A5003608094- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- RNA Interference and Gene Delivery
- Immune Cell Function and Interaction
- SARS-CoV-2 and COVID-19 Research
- CAR-T cell therapy research
- Antimicrobial Peptides and Activities
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- Immune Response and Inflammation
- Extracellular vesicles in disease
- Animal Virus Infections Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- HIV Research and Treatment
- vaccines and immunoinformatics approaches
- Animal Genetics and Reproduction
Thomas Jefferson University
2019-2025
Baylor University
2018-2022
Baylor Medical Center at Garland
2019-2020
Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against COVID-19. Clinical trials and ongoing vaccinations present with varying degrees of protection levels side effects. However, the drivers reported effects remain poorly defined. Here we evidence that Acuitas' LNPs in preclinical nucleoside-modified mRNA vaccine studies highly inflammatory mice. Intradermal intramuscular injection these led to rapid robust responses,...
Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against coronavirus disease in 2019 (COVID-19). Clinical trials and ongoing vaccinations present with very high protection levels varying degrees of side effects. However, the nature reported effects remains poorly defined. Here we evidence that LNPs many preclinical studies highly inflammatory mice. Intradermal injection these led to rapid robust responses, characterized...
To determine the contribution of skin DC subsets in regulation humoral immunity, we used a well-characterized antigen targeting system to limit availability and presentation certain skin-derived subsets. Here show that delivery foreign steady state Langerhans cells (LCs) cDC1s through same receptor (Langerin) led to, respectively, robust versus minimal-to-null immune response. LCs, unlike cDC1s, supported formation germinal center T follicular helper (GC-Tfh) dose-dependently then, likely...
Hundreds of millions SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding the immune effects this platform. The mRNA-LNP-based is highly inflammatory, and its synthetic ionizable lipid component responsible for induction inflammation has long in vivo half-life. Since chronic can lead exhaustion non-responsiveness, sought determine pre-exposure on adaptive responses innate fitness. We found that mRNA-LNPs or LNP alone led...
Nucleoside modified mRNA combined with Acuitas Therapeutics’ lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later humans the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due LNPs’ ionizable component. The property key development of potent responses. However, mechanism by which drives T follicular helper (Tfh) cells remains unknown. Here we show lack Langerhans or...
Dendritic cells (DCs) are key regulators of adaptive immunity, guiding T helper (Th) cell differentiation through antigen presentation, co-stimulation, and cytokine production. However, in steady-state conditions, certain DC subsets, such as Langerhans (LCs), induce follicular (Tfh) B responses without inflammatory stimuli. Using multiple mouse models vitro systems, we investigated the mechanisms underlying LC-induced immune responses. We found that LCs drive germinal center Tfh antibody...
CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. regulates many aspects B and T cell immunity
Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the local that often come in form of secreted factors, such as cytokines. These factors known impact cells' biology. However, very little is about whether tissue resident return also affect environment. In this study, with help RNA-sequencing, we show for first time long-term absence epidermal Langerhans led significant gene expression changes keratinocytes dendritic T cells. Thus, might play an...
CD40 is a potent activating receptor within the TNFR family expressed on APCs of immune system, and it regulates many aspects B T cell immunity via interaction with ligand (CD40L; CD154) surface activated cells. Soluble CD40L agonistic mAbs directed to are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize soluble monomeric CD40L. We show that direct fusion certain confers superagonist properties, reducing dose required for efficacy, notably...
Hundreds of millions SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding the immune effects this platform. The mRNA-LNP-based is highly inflammatory, and its synthetic ionizable lipid component responsible for induction inflammation has long in vivo half-life. Since chronic can lead exhaustion non-responsiveness, sought determine pre-exposure on adaptive responses innate fitness. We found that mRNA-LNPs or LNP alone led...
The main avenue for the development of an HIV-1 vaccine remains induction protective antibodies. A rationale approach is to target antigen specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting skin Langerhans (LC) with anti-Langerin mAbs Gag drives antigen-specific humoral responses. these immunization strategies in humans requires a better understanding early immune events driven by human LC. We therefore produced...
In a previous report, keratinocytes were shown to share their gene expression profile with surrounding Langerhans cells (LCs), influencing LC biology.Here, we investigated whether transferred material could substitute for lost products in subjected Cre/Lox conditional deletion.We found that human Langerin-Cre mice, epidermal LCs and CD11b+CD103+ mesenteric DCs overcome deletion if the deleted was expressed by neighboring cells.The mechanism of transfer differed from traditional antigen...
Macrophages and dendritic cells (DCs) in peripheral tissue interact closely with their local microenvironment by scavenging protein nucleic acids released neighboring cells. Material transfer between cell types is necessary for pathogen detection antigen presentation, but thought to be relatively limited scale. Recent reports, however, demonstrate that the quantity of transferred material can quite large when DCs are direct contact live This observation may problematic conditional gene...
Abstract Langerhans cells (LCs) can support the induction of antibody responses against foreign antigens without a danger signal. These findings contradict model proposed to define how adaptive immune are mounted. Deciphering LCs, and some other dendritic cell subsets, in steady-state could lead better understanding induced regulated and, ultimately, developing more efficient immunotherapeutics for autoimmune- infectious diseases. Here we used well-established antigen targeting dissect...
Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNP) have been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later humans the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due LNPs' ionizable component. The property key development of potent responses. However, mechanism by which drives T follicular helper cells (Tfh) remains unknown. Here we show lack Langerhans or...
Abstract Soluble CD40L and agonistic anti-CD40 monoclonal antibody are adjuvants used in vaccination settings. Vaccines based on antibodies fused to HIV-1 antigens clinical development. Studies with current anti-CD40-based dendritic cell (DC) targeting vaccines show that co-administration of an adjuvant is needed for maximal immune responses. We by fusing CD40-targeting antibodies, activation DCs concomitant antigen uptake processing maximized, this provides a context intrinsic activity....
Abstract The ability of dendritic cells (DCs) to acquire antigen from their environment is critical for the induction an adaptive immune response and maintenance tolerance. Despite its importance, it tacitly assumed that DCs by scavenging extracellular material via endocytosis or macropinocytosis. Here, using labeled RNA time lapse imaging, we observe siphoning directly live neighboring keratinocytes. This contact dependent mechanism uptake – which term intracellular monitoring– accounts a...
Abstract During the ongoing SARS-CoV-2 pandemic, hundreds of millions people have been exposed to experimental mRNA-LNP-based COVID vaccines, which long-term immune effects are unknown. We previously showed that this vaccine platform is highly inflammatory. Its synthetic ionizable lipid component, has a long in vivohalf-life, responsible for induction inflammation and adaptive responses. The inflammatory component’s vivohalf-life could be reminiscence chronic infection, known lead exhaustion...
Abstract Our knowledge of humoral immunity mainly comes from experimental vaccine models that use high antigen doses injected into the periphery in combination with adjuvants. This allows extended exposure to antigen/adjuvant by all immune cells. Thus, contribution a specific cell responses cannot be easily determined. To better understand roles different dendritic (DC) subsets regulating immunity, we developed system limit availability and presentation certain skin DC subsets. We found...
Abstract HuLangerin-Cre-YFP f/f mice were generated to specifically mark a subset of antigen presenting immune cells, called Langerhans cells (LCs). During histological characterization these mice, we found that, in addition LCs an uncharacterized cell population the central nervous system (CNS) also expressed YFP. In this study, that CNS YFP + negative for microglia and astrocyte markers, but they mature neuronal marker NeuN showed localization/morphology. Thus, might be used study...
ABSTRACT Tissue-resident and infiltrating immune cells are continuously exposed to molecules derived from the niche that often come in form of secreted factors, such as cytokines. These factors known impact cells’ biology. However, very little is about whether tissue resident return also affect local environment. In this study, with help RNA-sequencing, we show for first time long-term absence epidermal Langerhans (LCs) led significant gene expression changes keratinocytes dendritic T cells....
Abstract We recently identified that epidermal resident Langerhans Cells (LCs) acquire gene expression fingerprints from surrounding Keratinocytes (KCs) in the form of mRNA and protein. In present study, we aimed to determine whether this transfer can also overcome deficiencies. For purpose, using Cre/Lox system, specifically deleted genes for Connexin 43 (Cx43), MyD88, MHC-II LCs. While all three underwent recombination, reduced protein levels were only observed MHC-II, whereas Cx43 MyD88...
Abstract We previously compared the contributions of different skin dendritic cell subsets in induction humoral immune responses. found that antigen delivery without adjuvants to Langerhans cells (LCs) through c-type lectin receptor Langerin, unlike cDC1, induces germinal center T follicular helper (GC-Tfhs), GC B cells, and high antibody titers. also showed targeting LCs with higher dose induced significantly lower responses To better understand role this response, we assessed following...