Publications by authors named "G Silvestri"

897 Publications

Combined PET and whole-tissue imaging of lymphatic-targeting vaccines in non-human primates.

Biomaterials 2021 May 14;275:120868. Epub 2021 May 14.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA, 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA; Departments of Biological Engineering and Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. Electronic address:

Antigen accumulation in lymph nodes (LNs) is critical for vaccine efficacy, but understanding of vaccine biodistribution in humans or large animals remains limited. Using the rhesus macaque model, we employed a combination of positron emission tomography (PET) and fluorescence imaging to characterize the whole-animal to tissue-level biodistribution of a subunit vaccine comprised of an HIV envelope trimer protein nanoparticle (trimer-NP) and lipid-conjugated CpG adjuvant (amph-CpG). Following immunization in the thigh, PET imaging revealed vaccine uptake primarily in inguinal and iliac LNs, reaching distances up to 17 cm away from the injection site. Within LNs, trimer-NPs exhibited striking accumulation on the periphery of follicular dendritic cell (FDC) networks in B cell follicles. Comparative imaging of soluble Env trimers (not presented on nanoparticles) in naïve or previously-immunized animals revealed diffuse deposition of trimer antigens in LNs following primary immunization, but concentration on FDCs in pre-immunized animals with high levels of trimer-specific IgG. These data demonstrate the capacity of nanoparticle or "albumin hitchhiking" technologies to concentrate vaccines in genitourinary tract-draining LNs, which may be valuable for promoting mucosal immunity.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120868DOI Listing
May 2021

Broad auto-reactive IgM responses are common in critically ill patients, including those with COVID-19.

Cell Rep Med 2021 Jun 28;2(6):100321. Epub 2021 May 28.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

The pathogenesis of severe coronavirus disease 2019 (COVID-19) remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM) and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgMs preferentially recognize primary human lung cells , including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.
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http://dx.doi.org/10.1016/j.xcrm.2021.100321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160082PMC
June 2021

Histopathological findings and clinicopathologic correlation in COVID-19: a systematic review.

Mod Pathol 2021 May 24. Epub 2021 May 24.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has had devastating effects on global health and worldwide economy. Despite an initial reluctance to perform autopsies due to concerns for aerosolization of viral particles, a large number of autopsy studies published since May 2020 have shed light on the pathophysiology of Coronavirus disease 2019 (COVID-19). This review summarizes the histopathologic findings and clinicopathologic correlations from autopsies and biopsies performed in patients with COVID-19. PubMed and Medline (EBSCO and Ovid) were queried from June 4, 2020 to September 30, 2020 and histopathologic data from autopsy and biopsy studies were collected based on 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 58 studies reporting 662 patients were included. Demographic data, comorbidities at presentation, histopathologic findings, and virus detection strategies by organ system were collected. Diffuse alveolar damage, thromboembolism, and nonspecific shock injury in multiple organs were the main findings in this review. The pathologic findings emerging from autopsy and biopsy studies reviewed herein suggest that in addition to a direct viral effect in some organs, a unifying pathogenic mechanism for COVID-19 is ARDS with its known and characteristic inflammatory response, cytokine release, fever, inflammation, and generalized endothelial disturbance. This study supports the notion that autopsy studies are of utmost importance to our understanding of disease features and treatment effect to increase our knowledge of COVID-19 pathophysiology and contribute to more effective treatment strategies.
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http://dx.doi.org/10.1038/s41379-021-00814-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141548PMC
May 2021

IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques.

Nat Commun 2021 05 17;12(1):2866. Epub 2021 May 17.

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.

Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/cCD16) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/cCD16 natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.
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http://dx.doi.org/10.1038/s41467-021-23189-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129202PMC
May 2021

Response.

Chest 2021 May;159(5):2122

Thoracic Oncology Research Group, Charleston, SC; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC.

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http://dx.doi.org/10.1016/j.chest.2021.01.027DOI Listing
May 2021