Clinically available immunosuppression averts rejection but not systemic inflammation after porcine islet xenotransplant in cynomolgus macaques.

A safe, efficacious, and clinically applicable immunosuppressive regimen is necessary for islet xenotransplantation to become a viable treatment option for diabetes. We performed intraportal transplants of wild-type adult porcine islets in 25 streptozotocin-diabetic cynomolgus monkeys. Islet engraftment was good in 21, partial in 3, and poor in 1 recipient. Median xenograft survival was 25 days with rapamycin and CTLA4Ig immunosuppression. Adding basiliximab induction and maintenance tacrolimus to the base regimen significantly extended median graft survival to 147 days (p < .0001), with three animals maintaining insulin-free xenograft survival for 265, 282, and 288 days. We demonstrate that this regimen suppresses non-Gal anti-pig antibody responses, circulating effector memory T cell expansion, effector function, and infiltration of the graft. However, a chronic systemic inflammatory state manifested in the majority of recipients with long-term graft survival indicated by increased neutrophil to lymphocyte ratio, IL-6, MCP-1, CD40, and CRP expression. This suggests that this immunosuppression regimen fails to regulate innate immunity and resulting inflammation is significantly associated with increased incidence and severity of adverse events making this regimen unacceptable for translation. Additional studies are needed to optimize a maintenance regimen for regulating the innate inflammatory response.

Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders.

Cystic fibrosis (CF) is a genetic disorder caused by defective CF Transmembrane Conductance Regulator (CFTR) function. Insulin producing pancreatic islets are located in close proximity to the pancreatic duct and there is a possibility of impaired cell-cell signaling between pancreatic ductal epithelial cells (PDECs) and islet cells as causative in CF. To study this possibility, we present an in vitro co-culturing system, pancreas-on-a-chip. Furthermore, we present an efficient method to micro dissect patient-derived human pancreatic ducts from pancreatic remnant cell pellets, followed by the isolation of PDECs. Here we show that defective CFTR function in PDECs directly reduced insulin secretion in islet cells significantly. This uniquely developed pancreatic function monitoring tool will help to study CF-related disorders in vitro, as a system to monitor cell-cell functional interaction of PDECs and pancreatic islets, characterize appropriate therapeutic measures and further our understanding of pancreatic function.

Interferon-gamma drives programmed death-ligand 1 expression on islet ß cells to limit T cell function during autoimmune diabetes.

Type 1 diabetes is caused by autoreactive T cell-mediated ß cell destruction. Even though co-inhibitory receptor programmed death-1 (PD-1) restrains autoimmunity, the expression and regulation of its cognate ligands on ß cell remains unknown. Here, we interrogated ß cell-intrinsic programmed death ligand-1 (PD-L1) expression in mouse and human islets. We measured a significant increase in the level of PD-L1 surface expression and the frequency of PD-L1+ ß cells as non-obese diabetic (NOD) mice aged and developed diabetes. Increased ß cell PD-L1 expression was dependent on T cell infiltration, as ß cells from Rag1-deficient mice lacked PD-L1. Using Rag1-deficient NOD mouse islets, we determined that IFN-γ promotes ß cell PD-L1 expression. We performed analogous experiments using human samples, and found a significant increase in ß cell PD-L1 expression in type 1 diabetic samples compared to type 2 diabetic, autoantibody positive, and non-diabetic samples. Among type 1 diabetic samples, ß cell PD-L1 expression correlated with insulitis. In vitro experiments with human islets from non-diabetic individuals showed that IFN-γ promoted ß cell PD-L1 expression. These results suggest that insulin-producing ß cells respond to pancreatic inflammation and IFN-γ production by upregulating PD-L1 expression to limit self-reactive T cells.

A case of hemiagenesis of thyroid with double ectopic thyroid tissue.

Developmental abnormalities of the thyroid gland are very rare. The most common abnormalities include ectopic thyroid tissues that are commonly seen in lingual or sublingual location, agenesis, and hemiagenesis of the thyroid gland. These developmental defects may or may not be associated with thyroid dysfunction. Our case is an 18-year-old male who presented with swelling in the neck of 4-year duration. Clinical examination revealed an oval-shape swelling in the left side of the thyroid gland. The ultrasound and the nuclear scan report revealed the presence of thyroid hemiagenesis of the right lobe with isthmus along with double ectopic thyroid tissue at suprahyoid and infrahyoid region. His thyroid function test showed elevated thyroid-stimulating hormone (TSH) and normal free T4. We report a very rare case of thyroid hemiagenesis with double ectopic thyroid tissue; and to the best of our knowledge, this is the first report in the world literature.