News From The Journal Of Clinical Investigation

(HCMV) is a major cause of disability and death in individuals whose immune system is compromised and in the developing fetus. Developing a vaccine is a priority for those in vaccine research, but has thus far proven challenging. A team of researchers, led by Stipan Jonjic, at the University of Rijeka, Croatia, has now developed a vaccine that induced in mice robust immune protection from mouse CMV (MCMV). 

One of the obstacles to developing an HCMV vaccine is that the virus has evolved many ways to evade the antiviral immune response. MCMV has evolved similar immune evasion mechanisms; for example, its genome includes a gene (m152) that generates a protein that decreases expression in infected cells of the protein RAE-1-gamma, which promotes the antiviral effects of immune cells known as NK cells. The team engineered the MCMV genome such that it no longer included the m152 gene and instead included the gene responsible for making the protein RAE-1-gamma. The resulting virus functioned as a safe and effective vaccine when administered to mice. Furthermore, maternal vaccination protected neonatal mice from MCMV infection. The authors therefore suggest that a similar approach could yield a safe and effective HCMV vaccine, a hope echoed in an accompanying commentary by Mark Schleiss, at the University of Minnesota Medical School, Minneapolis. 

TITLE: Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties 

ACCOMPANYING COMMENTARY TITLE: Can we build it better? Using BAC genetics to engineer more effective cytomegalovirus vaccines 

TRANSPLANTATION: Targeting the protein LFA-1 brings transplant rejection to a halt 

Organ transplantation has changed the life of many individuals. However, outcomes remain sub-optimal, with poor long-term graft survival and severe side effects associated with the current drugs that need to be taken by transplant recipients to stop their immune cells rejecting the transplanted organs. Researchers have therefore been seeking to develop alternative immunosuppressive strategies that have fewer side effects than the drugs currently in use. Christian Larsen and colleagues, at Emory University, Atlanta, have now developed a new immuosuppressive protocol that substantially prolongs the survival of transplanted pancreatic islets in nonhuman primates. Specifically, they added short-term treatment with a molecule that targets the protein LFA-1 on immune cells known as T cells to long-term treatment with drug combinations that have previously failed to prevent graft rejection in nonhuman primates. These data provide rationale for the further investigation of therapies targeting LFA-1 as a treatment for transplantation. TITLE: LFA-1 - specific therapy prolongs allograft survival in rhesus macaques

ONCOLOGY: New role for the tumor suppressor protein RB 

The protein RB is a tumor suppressor protein that has a key role in preventing tumors from first developing. Indeed, inactivation of RB function is a common early event in human cancers. However, a team of researchers, led by Karen Knudsen, at Thomas Jefferson University, Philadelphia, has now found that in human prostate cancer, RB loss is a late event that it is associated with the transition from treatable disease to incurable castrate-resistant metastatic disease. Detailed analyses by the team provided mechanistic insight into why RB loss leads to the transition from drug-responsive to drug-unresponsive disease, providing potential new therapeutic targets.

In an accompanying commentary, Kay Macleod, at the University of Chicago, Chicago, discusses this novel finding and suggests that it might be prudent to reassess RB loss in other cancers in terms of timing, function in disease, and relevance for therapy. 

TITLE: The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression 

ACCOMPANYING COMMENTARY TITLE: The RB tumor suppressor: a gatekeeper to hormone independence in prostate cancer? 

IMMUNOLOGY: Targeting cells key to autoimmune disease via the protein alpha-v integrin 

Key to the immune response to certain bacteria and fungi is a subset of immune cells known as Th17 cells. However, these cells have a downside - they have been implicated in deleterious inflammatory and autoimmune disorders such as multiple sclerosis. Two independent research groups have now identified a new molecular step that seems critical to the generation of Th17 cells in mice, which they suggest could be targeted therapeutically for the treatment of inflammatory and autoimmune diseases, a conclusion with which Jay Kolls and Derek Pociask, at Louisiana State University, New Orleans, concur in an accompanying commentary. 

The molecule TGF-beta has been shown to be required for the generation of Th17 cells. However, TGF-beta is secreted from cells in an inactive form, and how it is locally processed to support the generation of Th17 cells has not been determined. The two research groups - one led by Dean Sheppard, at the University of California at San Francisco, and one led by Adam Lacy-Hulbert, at Harvard Medical School, Boston, - have now found that inactive TGF-beta is processed by protein complexes containing alpha-v integrin at the interface between T cells and the immune cells that activate them (dendritic cells). Importantly, both groups found that this alpha-v integrin-mediated activation of TGF-beta was required for the generation of Th17 cells in mice and the development of disease in a mouse model of multiple sclerosis. These data led both teams of researchers to suggest that alpha-v integrins could be targets for the treatment of Th17-driven inflammatory and autoimmune disorders. 

TITLE: Expression of alpha-v-beta-8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice 

ACCOMPANYING ARTICLE TITLE: alpha-v Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice 

ACCOMPANYING COMMENTARY TITLE: Integral role of integrins in Th17 development 

IMMUNOLOGY: Disease-causing immune cells boost the cells that suppress them 

Autoimmune diseases arise when an individual's immune system turns on a cell type or tissue of their body. For example, type 1 diabetes arises when the immune system attacks and destroys cells in the pancreas that produce the hormone insulin. One of the main ways in which autoimmune diseases are kept at bay is through the ability of immune cells known as Tregs to suppress the function of cells that could mount deleterious immune responses (Teffs). Understanding how Tregs do this has been an area of intensive research, but little has been uncovered about how Teffs affect Tregs. Benoît Salomon, Eliane Piaggio, and colleagues, at Université Pierre et Marie Curie, France, have now changed this with their study of the effects of diabetes-causing Teffs on Tregs in mice. Surprisingly, they found that diabetes-causing Teffs (the very cells that the Tregs suppress) act to boost the expansion and suppressive activity of Tregs and that this provided sustained protection from type 1 diabetes in two mouse models of the disease. 

In an accompanying commentary, Juan Lafaille and Angelina Bilate, at New York University School of Medicine, discuss the implications of these data and the fact that Salomon, Piaggio, and colleagues found that the effects of Teffs on Tregs were partially dependent on TNF-alpha, a molecule normally considered proinflammatory. 

TITLE: Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs 

ACCOMPANYING COMMENTARY TITLE: Can TNF-alpha boost regulatory T cells? 

HEMATOLOGY: Disease-causing mutation linked to control of gene expression 

Hereditary spherocytosis is an inherited blood disorder characterized by anemia,jaundice, and an enlarged spleen. It is most commonly caused by mutations in the gene responsible for making ankyrin, a protein that is key to maintaining the integrity of the red blood cell membrane. In some patients, the disease-causing mutations are upstream of this gene, and how they cause defective ankyrin expression was not clear. However, a team of researchers - led by Patrick Gallagher, at Yale University School of Medicine, New Haven, and David Bodine, at the National Institutes of Health, Bethesda - has now determined how these mutations cause hereditary spherocytosis. Specifically, they found that the mutations are in a region of DNA that functions to protect ("insulate") the ankyrin gene from the general shutdown in gene expression that occurs as a red blood cell matures. DNA sequences with this function are known as barrier insulators, and these data are the first to show that disruption of a barrier insulator can cause human disease. 

Edward Benz, at Harvard Medical School, Boston, distils the complexities of this study in his accompanying commentary and suggests that perhaps other disease-linked DNA variants could reside in barrier insulators. 

TITLE: Mutation of a barrier insulator in the human ankyrin-1 gene is associated with hereditary spherocytosis 

ACCOMPANYING COMMENTARY TITLE: Learning about genomics and disease from the anucleate human red blood cell 

Source: 
Karen Honey 
Journal of Clinical Investigation