibular system, and inflammatory reactions may impair hearing and balance. Vestibular disorders comprise a variety of conditions, such as vestibular neuritis, benign paroxysmal positional vertigo, Meniere's disease, vestibular migraine, posterior circulation ischemia, and bilateral vestibular disease. Moreover, some patients with autoimmune diseases develop vestibulocochlear symptom. This paper offers an overview of prevalent vestibular diseases and discusses associations between vestibular dysfunction and immune diseases. [ABSTRACT FROM AUTHOR]

In this paper, the dynamical behaviors of a multiple delayed HIV-1 infection model which describes the interactions of humoral, cytotoxic T lymphocyte (CTL) immune responses, and two modes of transmission that are the classical virus-to-cell infection and the direct cell-to-cell transmission are investigated. The model incorporates three delays, including the delays of cell infection, virus production and activation of immune response. We first prove the well-posedness of the model, and calculate the biological existence of equilibria and the reproduction numbers, which contain virus infection, humoral immune response, CTL immune response, CTL immune competition, and humoral immune competition. Further, the threshold conditions for the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response, and interior are established by utilizing linearization method and the Lyapunov functionals. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are carried out to illustrate the theoretical results and reveal the effects of some key parameters on viral dynamics. [ABSTRACT FROM AUTHOR]

The paper is focused on computation of stable periodic solutions to systems of delay differential equations modelling the dynamics of infectious diseases and immune response. The method proposed here is described by an example of the well-known model of dynamics of experimental infection caused by lymphocytic choriomeningitis viruses. It includes the relaxation method for forming an approximate periodic solution, a method for estimating the approximate period of this solution based on the Fourier series expansion, and a Newton-type method for refining the approximate period and periodic solution. The results of numerical experiments are presented and discussed. The proposed method is compared to known ones. [ABSTRACT FROM AUTHOR]

In this paper, we provide the ML (Maximum Likelihood) and the REML (REstricted ML) criteria for consistently estimating multivariate linear mixed-effects models with arbitrary correlation structure between the random effects across dimensions, but independent (and possibly heteroscedastic) residuals. By factorizing the random effects covariance matrix, we provide an explicit expression of the profiled deviance through a reparameterization of the model. This strategy can be viewed as the generalization of the estimation procedure used by Douglas Bates and his co-authors in the context of the fitting of one-dimensional linear mixed-effects models. Beside its robustness regarding the starting points, the approach enables a numerically consistent estimate of the random effects covariance matrix while classical alternatives such as the EM algorithm are usually non-consistent. In a simulation study, we compare the estimates obtained from the present method with the EM algorithm-based estimates. We finally apply the method to a study of an immune response to Malaria in Benin. [ABSTRACT FROM AUTHOR]

In this paper a problem of specifying HIV-infection parameters and immune response using additional measurements of the concentrations of the T-lymphocytes, the free virus and the immune effectors at fixed times for a mathematical model of HIV dynamics is investigated numerically. The problem of the parameter specifying of the mathematical model (an inverse problem) is reduced to a problem of minimizing an objective function describing the deviation of the simulation results from the experimental data. A genetic algorithm for solving the least squares function minimization problem is implemented and investigated. The results of a numerical solution of the inverse problem are analyzed. [ABSTRACT FROM AUTHOR]

In quest to contain and subsequently eradication Human Immunodeficiency virus (HIV) in the society, mathematical modelling remains an important research tool. In this paper, we formulated a mathematical model to study the effects of cortisol on immune response to HIV capturing the roles played by dendritic cells, T helper cells, regulatory T cells and cytotoxic T cells in the virus replication dynamics. The primary source of concentration of cortisol in this work is through psychological stress. Numerical experiments are performed to examine the effect of cortisol on selective inhibition of antigen presentation activities and up-regulation of naive cytotoxic T cells activation in the case of acute and persistent stressful conditions. [ABSTRACT FROM AUTHOR]

Colon cancer patients were analyzed to compare the effects of surgical trauma on immune function by detecting the activation degree of cell inflammatory cytokines levels after different surgical procedures. In total, 107 patients with colon cancer were divided into open surgery group and laparoscopic surgery group. Serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), toll-like receptor 4 (TLR4), cluster of differentiation 14 (CD14) and myeloid differentiation protein-2 (MD-2) levels were detected before, after and one day after surgery. Serum CRP, IL-6 and TNF-α levels in both groups were significantly increased at all postoperative time points after surgery compared with those preoperatively. CRP, IL-6 and TNF-α levels in the laparoscopic group were lower than that in the open surgery group at all time points after surgery. Serum IL-6 and TNF-α levels in open surgery group were significantly lower than those in the laparoscopic surgery group after LPS stimulation. Laparoscopic surgery led to the decrease of serum CD14, TLR4 and MD-2 levels. The incidence of postoperative complications in laparoscopic group was significantly less as compared to the open surgery group. Cellular immunity may be better presented after laparoscopic surgery in comparison with open surgery. Laparoscopic complete mesenteric resection surgery is effective in the treatment of colon cancer. [ABSTRACT FROM AUTHOR]

A major goal of vaccine development is the identification of immune responses that are responsible for vaccine efficacy. In theory, modest vaccines could be successfully improved by increasing such immune responses. And for a vaccine with a great benefit in one population, inducing such immune response in a different population could help one conclude the vaccine would have great benefit there. Such identification is tricky because the immune response to vaccination can only be measured in the vaccine group and thus immune responses might only be identifying individuals with a constitutional ability to remain uninfected, rather than being causal. Define the vaccine induced immune response as X(1). The value X(1) is a potential outcome; it is measured directly in vaccinees but unobserved in the placebo group. Our goal is to regress outcome on X(1) separately in the vaccine and placebo groups and to see if the vaccine effect varies with X(1). Put another way, our goal is to see if there is a vaccine by X(1) interaction. Regression of outcome on X(1) is easy to do in the vaccine group, but difficult in the placebo group as X(1) is not observed. In this paper we derive bounds on the regression curve in the placebo group. For a continuous endpoint these bounds can be unhelpful, or can help modestly temper our enthusiasm for a role of X(1) on the vaccine effect. For binary outcomes with 100% placebo infection the bound is very tight but unhelpful as 100% infection precludes identification of any covariate with a differential effect on placebo infection. We apply these methods to experiments of anthrax vaccine in rabbits with survival to challenge as the outcome and demonstrate how to extrapolate the model to humans. [ABSTRACT FROM AUTHOR]

After exceptional research efforts, several vaccines were developed against SARS-CoV-2 which sustains the pandemic COVID-19. The Comirnaty vaccine showed high efficacy in clinical trials and was the first to be approved for its distribution to the general population. We evaluated the immune response induced by the first vaccine dose in different sex/age groups and subjects with or without naturally present anti-SARS-CoV-2 antibodies. As part of an Italian multicenter project (Covidiagnostix), serum samples from 4,290 health-professionals were serologically tested the day of the first vaccination dose, and 21 days later, using two different instrumentations (Siemens-Healthineers and Roche). In total, 97% of samples showed the presence of specific antibodies 21 days after the vaccination dose; the percentage of non-responders increased with age in both genders. Remarkably, naturally seropositive individuals showed antibody persistence up to 11 months and an exceptionally higher vaccination response compared to subjects never infected by SARS-CoV-2. This study highlighted the importance of the serological test i) to identify naturally SARS-CoV-2 seropositive individuals and ii) to evaluate the antibody level elicited by the first vaccination dose. Both tests, highlighted differences in the immune response, when subjects were stratified by sex and age, and between naturally seropositive and seronegative subjects. The data obtained show how serological tests could play a crucial role in the triage of the population subjected to the vaccination campaign for COVID-19. The definition of suitable instrumentation-specific thresholds is needed to correctly follow eventually acquired post-vaccination immunity in the general population. [ABSTRACT FROM AUTHOR]

Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP's TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity in human PDAC cells (MIA PaCa-2), co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner. TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs. [ABSTRACT FROM AUTHOR]

The problem of guaranteed computation of all steady states of the Marchuk–Petrov model with fixed values of parameters and analysis of their stability are considered. It is shown that the system of ten nonlinear equations, nonnegative solutions of which are steady states, can be reduced to a system of two equations. The region of possible nonnegative solutions is analytically localized. An effective technology for computing all nonnegative solutions and analyzing their stability is proposed. The obtained results provide a computational basis for the study of chronic forms of viral infections using the Marchuk–Petrov model. [ABSTRACT FROM AUTHOR]

Leukocytes are professionals in recognizing and removing pathogenic or unwanted material. They are present in virtually all tissues, and highly motile to enter or leave specific sites throughout the body. Less than a decade ago, physical plasmas entered the field of medicine to deliver their delicate mix of reactive species and other physical agents for mainly dermatological or oncological therapy. Plasma treatment thus affects leukocytes via direct or indirect means: immune cells are either present in tissues during treatment, or infiltrate or exfiltrate plasma-treated areas. The immune system is crucial for human health and resolution of many types of diseases. It is therefore vital to study the response of leukocytes after plasma treatment in vitro and in vivo. This review gathers together the major themes in the plasma treatment of innate and adaptive immune cells, and puts these into the context of wound healing and oncology, the two major topics in plasma medicine. [ABSTRACT FROM AUTHOR]

The saponin natural product QS-21 is one of the most potent investigational adjuvants, which are substances added to vaccines to enhance the immunogenicity of the antigen and potentiate the immune response. While QS-21 has been coadministered with vaccines against cancers and infectious diseases in many clinical trials, its inherent liabilities (scarcity, heterogeneity, instability and dose-limiting toxicity) have limited its widespread clinical use. Furthermore, its molecular mechanisms of action are poorly understood. Structural modification of the natural product using chemical synthesis has become an important strategy to overcome these limitations. This review focuses mainly on research efforts in the group of the late Professor David Y. Gin on the development of optimized synthetic saponin adjuvants derived from QS-21. A number of QS-21 variants incorporating stable acyl chain amide linkages, truncated carbohydrate domains and targeted modifications at the triterpene and central glycosyl ester linkage were designed, chemically synthesized and immunologically evaluated. These studies delineated key minimal structural requirements for adjuvant activity, established correlations between saponin conformation and activity and provided improved, synthetically accessible saponin adjuvants. Moreover, leveraging these structure-activity relationships, novel saponin probes with high potency and reduced toxicity were developed and used in biodistribution and fluorescence imaging studies, yielding early insights into their enigmatic mechanisms of action. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy based on tumor vaccine is very promising and intriguing for carcinoma treatment. Herein, antitumor nanovaccines consisting of self-assembled chitosan (CS) nanoparticles and two-component mucin1 (MUC1) glycopeptide antigens were reported. Two different kinds of polyanionic electrolyte [sodium tripolyphosphate (TPP) and γ-poly-L-glutamic acid (γ-PGA)] were combined with chitosan polymers to fabricate the diameter of nearly 400-500 nm CS nanoparticles by electrostatic interactions. The nanovaccines were constructed by physically mixing MUC1 glycopeptide antigens with CS nanoparticles, which reduced vaccine constructing complexity compared with traditional chemical total synthetic vaccines. Immunological studies revealed that the CS/γ-PGA nanoparticle could dramatically enhance the immunogenicity of peptide epitope and produce significantly high titers of IgG antibody which was even better than Freund's adjuvant-containing vaccines. [ABSTRACT FROM AUTHOR]

The driving force for the constant improvement and development of new synthetic methodologies in carbohydrate chemistry is a growing demand for biologically important oligosaccharide ligands and neoglycoconjugates thereof for numerous biochemical investigations such as cell-to-pathogen interactions, immune response, cell adhesion, etc. Here we report our syntheses of the spacer-armed antigenic oligosaccharides related to three groups of the polysaccharides of the fungal cell-wall including α- and β-mannan, α- and β-glucan and galactomannan chains, which include new rationally designed synthetic blocks, efficient solutions for the stereoselective construction of glycoside bonds, and novel strategy for preparation of furanoside-containing oligosaccharides based on recently discovered pyranoside-into-furanoside (PIF) rearrangement. [ABSTRACT FROM AUTHOR]

Physical transfer of viable tumor cells from one organism to another is known as transmissible cancer, which is observed in dogs, Tasmanian devils, Syrian hamsters, and some soft-shell clams. Tasmanian devil facial tumor disease is transmitted like an infectious disease between individuals through biting and other close contact. This extinction type is quite different from the other extinction types such as ecological factors. Transmissible cancers' cellular metabolism is also different from the both normal cellular metabolism and other types of cancers' metabolism. The lack of an immune response against the Tasmanian devil facial tumor cells is the one of the key points in the transmission of the cancerous cells. The differentiated cellular metabolism and absence of immune reaction may be due to the organisms' enzymes. Cells may have altered surface proteins by altering enzymatic activities that cannot be recognized by both the innate and adaptive responses. The promiscuity of the key enzymes may be associated with unwanted side effects, such as cannot recognize molecular patterns on the transmitted cell or hypomethylation of DNA by altering catalytic properties enzymes or altered matrix metalloproteinases or cathelicidins. [ABSTRACT FROM AUTHOR]

There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity. [ABSTRACT FROM AUTHOR]

We develop a transport formula for predicting overall cumulative vaccine efficacy through time t (VE(t)) to prevent clinically significant infection with a genetically diverse pathogen (e. g., HIV infection) in a new setting for which a Phase III preventive vaccine efficacy trial that would directly estimate VE(t) has not yet been conducted. The formula integrates data from (1) a previous Phase III trial, (2) a Phase I/II immune response biomarker endpoint trial in the new setting where a follow-up Phase III trial is planned, (3) epidemiological data on background HIV infection incidence in the new setting; and (4) genomic epidemiological data on HIV sequence distributions in the previous and new settings. For (1), the randomized vaccine versus placebo Phase III trial yields estimates of vaccine efficacy to prevent particular genotypes of HIV in participant subgroups defined by baseline covariates X and immune responses to vaccination Sð1Þ measured at a fixed time point τ (potential outcomes if assigned vaccine); often one or more immune responses to vaccination are available that modify genotype-specific vaccine efficacy. The formula focuses on subgroups defined by X and Sð1Þ and being at-risk for HIV infection at τ under both the vaccine and placebo treatment assignments. For (2), the Phase I/II trial tests the same vaccine in a new setting, or a refined new vaccine in the same or new setting, and measures the same baseline covariates and immune responses as the original Phase III trial. For (3), epidemiological data in the new setting are used to project overall background HIV infection rates in the baseline covariate subgroups in the planned Phase III trial, hence re-calibrating for HIV incidence differences in the two settings; whereas for (4), data bases of HIV sequences measured from HIV infected individuals are used to re-calibrate for differences in the distributions of the circulating HIV genotypes in the two settings. The transport formula incorporates a user-specified bridging assumption function that measures differences in HIV genotype-specific conditional biological-susceptibility vaccine efficacies in the two settings, facilitating a sensitivity analysis. We illustrate the transport formula with application to HIV Vaccine Trials Network (HVTN) research. One application of the transport formula is to use predicted VE(t) as a rational criterion for ranking a set of candidate vaccines being studied in Phase I/II trials for their priority for down-selection into the follow-up Phase III trial. [ABSTRACT FROM AUTHOR]

The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-?B signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigenreceptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated 'chronic' CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas. [ABSTRACT FROM AUTHOR]

The immune response crucially determines the survival of patients with malignant tumors including breast carcinoma. The aim of the present study was to evaluate retrospectively an association of peripheral blood cell count (PBC)-derived ratios and urinary neopterin concentration with prognosis in breast cancer patients. Urinary neopterin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR) were retrospectively analyzed in a cohort of 474 breast cancer patients. NLR and PLR correlated positively with each other and negatively with LMR, but no correlation between neopterin concentrations and PBC-derived ratios was observed. Increased urinary neopterin concentration was a significant predictor of poor survival in patients with active disease, but PLR, NLR or LMR were not significantly associated with survival in multivariate analysis. In conclusion, increased urinary neopterin was a significant predictor of poor survival in patients with breast cancer and active disease. [ABSTRACT FROM AUTHOR]

The humoral immune responses of 69 active tuberculosis (TB) patients against three major mycobacterial lipid antigens, monoacyl phosphatidylinositol dimannoside (Ac-PIM2), trehalose 6,6′-dimycolate (TDM-T) and trehalose 6-monomycolate (TMM-T) from Mycobacterium bovis BCG Tokyo 172, were examined by ELISA. IgG antibodies from active TB patients were reactive against each of the three lipid antigens (Ac-PIM2, TDM-T and TMM-T), giving positive results of 42.0–59.4%. If tests were combined and an overall positive was scored when any of the three tests was positive, sensitivity was 71.0%, showing better discrimination between patients and normal subjects. Although this value is not satisfactory for the clinical diagnosis of active TB, it is still higher than values for Determinar TBGL (56.5%) and MycoDot (31.9%) test results, both of which are commercially available. IgG antibody responses to particular lipid antigens in an individual patient differed diversely between patients. Positive IgG antibody rates and IgG antibody levels to lipid antigens were mostly paralleled by the amount of mycobacteria excreted and by the severity of pathological lesions (size and cavity formation). Serologically positive responsiveness was shown in 60.0% of tuberculin skin test (TST)-negative TB patients. Furthermore, seropositivity for multiple-antigen ELISA in active TB patients was demonstrated in other possible immune-suppressed cases, such as senile, diabetes mellitus and fulminant TB patients. Therefore, in contrast to tests based on cellular immune responses such as the TST, the humoral immune responses of TB patients against mycobacterial lipid antigens were disease-specific and were shown to be useful for the early diagnosis of active TB disease in conjunction with smear and cultivation tests, even if cellular immune responses are decreased. [ABSTRACT FROM AUTHOR]

EBA-175 protein is used as a ligand in the binding of P. falciparum to red blood cells (RBCs). Evidence shows that the conserved peptide 1779 from this protein (with high red blood cell binding ability and known critical erythrocyte binding residues) plays an important role in the invasion process. This peptide is neither immunogenic nor protective; analogs having critical residues replaced by amino acids with similar volume or mass but different polarity were synthesized and inoculated into Aotus monkeys, and elicited different immunogenic and protective responses. Nuclear Magnetic Resonance (¹H-NMR) studies revealed that peptide analog 21696 (non-immunogenic and non-protective) presents a large helical fragment, that the peptide 14012 (immunogenic and non-protective) helical fragment is smaller, while the peptide 22812 (immunogenic and protective) α-helix is shorter in a different region and possesses greater flexibility at its N-terminus. The presence of methionine residues could affect the structural stability of peptide 22812 and ultimately its immunological response. Our results suggest a new strategy for designing a new malaria multi-component subunit-based vaccine. [ABSTRACT FROM AUTHOR]