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News From The Journal Of Clinical Investigation: Sept. 17, 2012

Improving pancreatic islet transplantation in humans

One of the major obstacles to widespread use of pancreatic islet transplantation for the treatment of diabetes is the risk of post-transplant inflammation and immune rejection. Additionally, generalized immune suppression has many side effects and there is a need for immunosuppressive therapies that specifically target the transplant site. In this issue of the Journal of Clinical Investigation, researchers at the San Raffaele Scientific Institute in Milan, Italy report that two cell surface receptors, CXCR1 and CXCR2, mediate immune responses to transplanted pancreatic islets in mice. Lorenzo Piemonti and colleagues found that blocking the activity of these receptors improved transplant engraftment and reduced immune system responses. Further, in a pilot study of human transplant patients, the CXCR1/2 inhibitor reparixin improved transplant outcomes and prevented damage to the transplanted islets. These findings suggest that therapies targeting CXCR1/2 signaling will help improve islet transplantation.

TITLE: CXCR1/2 inhibition enhances pancreatic islet survival after transplantation


Loss of thyroid stimulating hormone contributes to osteoporosis

Hyperthyroidism is a common condition in which the thyroid gland secretes excess thyroid hormone. It is frequently associated with decreased bone density and a higher risk of fractures. High thyroid hormone levels are known to suppress the production of thyroid stimulating hormone (TSH). TSH binds to receptors on bone to stimulate bone formation and low TSH levels are correlated with low bone mineral density. In a recent study in the Journal of Clinical Investigation, researchers led by Dr. Mone Zaidi at the Mt. Sinai School of Medicine examined the role of TSH in bone density by comparing the bone density of regular hyperthyroid mice and hyperthyroid mice that lacked the TSH receptor. Compared to normal mice, the mice lacking the TSH receptor had higher levels of bone loss, suggesting that TSH is important to the integrity of the skeleton. This study has implications for the treatment of thyroid disease in patients who are at risk for osteoporosis.

TITLE: Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling


Ferrets serve as a model of human cystic fibrosis-related diabetes

Almost a quarter of cystic fibrosis (CF) patients develop diabetes by the time they are in their teens. Cystic fibrosis-related diabetes (CFRD) is associated with worsening clinical status, reduced lung function, a decline in nutritional status, and increased mortality. Current animal models of CF do not develop CFRD, limiting our understanding of CFRD pathology. In this issue of the Journal of Clinical Investigation, researchers led by John Engelhardt at the University of Iowa report on a model of CFRD in ferrets. Engelhardt and colleagues found that CF kits had significant abnormalities in blood glucose and insulin regulation at a young age. Further, insulin-producing pancreatic β islets from newborn CF kits exhibited abnormal glucose-regulated insulin secretion. These findings indicate that metabolic irregularities occur early in CF and suggest that early intervention may help prevent the development of full-blown CFRD.

TITLE: Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets


Growing hematopoietic stem cells in vitro

Hematopoietic stem cell (HSC) transplantation is a medical procedure that is frequently performed on patients with cancers of the blood or bone marrow, such as leukemia, lymphoma, and multiple myeloma. Obtaining HSCs from patients is difficult, and most HSCs come from matched donors, who are only available in limited numbers. One solution is to grow HSCs outside of the body, but attempts to do this have been unsuccessful thus far. In this issue of the Journal of Clinical Investigation researchers led by Irving Goldschneider at the University of Connecticut report on the development of a recombinant growth factor, rIL-7/HGFβ, that stimulated the growth of HSCs outside of the body and maintained their ability to generate new blood cells once implanted in mice. The development of this recombinant growth factor has the potential to help overcome barriers to the widespread use of HSC transplantation.

TITLE: Recombinant IL-7/HGFβ efficiently induces transplantable murine hematopoietic stem cells


Drug used to treat blood clots may protect against osteoporosis

P2Y12 is a nucleotide-activated cell surface receptor that plays a critical role in blood clotting. P2Y12 antagonists, such as clopidogrel, are used clinically to prevent strokes and to treat heart disease. More recently, researchers have found that P2Y12 also plays a role in the activity of osteoclasts, or cells that break down bone. In a study published in the Journal of Clinical Investigation, Katherine Weilbaecher and colleagues at Washington University in St. Louis report that mice lacking P2Y12 receptors or that are treated with P2Y12 antagonists had decreased osteoclast activity and were partially protected from bone loss associated with age, arthritis, tumor growth, and estrogen loss. This study reveals a new role for P2Y12 receptors and suggests that drugs already being used in the clinic to protect against blood clots may also be useful for the treatment of osteoporosis.

TITLE: The ADP receptor P2Y12 regulates osteoclast function and pathologic bone remodeling


Mutation causes defective Natural Killer cells

Natural Killer (NK) cells defend the body against infectious diseases and cancer by recognizing and killing stressed or infected cells and patients with NK deficiencies are susceptible to severe viral infections. In this issue of the Journal of Clinical Investigation, researchers at Baylor College of Medicine report on a patient with an NK cell deficiency caused by a mutation in CD16, which codes for a protein on the surface of NK cells that recognizes antibodies. To determine the exact role of CD16 in NK cell cytotoxicity, Jordan Orange and colleagues studied the effect of mutant CD16 in a human NK cell line. The mutant CD16 was unable to interact with another NK cell protein, CD2, which is required for cytotoxic activity in NK cells. Patients carrying this mutation were highly susceptible to viral infection. This study identifies a potential cellular mechanism that underlies human congenital immunodeficiency.

TITLE: Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity


Exploring the causes of congenital heart defects

The heart is one of the first organs to form during vertebrate development and mutations in the genes that govern heart development are associated with congenital heart disease in humans. Myocardin, a protein that regulates gene expression, was previously shown to regulate the development of smooth muscle cells. In this issue of the Journal of Clinical Investigation, Michael Parmacek and colleagues at the University of Pennsylvania report that myocardin also contributes to heart growth, development of the chambers of the heart, and embryonic survival. Mice lacking myocardin had defective heart chambers, developed heart failure, and died as embryos. These defects were partially attributed to deficient signaling by a protein known as BMP10. Replacement of BMP10 rescued heart development. This study sheds light on the processes that regulate heart development and may help explain the origins of human congenital heart disease.

TITLE: Myocardin regulates BMP10 expression and is required for heart development



Journal of Clinical Investigation