Selected Grantee Publications
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- 13 results found
- Immunology
- T32
Extracted Plasma Cell-Free DNA Concentrations Are Elevated in Colic Patients With Systemic Inflammation
Bayless et al., Veterinary Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11435807
Researchers investigated cell-free DNA (cfDNA) as a potential biomarker to detect colic in humans. In horses, colic is a life-threatening gastrointestinal (GI) condition. Measurements of cfDNA released from damaged or dying cells in the blood of male and female horses with colic were compared across groups based on GI disease type, signs of inflammation, and survival status. Elevated cfDNA levels were prominent in horses with systemic inflammation, but did not significantly differ by GI disease type or survival. This study suggests that cfDNA may be linked to inflammatory responses in colic conditions. Supported by ORIP (T32OD011130).
A Comparative Review of Cytokines and Cytokine Targeting in Sepsis: From Humans to Horses
Hobbs et al., Cells. 2024.
https://pubmed.ncbi.nlm.nih.gov/39273060
Bacterial infections resulting in endotoxin or exotoxin exposure can lead to sepsis because of dysregulated host responses. Sepsis causes organ dysfunction that can lead to death if not treated immediately, yet no proven pharmacological treatments exist. Horses can serve as a comparative and translational model for sepsis in humans because both species share mechanisms of immune response, including severe neutropenia, cytokine storms, formation of neutrophil extracellular traps, and decreased perfusion. Research on sepsis has focused on the pathophysiological role of interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin10. Research on novel sepsis therapies has focused on monoclonal antibodies, cytokine antagonists, and cytokine removal through extracorporeal hemoperfusion. Future sepsis research should focus on optimizing therapeutic strategies of cytokine modulation and analyzing the underlying mechanisms of cytokine dysregulation. Supported by ORIP (T32OD011130).
Ultrasoft Platelet-Like Particles Stop Bleeding in Rodent and Porcine Models of Trauma
Nellenbach et al., Science Translational Medicine. 2024.
https://www.science.org/doi/10.1126/scitranslmed.adi4490
Platelet transfusions are the current standard of care to control bleeding in patients following acute trauma, but their use is limited by short shelf life and limited supply. Immunogenicity and contamination risks also are a concern. Using ultrasoft and highly deformable nanogels coupled to fibrin-specific antibody fragments, researchers developed synthetic platelet-like particles (PLPs) as an alternative for immediate treatment of uncontrolled bleeding. They report that PLPs reduced bleeding and facilitated healing of injured tissue in mice, rat, and swine models (sex not specified) for traumatic injury. These findings can inform further translational studies of synthetic PLPs for the treatment of uncontrolled bleeding in a trauma setting. Supported by ORIP (T32OD011130) and NHLBI.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
The Gene Expression Profile and Cell of Origin of Canine Peripheral T-Cell Lymphoma
Owens et al., BMC Cancer. 2024.
https://pubmed.ncbi.nlm.nih.gov/38166662/
Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-NOS (PTCL-not otherwise specified), and is a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. Canine CD4+ PTCL most closely resembles the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin. Supported by ORIP (T32OD010437).
Interferon Regulatory Factor 7 Modulates Virus Clearance and Immune Responses to Alphavirus Encephalomyelitis
Troisi et al., Journal of Virology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37772825/
Interferon regulatory factor 7 (IRF7)–deficient mice develop fatal paralysis after CNS infection with Sindbis virus, while wild-type mice recover. Irf7-/- mice produce low levels of IFN-α but high levels of IFN-β with induction of IFN-stimulated genes, so the reason for this difference is not understood. The current study shows that Irf7-/- mice developed inflammation earlier but failed to clear virus from motor neuron–rich regions of the brainstem and spinal cord. Therefore, IRF7 is either necessary for the neuronal response to currently identified mediators of clearance or enables the production of additional antiviral factor(s) needed for clearance. Supported by ORIP (T32OD011089, R01OD01026529) NINDS, and NIAID.
The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid
Jordan et al., Journal of Immunology. 2023.
Bullous pemphigoid is associated with eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies. Researchers previously established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice. In this study, they characterized the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury. Their work establishes the eotaxin-1/CCR3 axis and matrix metalloproteinase-9 as key players in the disease and as candidate therapeutic targets for drug development and testing. Supported by ORIP (T32OD011130) and NIAMS.
A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis
Peters et al., Science Translational Medicine. 2023.
https://www.science.org/doi/10.1126/scitranslmed.abn7491
Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.
Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis
Moley et al., American Journal of Pathology. 2023.
https://www.sciencedirect.com/science/article/pii/S0002944023001980?via%3Dihub=
Brucellosis is a globally significant zoonotic disease. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. Following pulmonary infection with B. melitensis, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Transcriptional analysis of Brucella-infected brains revealed marked upregulation of genes associated with inflammation and interferon responses. Collectively, these findings indicate that ILCs and interferons play an important role in prevention of focal complications during Brucella infection and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis. Supported by ORIP (T32OD011126) and NIAID.