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Full-Text Articles in Medicine and Health Sciences
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Department of Pharmacology and Experimental Therapeutics Faculty Papers
Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …
T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook
T-Cell Responses To Immunodominant Listeria Epitopes Limit Vaccine-Directed Responses To The Colorectal Cancer Antigen, Guanylyl Cyclase C, John C. Flickinger, Jagmohan Singh, Yanki Yarman, Robert D Carlson, Joshua Barton, Scott A Waldman, Adam E. Snook
Department of Pharmacology and Experimental Therapeutics Faculty Papers
The Gram-positive bacterium Listeria monocytogenes (Lm) is an emerging platform for cancer immunotherapy. To date, over 30 clinical trials have been initiated testing Lm cancer vaccines across a wide variety of cancers, including lung, cervical, colorectal, and pancreatic. Here, we assessed the immunogenicity of an Lm vaccine against the colorectal tumor antigen GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination did not prime naïve GUCY2C-specific CD8+ T-cell responses towards the dominant H-2Kd-restricted epitope, GUCY2C254-262. However, Lm-GUCY2C produced robust CD8+ T-cell responses towards Lm-derived peptides suggesting that GUCY2C254-262 peptide may be subdominant to Lm-derived peptides. Indeed, incorporating immunogenic Lm peptides into an adenovirus-based GUCY2C …
Human Gucy2c-Targeted Chimeric Antigen Receptor (Car)-Expressing T Cells Eliminate Colorectal Cancer Metastases., Michael S. Magee, Tara S. Abraham, Trevor R. Baybutt, John C. Flickinger, Natalie A. Ridge, Glen P Marszalowicz, Priyanka Prajapati, Adam R. Hersperger, Scott A. Waldman, Adam E. Snook
Human Gucy2c-Targeted Chimeric Antigen Receptor (Car)-Expressing T Cells Eliminate Colorectal Cancer Metastases., Michael S. Magee, Tara S. Abraham, Trevor R. Baybutt, John C. Flickinger, Natalie A. Ridge, Glen P Marszalowicz, Priyanka Prajapati, Adam R. Hersperger, Scott A. Waldman, Adam E. Snook
Department of Pharmacology and Experimental Therapeutics Faculty Papers
One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting …
Evidence That The Density Of Self Peptide-Mhc Ligands Regulates T-Cell Receptor Signaling., Nadia Anikeeva, Dimitry Gakamsky, Jørgen Schøller, Yuri Sykulev
Evidence That The Density Of Self Peptide-Mhc Ligands Regulates T-Cell Receptor Signaling., Nadia Anikeeva, Dimitry Gakamsky, Jørgen Schøller, Yuri Sykulev
Department of Microbiology and Immunology Faculty Papers
Noncognate or self peptide-MHC (pMHC) ligands productively interact with T-cell receptor (TCR) and are always in a large access over the cognate pMHC on the surface of antigen presenting cells. We assembled soluble cognate and noncognate pMHC class I (pMHC-I) ligands at designated ratios on various scaffolds into oligomers that mimic pMHC clustering and examined how multivalency and density of the pMHCs in model clusters influences the binding to live CD8 T cells and the kinetics of TCR signaling. Our data demonstrate that the density of self pMHC-I proteins promotes their interaction with CD8 co-receptor, which plays a critical role …
B1b Lymphocyte-Derived Antibodies Control Borrelia Hermsii Independent Of Fcα/Μ Receptor And In The Absence Of Host Cell Contact., Matthew J. Colombo, David Abraham, Akira Shibuya, Kishore R. Alugupalli
B1b Lymphocyte-Derived Antibodies Control Borrelia Hermsii Independent Of Fcα/Μ Receptor And In The Absence Of Host Cell Contact., Matthew J. Colombo, David Abraham, Akira Shibuya, Kishore R. Alugupalli
Department of Microbiology and Immunology Faculty Papers
The critical role of IgM in controlling pathogen burden has been demonstrated in a variety of infection models. In the murine model of Borrelia hermsii infection, IgM is necessary and sufficient for the rapid clearance of bacteremia. Convalescent, but not naïve, B1b cells generate a specific IgM response against B. hermsii, but the mechanism of IgM-mediated protection is unknown. Here, we show that neither Fcα/μR, a high-affinity receptor for IgM, nor IgM-dependent complement activation is required for controlling B. hermsii. Bacteria in diffusion chambers with a pore size impermeable to cells were killed when diffusion chambers were implanted into either …