Collective effects in flow-driven cell migration.

Autologous chemotaxis is the process in which cells secrete and detect molecules to determine the direction of fluid flow. Experiments and theory suggest that autologous chemotaxis fails at high cell densities because molecules from other cells interfere with a given cell's signal. We investigate autologous chemotaxis using a three-dimensional Monte Carlo-based motility simulation that couples spatial and temporal gradient sensing with cell-cell repulsion. Surprisingly, we find that when temporal gradient sensing dominates, high-density clusters chemotax faster than individual cells. To explain this observation, we propose a mechanism by which temporal gradient sensing allows cells to form a collective sensory unit. We demonstrate using computational fluid mechanics that that this mechanism indeed allows a cluster of cells to outperform single cells in terms of the detected anisotropy of the signal, a finding that we demonstrate with analytic scaling arguments. Our work suggests that collective autologous chemotaxis at high cell densities is possible and requires only known, ubiquitous cell capabilities.

Cutting Edge: Bispecific γδ T Cell Engager Containing Heterodimeric BTN2A1 and BTN3A1 Promotes Targeted Activation of Vγ9Vδ2+ T Cells in the Presence of Costimulation by CD28 or NKG2D.

Vγ9Vδ2+ T cell-targeted immunotherapy is of interest to harness its MHC-independent cytotoxic potential against a variety of cancers. Recent studies have identified heterodimeric butyrophilin (BTN) 2A1 and BTN3A1 as the molecular entity providing "signal 1" to the Vγ9Vδ2 TCR, but "signal 2" costimulatory requirements remain unclear. Using a tumor cell-free assay, we demonstrated that a BTN2A1/3A1 heterodimeric fusion protein activated human Vγ9Vδ2+ T cells, but only in the presence of costimulatory signal via CD28 or NK group 2 member D. Nonetheless, addition of a bispecific γδ T cell engager BTN2A1/3A1-Fc-CD19scFv alone enhanced granzyme B-mediated killing of human CD19+ lymphoma cells when cocultured with Vγ9Vδ2+ T cells, suggesting expression of costimulatory ligand(s) on tumor cells is sufficient to satisfy the "signal 2" requirement. These results highlight the parallels of signal 1 and signal 2 requirements in αß and γδ T cell activation and demonstrate the utility of heterodimeric BTNs to promote targeted activation of γδ T cells.

Autologous chemotaxis at high cell density.

Autologous chemotaxis, in which cells secrete and detect molecules to determine the direction of fluid flow, is thwarted at high cell density because molecules from other cells interfere with a given cell's signal. Using a minimal model of autologous chemotaxis, we determine the cell density at which sensing fails, and we find that it agrees with experimental observations of metastatic cancer cells. To understand this agreement, we derive a physical limit to autologous chemotaxis in terms of the cell density, the Péclet number, and the lengthscales of the cell and its environment. Surprisingly, in an environment that is uniformly oversaturated in the signaling molecule, we find that not only can sensing fail, but it can be reversed, causing backwards cell motion. Our results get to the heart of the competition between chemical and mechanical cellular sensing, and they shed light on a sensory strategy employed by cancer cells in dense tumor environments.

LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1/PD-L1 and TIGIT Checkpoint Blockade.

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition-resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition-resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTßR (lymphotoxin ß receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

Latent profiles of the feeding practices of caregivers of rural children with overweight and obesity and associations with child eating behaviors.

Previous research has shown that food parenting practices, which vary within the context of sociocultural factors, are associated with child weight, eating behaviors, and body dissatisfaction. While parents typically engage in multiple food parenting practices, few studies have examined what subgroups or combinations of food parenting practices are associated with child health outcomes and sociocultural factors. The current study examined profiles of food parenting practices among school-age children with overweight/obesity (OW/OB) from rural communities and examined how they may be associated with sociocultural factors, child-eating habits, and health outcomes. The study included 270 children with OW/OB aged 8-12 (Mage = 10.36 years) and their caregivers. Caregivers completed a measure assessing perceptions of their feeding practices and sociocultural questionnaires. Children completed measures assessing disordered eating habits, weight control behaviors, and body dissatisfaction. Weight status was measured for caregivers and children with height and weight measurements. Latent variable mixture modeling (LVMM) was conducted. Three profiles emerged: (a) Lower Parental Involvement, (b) Higher Parental Involvement, and (c) Mixed Parental Involvement. Lower family income and non-White child race were related to membership in the "Higher Parental Involvement" profile. After controlling for income and child race, children in the "Mixed Parental Involvement" profile reported significantly higher body dissatisfaction than children in the "Lower Parental Involvement" profile. There are subgroups of caregivers of rural children with OW/OB that demonstrate various patterns of parent feeding practices, and these subgroups differ by income, race, and child body dissatisfaction. Future research should consider how caregiver-specific feeding practices may impact child eating behaviors and their body image development, as well as the impact cultural factors may have on parent feeding practices.

Impact of mothers' distress and emotional eating on calories served to themselves and their young children: An experimental study.

BACKGROUND: Parents play a significant role in children's eating behaviours and food environment. Emotional eating (i.e., eating due to/to cope with emotions regardless of hunger) can contribute to excess energy consumption and subsequent weight gain. Yet, there is a paucity of research examining mothers' feeding and eating behaviours in the presence of their young children during times of acute distress. OBJECTIVE: The current study examined whether manipulated maternal mood impacted subsequent eating and parental-feeding in mothers with overweight or obesity with their preschool aged children in a laboratory-based experiment. METHODS: Mothers (n = 47) with overweight or obesity and their preschool aged children were randomized to either an acute distress or control group. After completing a task which manipulated mothers' moods, respectively, dyads were offered a buffet of snack foods. Measures of mothers' reported emotional eating and distress were collected, and calories served and consumed were objectively measured. RESULTS: There were no between-group differences regarding calories served or consumed. Mothers across both groups who reported higher emotional eating served themselves (p = 0.014) and their children (p = 0.007) less food, and mothers consumed less food (p = 0.045). Mothers who reported higher emotional eating and increased acute distress fed their children less food (p = 0.02) and both children and mothers ate less food (p < 0.05). CONCLUSIONS: Results suggest that mothers who report emotional eating tendencies may feed their children less food during periods of acute distress.

Meta-analysis of lifestyle modification interventions addressing overweight and obesity in preschool-age children.

OBJECTIVE: Increased rates of pediatric obesity extend into early childhood. There have been increasing calls for intervention programs specifically designed to address obesity in preschool-age youth. A review of the literature is critical to guide intervention and future research. The objective of this study was to conduct a meta-analysis of randomized, controlled trials examining the efficacy of lifestyle modification interventions to address overweight and obesity in preschool-age children. METHOD: Six electronic databases were searched for articles through December 8, 2020. After screening articles for inclusion criteria, 14 articles with 12 randomized, controlled trials (41 effect sizes, 2,525 participants) were included in this meta-analysis. Weighted-standardized mean differences for body mass index-related variables were calculated using random-effects models to estimate effect sizes. Risk of bias assessment was conducted. RESULTS: There was a statistically significant impact of the interventions on child weight outcomes. Cohen's d was .32 (95% CI [.09, .55]). The quality of evidence was assigned a "low" GRADE rating. CONCLUSIONS: Lifestyle modification interventions for overweight and obesity in preschool-age children produce small but significant changes in child weight status. However, few new trials have been published in the last 5 years and the quality of evidence in this area is low, limiting confidence in the estimates and the power to examine potential moderator effects. Additional quality, randomized, control trials that report study information consistent with consort guidelines, use intent-to-treatment procedures, assess and report health behaviors and treatment adherence to explore mechanisms of change, and examine sustained effects of interventions are needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Investigation of S-Nitrosoglutathione in stroke: A systematic review and meta-analysis of literature in pre-clinical and clinical research.

BACKGROUND: S-Nitrosoglutathione (GSNO) is a nitric oxide donor that has been investigated for neuroprotective and neuro-recovery effect. We aimed to conduct a systematic review on the published literatures using GSNO in both pre-clinical and clinical stroke studies. METHODS: We searched PubMed up to June 30, 2019, using the following keywords: S-Nitrosoglutathione, GSNO, stroke, cerebrovascular, carotid arteries, middle cerebral artery, and middle cerebral artery occlusion. Only studies published in the English language providing efficacy results of GSNO on ischemic stroke were included. Stroke Therapy Academic Industry Roundtable (STAIR) score was used to assess the quality of pre-clinical studies and PEDro score for clinical trials. A meta-analysis was conducted to compare the effect size. RESULTS: Of 39 articles identified, 10 (6 for pre-clinical and 4 for clinical studies) met the eligibility criteria and were included. The median STAIR score across the pre-clinical studies was 5.5 (range: 4-7), and the median PEDro score for the 4 clinical trials was 10 (ranged: 6 to 10). Among the 6 pre-clinical studies, GSNO reduced infarct size in 6 studies and improved neurological behavior scales in 5 studies compared to placebo. Inverse-variance weighted linear meta-analysis of standardized mean difference (Hedge's g) on 4 human studies revealed a big effect size (Hedge's g = -0.82, 95% CI: [-1.26, -0.38], P = .0003) favoring the GSNO group in term of reducing embolic signals. I2 value was 0 across the included clinical studies in the meta-analysis. CONCLUSIONS: Pre-clinical studies showed positive benefit of GSNO in animal stroke models. The meta-analysis of clinical studies demonstrated that GSNO is effective in reducing embolic signals in patients with symptomatic internal carotid artery stenosis undergoing carotid endarterectomy or stenting. Further investigation of this molecule is warranted.

Pre-surgical stress and social support predict post-surgical percent excess weight loss in a population of bariatric surgery patients.

Although bariatric surgery is an effective treatment of morbid obesity, many patients fail to lose significant weight or regain weight over time. This study examined pre-surgical psychosocial predictors (stress, social support for healthy eating, emotion regulation, and sleep quality/quantity) of three-month post-surgical percent excess weight loss (EWL) in a population of adult bariatric surgery patients. Overall, findings suggest higher levels of stress (B = -.248, p =.017) and less social support for healthy eating (B =.311, p =.013) predict lower three-month post-surgery percent EWL. Emotion regulation, and sleep measures did not predict post-surgery percent EWL. Therefore, level of stress and social support should be assessed prior to bariatric surgery and considered important pre-surgical intervention targets.

Neurocognitive Deficits in a Cohort With Class 2 and Class 3 Obesity: Contributions of Type 2 Diabetes and Other Comorbidities.

OBJECTIVE: This study examined the relationship between specific metabolic and vascular risk factors and cognition in adults with severe obesity. METHODS: A total of 129 adults (with BMI ≥ 35 kg/m2 ) underwent a baseline clinical evaluation and neuropsychological assessment. Regression analyses examined the relationship between cognition and medical factors (BMI, hemoglobin A1c, diabetes, hypertension, continuous positive airway pressure use, obstructive sleep apnea [OSA], and osteoarthritis). RESULTS: Diabetes was associated with deficits in overall cognitive performance and with deficits in the executive processing speed and verbal fluency domains. Hemoglobin A1c was inversely related to overall cognitive performance and deficits in the attention domain. Participants using continuous positive airway pressure to treat OSA had stronger learning and memory performance, whereas OSA was associated with reduced total learning. Elevated BMI together with diabetes diagnosis was associated with reduced verbal fluency and greater variability in sustained attention. CONCLUSIONS: Obesity-associated comorbidities most notably appeared to have a greater relative influence on cognitive performance than BMI itself in adults with severe obesity. This likely reflects the fact that a very elevated BMI was ubiquitous and thereby probably exerted a similar influence among all adults in the cohort. Accordingly, in the context of severe obesity, diabetes and other comorbidities may have greater sensitivity to cognitive deficits than BMI alone.

Urinary Cytokine Profile to Predict Response to Intravesical BCG with or without HS-410 Therapy in Patients with Non-muscle-invasive Bladder Cancer.

BACKGROUND: Despite extensive research to identify biomarkers of response in patients with non-muscle-invasive bladder cancer (NMIBC), there is no biomarker to date that can serve this purpose. Herein, we report how we leveraged serial urine samples to query a panel of cytokines at varying time points in an attempt to identify predictive biomarkers of response in NMIBC. METHODS: Serial urine samples were collected from 50 patients with intermediate- or high-risk NMIBC enrolled in a phase II study, evaluating intravesical BCG ± intradermal HS-410 therapy. Samples were collected at baseline, week 7, week 13, week 28, and at end of treatment. A total of 105 cytokines were analyzed in each sample. To predict outcome of time-to-event (recurrence or progression), univariate and multivariable Cox analyses were performed. RESULTS: Fifteen patients developed recurrence and 4 patients progressed during the follow-up period. Among clinicopathologic variables, ever-smoker versus nonsmoker status was associated with an improved response rate (HR 0.38; 95% confidence interval (CI), 0.14-0.99; P = 0.04). In the most clinically relevant model, the percent change (for 100 units) of IL18-binding protein-a (HR 1.995; 95% CI, 1.16-3.44; P = 0.01), IL23 (HR 1.12; 95% CI, 1.01-1.23; P = 0.03), IL8 (HR 0.27; 95% CI, 0.07-1.08; P = 0.06), and IFNγ-induced protein-10 (HR 0.95; 95% CI, 0.91-0.99; P = 0.04) at week 13 from baseline best predicted time to event. CONCLUSIONS: Urinary cytokines provided additional value to clinicopathologic features to predict response to immune-modulating agents in patients with NMIBC. IMPACT: This study serves as a hypothesis-generating report for future studies to evaluate the role of urine cytokines as a predictive biomarker of response to immune treatments.

Altered immune cell follicular dynamics in HIV infection following influenza vaccination.

HIV infection changes the lymph node (LN) tissue architecture, potentially impairing the immunologic response to antigenic challenge. The tissue-resident immune cell dynamics in virologically suppressed HIV+ patients on combination antiretroviral therapy (cART) are not clear. We obtained LN biopsies before and 10 to 14 days after trivalent seasonal influenza immunization from healthy controls (HCs) and HIV+ volunteers on cART to investigate CD4+ T follicular helper (Tfh) and B cell dynamics by flow cytometry and quantitative imaging analysis. Prior to vaccination, compared with those in HCs, HIV+ LNs exhibited an altered follicular architecture, but harbored higher numbers of Tfh cells and increased IgG+ follicular memory B cells. Moreover, Tfh cell numbers were dependent upon preservation of the follicular dendritic cell (FDC) network and were predictive of the magnitude of the vaccine-induced IgG responses. Interestingly, postvaccination LN samples in HIV+ participants had significantly (P = 0.0179) reduced Tfh cell numbers compared with prevaccination samples, without evidence for peripheral Tfh (pTfh) cell reduction. We conclude that influenza vaccination alters the cellularity of draining LNs of HIV+ persons in conjunction with development of antigen-specific humoral responses. The underlying mechanism of Tfh cell decline warrants further investigation, as it could bear implications for the rational design of HIV vaccines.

Pathological significance of lipoprotein(a) in aortic valve stenosis.

BACKGROUND AND AIMS: Aortic valve stenosis (AVS) affects a significant percentage of our elderly population and younger subjects with familial hypercholesterolemia. Lipoprotein(a) [Lp(a)] has been associated with AVS in recent genetic studies. The purpose of this study was to determine the effects of Lp(a) on human aortic valve interstitial cells (HAVICs), and to identify apolipoproteins and phospholipids in diseased human aortic valves. METHODS: We examined the effects of Lp(a) on HAVICs mineralization and oxidant formation. Proteomic analyses were used to determine the effects of Lp(a) on downstream intracellular markers. We also used mass spectroscopy to identify the different lipoproteins and oxidized phospholipids in calcified aortic valves. RESULTS: HAVICs incubated with either LDL or Lp(a) had significantly higher calcium deposition, compared to control (p<0.001), with Lp(a) having the most significant effect (p<0.01) compared to LDL. Proteomic analysis after 10 days of treatment with Lp(a) resulted in enrichment of proteins involved in calcium deposition and vesicle biogenesis. Treatment of HAVICs with Lp(a) significantly increased ROS formation (p<0.05). Patients with calcific aortic stenosis had higher plasma Lp(a) concentrations compared to non-CAD individuals (p<0.001). LC-MS/MS revealed the presence of apolipoproteins and phospholipids in calcified human aortic valves. CONCLUSIONS: The present study outlines an association between Lp(a) and AVS, and suggests that Lp(a) may serve as a potential target for therapeutic purposes to manage the progression of AVS.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age.

Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old (>60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort.

HIV-infected patients of all ages frequently underperform in response to seasonal influenza vaccination, despite virologic control of HIV. The molecular mechanisms governing this impairment, as well as predictive biomarkers for responsiveness, remain unknown. This study was performed in samples obtained prevaccination (T0) from HIV-infected children who received the 2012-2013 seasonal influenza vaccine. Response status was determined based on established criterion for hemagglutination inhibition titer; participants with a hemagglutination titer ≥1:40 plus a ≥4-fold increase over T0 at 3 wk postvaccination were designated as responders. All children had a history of prior influenza vaccinations. At T0, the frequencies of CD4 T cell subsets, including peripheral T follicular helper (pTfh) cells, which provide help to B cells for developing into Ab-secreting cells, were similar between responders and nonresponders. However, in response to in vitro stimulation with influenza A/California/7/2009 (H1N1) Ag, differential gene expression related to pTfh cell function was observed by Fluidigm high-density RT-PCR between responders and nonresponders. In responders, H1N1 stimulation at T0 also resulted in CXCR5 induction (mRNA and protein) in CD4 T cells and IL21 gene induction in pTfh cells that were strongly associated with H1N1-specific B cell responses postvaccination. In contrast, CD4 T cells of nonresponders exhibited increased expression of IL2 and STAT5 genes, which are known to antagonize peripheral Tfh cell function. These results suggest that the quality of pTfh cells at the time of immunization is important for influenza vaccine responses and provide a rationale for targeted, ex vivo Ag-driven molecular profiling of purified immune cells to detect predictive biomarkers of the vaccine response.

Removal of Arsenic from water using synthetic Fe7S8 nanoparticles.

In the present study, pyrrhotite was used to remove arsenite and arsenate from aqueous solutions. The Fe7S8 was synthesized using a solvothermal synthetic method and it was characterized using XRD and SEM micrographs. Furthermore, the particle size for the nanomaterial Fe7S8 was determined to be 29.86 ± 0.87 nm using Scherer's equation. During the pH profile studies, the optimum pH for the binding of As (III) and As (V) was determined to be pH 4. Batch isotherm studies were performed to determine the binding capacity of As(III) and As(V), which was determined to be 14.3 mg/g and 31.3 mg/g respectively for 25°C. The thermodynamic studies indicated that the ΔG for the sorption of As(III) and As(V) ranged from -115.5 to -0.96 kJ/mol, indicating a spontaneous process was occurring. The enthalpy indicated that an exothermic reaction was occurring during the adsorption in which the ΔH was -53.69 kJ/mol and -32.51 kJ/mol for As(III) and As(V) respectively. In addition, ΔS values for the reaction had negative values of -160.46 J/K and -99.77 J/K for the adsorption of As(III) and As(V) respectively which indicated that the reaction was spontaneous at low temperatures. Furthermore, the sorption for As(III) and As(V) was determined to follow the second order kinetics adsorption model.

Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria.

Perforin-2 (MPEG1) is a pore-forming, antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric infection respectively. In contrast, Perforin-2-sufficient littermates clear the infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100 Å pores in the bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system.

Multiple low-dose challenges in a rhesus macaque AIDS vaccine trial result in an evolving host response that affects protective outcome.

Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.

Humanized mice: novel model for studying mechanisms of human immune-based therapies.

The lack of relevant animal models is the major bottleneck for understanding human immunology and immunopathology. In the last few years, a novel model of humanized mouse has been successfully employed to investigate some of the most critical questions in human immunology. We have set up and tested in our laboratory the latest technology for generating mice with a human immune system by reconstituting newborn immunodeficient NOD/SCID-γ(c)(-/-) mice with human fetal liver-derived hematopoietic stem cells. These humanized mice have been deemed most competent as human models in a thorough comparative study with other humanized mouse technologies. Lymphocytes in these mice are of human origin while other hematopoietic cells are chimeric, partly of mouse and partly of human origin. We demonstrate that human CD8 T lymphocytes in humanized mice are fully responsive to our novel cell-based secreted heat shock protein gp96(HIV)-Ig vaccine. We also show that the gp96(HIV)-Ig vaccine induces powerful mucosal immune responses in the rectum and the vagina, which are thought to be required for protection from HIV infection. We posit the hypothesis that vaccine approaches tested in humanized mouse models can generate data rapidly, economically and with great flexibility (genetic manipulations are possible), to be subsequently tested in larger nonhuman primate models and humans.

Cutting edge: novel vaccination modality provides significant protection against mucosal infection by highly pathogenic simian immunodeficiency virus.

Vaccine-induced protection against infection by HIV or highly pathogenic and virulent SIV strains has been limited. In a proof-of-concept study, we show that a novel vaccine approach significantly protects rhesus macaques from mucosal infection by the highly pathogenic strain SIVmac251. We vaccinated three cohorts of 12 macaques each with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig. Cohort 1 was vaccinated with cells secreting gp96(SIV)Ig carrying SIV peptides. In addition, Cohort 2 received recombinant envelope protein SIV-gp120. Cohort 3 was injected with cells secreting gp96-Ig (no SIV Ags) vaccines. Cohort 2 was protected from infection. After seven rectal challenges with highly pathogenic SIVmac251, the hazard ratio was 0.27, corresponding to a highly significant, 73% reduced risk for viral acquisition. The apparent success of the novel vaccine modality recommends further study.