FasL microgels induce immune acceptance of islet allografts in nonhuman primates.

Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3+ cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in ß cell replacement for treating type 1 diabetes.

Cytotoxic Escherichia coli strains encoding colibactin, cytotoxic necrotizing factor, and cytolethal distending toxin colonize laboratory common marmosets (Callithrix jacchus).

Cyclomodulins are virulence factors that modulate cellular differentiation, apoptosis, and proliferation. These include colibactin (pks), cytotoxic necrotizing factor (cnf), and cytolethal distending toxin (cdt). Pathogenic pks+, cnf+, and cdt+ E. coli strains are associated with inflammatory bowel disease (IBD) and colorectal cancer in humans and animals. Captive marmosets are frequently afflicted with IBD-like disease, and its association with cyclomodulins is unknown. Cyclomodulin-encoding E. coli rectal isolates were characterized using PCR-based assays in healthy and clinically affected marmosets originating from three different captive sources. 139 E. coli isolates were cultured from 122 of 143 marmosets. The pks gene was detected in 56 isolates (40%), cnf in 47 isolates (34%), and cdt in 1 isolate (0.7%). The prevalences of pks+ and cnf+ E. coli isolates were significantly different between the three marmoset colonies. 98% of cyclomodulin-positive E. coli belonged to phylogenetic group B2. Representative isolates demonstrated cyclomodulin cytotoxicity, and serotyping and whole genome sequencing were consistent with pathogenic E. coli strains. However, the presence of pks+, cnf+, or cdt+ E. coli did not correlate with clinical gastrointestinal disease in marmosets. Cyclomodulin-encoding E. coli colonize laboratory common marmosets in a manner dependent on the source, potentially impacting reproducibility in marmoset models.

Risk indicators of metabolic syndrome in young adults: a preliminary investigation on the influence of tobacco smoke exposure and gender.

BACKGROUND: Metabolic syndrome is characterized by hypertension, dyslipidemia, insulin resistance, and obesity. Limited investigations have studied early indicators of metabolic syndrome in healthy young adults before diagnosis of disease. PURPOSE: The purpose of this investigation is to identify shifts in cardiovascular (CV), metabolic, and immune variables consistent with metabolic syndrome but occurring before development of the disorder, and to determine whether these variables are influenced by gender or cigarette smoking. METHODS: A pilot study of 41 subjects ages 18 to 39 years, with 20 smokers and 21 nonsmokers, was undertaken. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured to evaluate CV status; cholesterol, body mass index, leptin, percent glycated albumin, and homocysteine were measured to evaluate metabolic status; C-reactive protein, interleukin-1beta, and interleukin-10 were measured to evaluate immunologic status. Risk scores were assigned to each indicator, and total risk score was computed. RESULTS: Men had higher SBP (P<.001), DBP (P=.046), and body mass index (P=.01), whereas women had higher leptin (P=.002). Total risk scores in men were greater (P=.02). There was no effect of smoking on risk score, related to the increase in two risks for smokers (SBP, P=.04, DBP; P=.027) reciprocated by a decrease in another (percentage of glycated albumin; P=.02). CONCLUSION: Risk factors contributing to metabolic syndrome are present and highest in young men compared with women, whereas the effects of cigarette smoking on the syndrome are mixed. Early intervention to reduce modifiable risks may prevent full expression of disease.