Mucosal Addressin Cell Adhesion Molecule-1 Mediates T Cell Migration into Pancreas-Draining Lymph Nodes for Initiation of the Autoimmune Response in Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease that is caused by autoreactive T cell-mediated destruction of insulin-producing β cells in the pancreatic islets. Although naive autoreactive T cells are initially primed by islet antigens in pancreas-draining lymph nodes (pan-LNs), the adhesion molecules that recruit T cells into pan-LNs are unknown. We show that high endothelial venules in pan-LNs of young nonobese diabetic mice have a unique adhesion molecule profile that includes strong expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1).

LFA-1/ICAM-1 Adhesion Pathway Mediates the Homeostatic Migration of Lymphocytes from Peripheral Tissues into Lymph Nodes through Lymphatic Vessels.

Lymphocyte function-associated antigen-1 (LFA-1) and its endothelial ligand intercellular adhesion molecule-1 (ICAM-1) are important for the migration of lymphocytes from blood vessels into lymph nodes. However, it is largely unknown whether these molecules mediate the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes through lymphatic vessels. In this study, we find that, in naive mice, ICAM-1 is expressed on the sinus endothelia of lymph nodes, but not on the lymphatic vessels of peripheral tissues.

Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model.

Objective: We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively.

Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease.

Objective: Mural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease.

Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms.

Objective: Angiotensin (Ang) II type 1 receptor (AT1) activation is essential for the development of exogenous Ang II-induced abdominal aortic aneurysms (AAAs) in hyperlipidemic animals. Experimental data derived from this modeling system, however, provide limited insight into the role of endogenous Ang II in aneurysm pathogenesis. Consequently, the potential translational value of AT1 inhibition in clinical AAA disease management remains incompletely understood on the basis of the existing literature.

Diagnostic Dilemma in the Treatment of a Fatal Case of Bloody Diarrhea.

Although diarrhea is the most commonly reported pediatric illness in the United States, mortality is usually a rare and unexpected event. We report the case of a healthy 13-month-old male that succumbed to a diarrheal illness of unclear etiology. Presenting signs included frequent nonbloody stools that progressed to frankly bloody stools over 72 hours.

Humanized thymidine kinase-NOG mice can be used to identify drugs that cause animal-specific hepatotoxicity: a case study with furosemide.

Interspecies differences have limited the predictive utility of toxicology studies performed using animal species. A drug that could be a safe and effective treatment in humans could cause toxicity in animals, preventing it from being used in humans. We investigated whether the use of thymidine kinase (TK)-NOG mice with humanized livers could prevent this unfortunate outcome (i.

A silk-based encapsulation platform for pancreatic islet transplantation improves islet function in vivo.

The success of pancreatic islet (PI) transplantation is challenged by PI functional damage during the peritransplantation period. A silk-based encapsulation platform including mesenchymal stromal cells (MSCs) was evaluated for islet cell delivery in vivo. Islet equivalents (IEQs) were transplanted into the epididymal fat pads of mice with streptozotocin-induced diabetes.

Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.

Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug.

VCAM-1/α4β1 integrin interaction is crucial for prompt recruitment of immune T cells into the brain during the early stage of reactivation of chronic infection with Toxoplasma gondii to prevent toxoplasmic encephalitis.

Reactivation of chronic infection with Toxoplasma gondii can cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection.

Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

Background: Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans.

CCR7 directs the recruitment of T cells into inflamed pancreatic islets of nonobese diabetic (NOD) mice.

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of insulin-producing β cells in the pancreatic islets. The migration of T cells from blood vessels into pancreas is critical for the development of islet inflammation and β cell destruction in T1D. To define the roles of C-C chemokine receptor type 7 (CCR7) in recruitment of T cells into islets, we used laser capture microdissection to isolate tissue from inflamed islets of nonobese diabetic (NOD) mice and uninflamed islets of BALB/c and young NOD mice.

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model.

Introduction: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Despite extensive studies to understand the disease process utilizing human and mouse models, the intersection between these species remains elusive. To address this gap, we utilized a novel systems biology approach to identify disease-related gene modules and signaling pathways that overlap between humans and mice.

Protein polymer hydrogels: effects of endotoxin on biocompatibility.

Protein polymer-based hydrogels have shown potential for tissue engineering applications, but require biocompatibility testing for in vivo use. Enzymatically crosslinked protein polymer-based hydrogels were tested in vitro and in vivo to evaluate their biocompatibility. Endotoxins present in the hydrogel were removed by Trition X-114 phase separation.

Text-mining applied to autoimmune disease research: the Sjögren's syndrome knowledge base.

Background: Sjögren's syndrome is a tissue-specific autoimmune disease that affects exocrine tissues, especially salivary glands and lacrimal glands. Despite a large body of evidence gathered over the past 60 years, significant gaps still exist in our understanding of Sjögren's syndrome. The goal of this study was to develop a database that collects and organizes gene and protein expression data from the existing literature for comparative analysis with future gene expression and proteomic studies of Sjögren's syndrome.

Alpha4beta7 integrin/MAdCAM-1 adhesion pathway is crucial for B cell migration into pancreatic lymph nodes in nonobese diabetic mice.

Although B cells are crucial antigen-presenting cells in the initiation of T cell autoimmunity to islet beta cell autoantigens in type 1 diabetes (T1D), adhesion molecules that control migration of B cells into pancreatic lymph nodes (PanLN) in the nonobese diabetic (NOD) mouse model of human T1D have not been defined. In this study, we found that B cells from PanLN of 3-4-week-old female NOD mice expressed high levels of alpha(4) integrin and LFA-1 and intermediate levels of beta(7) integrin; half of B cells were L-selectin(high). In short-term in vivo lymphocyte migration assays, B cells migrated from the bloodstream into PanLN more efficiently than into peripheral LNs.

Removal of Toxoplasma gondii cysts from the brain by perforin-mediated activity of CD8+ T cells.

Chronic infection with Toxoplasma gondii is one of the most common parasitic infections in humans. Formation of tissue cysts is the basis of persistence of the parasite in infected hosts, and this cyst stage has generally been regarded as untouchable. Here we provide the first evidence that the immune system can eliminate T.

Expression of endothelia and lymphocyte adhesion molecules in bronchus-associated lymphoid tissue (BALT) in adult human lung.

Background: Bronchus-associated lymphoid tissue (BALT) is the secondary lymphoid tissue in bronchial mucosa and is involved in the development of bronchopulmonary immune responses. Although migration of lymphocytes from blood vessels into secondary lymphoid tissues is critical for the development of appropriate adaptive immunity, the endothelia and lymphocyte adhesion molecules that recruit specific subsets of lymphocytes into human BALT are not known. The aim of this study was to determine which adhesion molecules are expressed on lymphocytes and high endothelial venules (HEVs) in human BALT.

PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance.

Macrophages rapidly engulf apoptotic cells to limit the release of noxious cellular contents and to restrict autoimmune responses against self antigens. Although factors participating in recognition and engulfment of apoptotic cells have been identified, the transcriptional basis for the sensing and the silent disposal of apoptotic cells is unknown. Here we show that peroxisome proliferator-activated receptor-delta (PPAR-delta) is induced when macrophages engulf apoptotic cells and functions as a transcriptional sensor of dying cells.

Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta.

Tumor-associated macrophages (TAMs) are frequently found in glioblastomas and a high degree of macrophage infiltration is associated with a poor prognosis for glioblastoma patients. However, it is unclear whether TAMs in glioblastomas promote tumor growth. In this study, we found that folate receptor beta (FR beta) was expressed on macrophages in human glioblastomas and a rat C6 glioma implanted subcutaneously in nude mice.

Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymphoma in parotid glands.

Objective: To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa-associated lymphoid tissue (MALT) lymphoma phenotypes.

Methods: A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non-primary SS controls). The tissue samples were assessed concurrently by gene-expression microarray profiling and proteomics analysis, followed by weighted gene-coexpression network analysis.

Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice.

With the goal of identifying changes in gene expression in CD4(+) T cells during the development of diabetes in the nonobese diabetic (NOD) mouse, we used DNA microarrays to analyze gene expression in CD4(+) T cells from the pancreatic draining lymph nodes of NOD/BDC 2.5 T cell receptor transgenic and WT NOD mice at different ages. At 4 and 6 weeks of age, we found up-regulation of a number of genes that are known to be induced by IFN-alpha.

Keratin overexpression levels correlate with the extent of spontaneous pancreatic injury.

Mutation of the adult hepatocyte keratins K8 and K18 predisposes to liver disease. In contrast, exocrine pancreas K8 and K18 are dispensable and are co-expressed with limited levels of membrane-proximal K19 and K20. Overexpression of mutant K18 or genetic ablation of K8 in mouse pancreas is well tolerated whereas overexpression of K8 causes spontaneous chronic pancreatitis.

Lack of lymphoid chemokines CCL19 and CCL21 enhances allergic airway inflammation in mice.

Lymphoid chemokines CCL19 and CCL21 are crucial for the recruitment of circulating naive T cells into lymph nodes. However, it is not completely known how they contribute to the development of allergic diseases. To determine whether the lack of CCL19 and CCL21 affects allergic airway inflammation, CCL19- and CCL21-deficient [paucity of lymph node T cells (plt/plt)] and wild-type (WT) mice were immunized intra-peritoneally and then challenged intra-nasally with chicken ovalbumin (OVA).

Importance of IFN-gamma-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii.

Interferon-gamma (IFNgamma) is essential for preventing reactivation of chronic infection with Toxoplasma gondii in the brain. We examined the role of IFNgamma on lymphocyte and endothelial adhesion molecule expression and T cell recruitment into the brain during chronic infection with T. gondii in IFNgamma knockout (IFNgamma(-/-)) and wild-type (WT) mice.