Selected Grantee Publications
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- 106 results found
- Immunology
- Genetics
Neuropeptide S Receptor 1 is a Nonhormonal Treatment Target in Endometriosis
Tapmeier et al., Science Translational Medicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34433639
Investigators analyzed genetic sequences of humans (n=32 families) and pedigree rhesus macaques (n=849) with spontaneous endometriosis to uncover potential targets for treatment. Target associations indicated a common insertion/deletion variant in NPSR1, the gene encoding neuropeptide S receptor 1. Immunocytochemistry, RT-PCR, and flow cytometry experiments indicated NPSR1 was expressed in the glandular epithelium of eutopic and ectopic endometrium. In a mouse model for endometriosis, an inhibitor of NPSR1-mediated signaling blocked proinflammatory TNFα release, monocyte chemotaxis, and inflammatory cell infiltrate. Further studies in nonhuman primates are needed; however, these results provide support for a nonhormonal treatment of endometriosis. Supported by ORIP (R24OD011173, P51OD011106).
Interleukin-15 Response Signature Predicts RhCMV/SIV Vaccine Efficacy
Barrenäs et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009278
Standard immunogenicity measures do not predict efficacy of a vaccine based on strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV). This vaccine robustly protects just over half of immunized monkeys. Using functional genomics, researchers found that RhCMV/SIV efficacy is correlated with a vaccine-induced response to interleukin-15 (IL-15) that includes modulation of immune cell, inflammation, toll-like receptor signaling, and cell death programming pathways. RhCMV/SIV imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited CD8+ T cells to mediate protection against SIV. Supported by ORIP (P51OD010425, P51OD011092), NIAID, and NCI.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
Protection of Newborn Macaques by Plant-Derived HIV Broadly Neutralizing Antibodies: A Model for Passive Immunotherapy During Breastfeeding
Rosenberg et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00268-21
Preventing vertical transmission of HIV to newborns is an unmet medical need in resource poor countries. Using a breastfeeding macaque model with multiple simian-human immunodeficiency virus challenge, researchers assessed the protective efficacy of two human broadly neutralizing antibodies (bnAbs) against HIV, PGT121 and VRC07-523, which are produced by a plant expression system. Despite the transient presence of plasma viral RNA, the bnAbs prevented productive infection in all newborns with no sustained plasma viremia, compared to viral loads ranging from 103 to 5x108 in four untreated controls. Thus, plant-expressed antibodies show promise as passive immunoprophylaxis in a breastfeeding model in newborns. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.
Tissue-Specific Transcriptional Profiling of Plasmacytoid Dendritic Cells Reveals a Hyperactivated State in Chronic SIV Infection
Lee et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009674
Persistent immune activation is an obstacle to optimal health for people living with HIV. Using RNA sequencing, researchers investigated the immunostimulatory potential of plasmacytoid dendritic cells (pDCs) in chronic SIV infection in rhesus macaques. They observed that pDCs have highly activated profiles in these animals. In contrast, pDCs from SIV-infected sooty mangabeys (natural hosts for SIV) had expression profiles similar to uninfected animals. In chronically infected rhesus macaques, interferon alpha transcripts were readily detected in lymph node-homing pDCs, but not those from blood. Therefore, pDCs are a major producer of type-I interferon in chronic SIV infection and could be a useful immunotherapy target. Supported by ORIP (R24OD010445, P51OD011132, P51OD011092, S10OD026799) and NIAID.
Gut Germinal Center Regeneration and Enhanced Antiviral Immunity by Mesenchymal Stem/Stromal Cells
Weber et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.149033
Researchers investigated the effects of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression in SIV-infected rhesus macaques. MSC treatment heightened virus-specific responses and reduced viral load. Clearance of SIV-positive cells from gut mucosal effector sites was correlated with regeneration of germinal centers, restoration of follicular B cells and T follicular helper cells, and enhanced antigen presentation by viral trapping within the follicular dendritic cell network. These changes were associated with enhanced gene expression for type I/II interferon signaling, B cell proliferation, and interleukin 7. MSC treatment also activated metabolic pathways associated with enhanced immunity and viral reduction. Supported by ORIP (P51OD011107) and NIAID.
Antibody-Based CCR5 Blockade Protects Macaques From Mucosal SHIV Transmission
Chang et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23697-6
The efficacy of antiretroviral therapy (ART) as pre-exposure prophylaxis against HIV is hindered by incomplete patient adherence and ART-resistant variants. Researchers found that competitive inhibition of HIV Env-CCR5 binding via the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges with a CCR5-tropic simian-human immunodeficiency virus (SHIVSF162P3). Biweekly injection of Leronlimab at 50 mg/kg provided complete protection from SHIV infection. Tissue biopsies from protected macaques post-challenge revealed complete CCR5 receptor occupancy and an absence of viral DNA. After Leronlimab washout, transfer of hematologic cells into naïve monkeys did not transmit infection, supporting the initiation of clinical trials. Supported by ORIP (P51OD011092, K01OD026561, P40OD028116) and NIAID.
Single-Cell Protein Activity Analysis Identifies Recurrence-Associated Renal Tumor Macrophages
Obradovic et al., Cell. 2021.
https://doi.org/10.1016/j.cell.2021.04.038
Post-surgery course of clear cell renal carcinoma (ccRCC) is mixed because of the heterogeneity of the disease. Using high-performance computing cluster and storage systems, investigators established an inclusive ccRCC tumor microenvironment (TME) map by using single-cell RNA sequencing data of subpopulations of tumor and tumor-adjacent tissues. Analysis of the data identified key TME subpopulations as well as their master regulators and candidate cell-cell interactions, revealing clinically relevant cell populations. Specifically, the study uncovered a tumor-specific macrophage subpopulation, validated by spatially resolved, quantitative multispectral immunofluorescence. In a large clinical validation cohort, markers of this subpopulation were significantly enriched in tumors from patients who recurred following surgery. Supported by ORIP (S10OD012351, S10OD021764) and others.
IL-21 and IFNα Therapy Rescues Terminally Differentiated NK Cells and Limits SIV Reservoir in ART-Treated Macaques
Harper et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-23189-7
Nonpathogenic simian immunodeficiency virus (SIV) infections in natural hosts, such as vervet monkeys, are characterized by a lack of gut microbial translocation, robust secondary lymphoid natural killer cell responses, and limited SIV dissemination in lymph node B-cell follicles. Using antiretroviral therapy-treated, SIV-infected rhesus monkeys—a pathogenic model—researchers showed that interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. The correlated reduction of replication-competent SIV in lymph node demonstrates that vervet-like natural killer cell differentiation can be rescued in rhesus monkeys to promote viral clearance. Supported by ORIP (P51OD011132, R24OD010947), NIAID, and NCI.
A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies
McCann et al., Journal of Experimental Medicine. 2021.
https://doi.org/10.1084/jem.20201908
HIV-specific CD8+ T cells partially control viral replication but rarely provide lasting protection due to immune escape. Investigators showed that engrafting NSG mice with memory CD4+ T cells from HIV+ donors enables evaluation of autologous T cell responses while avoiding graft-versus-host disease. Treating HIV-infected mice with clinically relevant T cell products reduced viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an Interleukin-15 superagonist but was ultimately limited by the pervasive selection of escape mutations, recapitulating human patterns. This “participant-derived xenograft” model provides a powerful tool for developing T cell-based therapies for HIV. Supported by ORIP (R01OD011095), NIAID, NIDA, NIMH, NINDS, and NCATS.