'Multi-target' Therapy Improves Lupus Nephritis Outcomes
Abnormal 'Editing' of Gene Messages May Be Cause of Lupus
Cell Signaling Glitch Leads to Lupus Progression
Scientists Find Genetic Variants That Increase Lupus Risk
Researchers Discover a Way to Turn Off Immune System Cells
New Approach for Attacking Lupus Identified
Compounds May Help Doctors Detect Lupus Kidney Disease
CellCept Linked to Pregnancy Loss and Birth Defects
Vaccine-like Treatment Shows Promise Against Lupus
Researchers May Have Found a New Form of Lupus
Transplant Drug May Be Useful for Treating Lupus
'Multi-target' immune therapy improves outcomes of severe lupus nephritis
From China comes some promising lupus news. A new treatment using a combination of drugs targeting different parts of the immune system improves the recovery rate for patients with severe lupus involving the kidneys, according to a new Chinese study reported in the Journal of the American Society of Nephrology.
The study included 40 patients with severe lupus nephritis, characterized by widespread inflammation and decreasing kidney function. Typically such disease is treated with a single immunosuppressive drug, but efficacy is usually poor. Because the impact of severe lupus on the kidney involves various parts of the immune system, researchers at the Research Institute of Nephrology of Jinling Hospital in Nanjing, China, decided to treat the different immune targets with a combination of immunosuppressant drugs.
Participants were divided into two groups – one group of patients received this "multi-target" therapy, consisting of the immunosuppressant drugs tacrolimus (Prograf) and mycophenolate mofetil (CellCept) – commonly used as anti-rejection drugs in transplant patients – plus a steroid. The other group received standard treatment with a single immunosuppressant drug, cyclophosphamide (Cytoxan).
The complete remission rate, with recovery of normal kidney function, was about four times higher among lupus patients receiving the three-drug combination. Overall, 95 percent of patients in the multi-target therapy group had partial or complete remission, compared to 55 percent with single-drug therapy. The rate of most adverse effects was also lower with multi-target therapy.
Although the study was small, its results suggest using a combination of drugs that affect different immune targets improves the chances of remission for patients with severe lupus nephritis. Larger, longer-term studies are needed to confirm the findings.
Abnormal 'editing' of gene messages may be cause of lupus
Researchers at Wake Forest University in Winston-Salem, N.C., have uncovered evidence that the abnormal “editing” of gene messages in a type of white blood cell may be behind the development of lupus.
The findings, reported online in the journal Immunology, involve an enzyme that “edits” and modifies the messages of genes before the protein-making process. Protein molecules are what carry out the instructions of our genes and determine how an organism looks, how well its body metabolizes food or fights infection, and even how it behaves.
In lupus, the normal editing process goes awry, causing a shift in the balance of proteins that results in impaired functions in T cells, a type of white blood cell involved in the regulation of immune functions. The current research was based on earlier findings that one of the three enzymes involved in editing gene messages,150-kDa ADAR1, is higher in the T cells of lupus patients compared to those without lupus.
Senior author Dama Laxminarayana, PhD, made the initial finding about 150-kDa ADAR1 levels in 2002 and has been working to solve the mystery of how it is related to the development of lupus. In the current study, he found that the higher levels of 150-kDa ADAR1 alter the editing induced by two other enzymes and may cause an imbalance of proteins, causing normal editing to go awry. The researchers are now working to find a safe way to block the enzyme to treat the disease, so stay tuned for more lupus news.
In addition, Laxminarayana says 150-kDa ADAR1 could be used as a biomarker to detect the disease earlier, to monitor how patients respond to therapy, and to measure disease intensity.
Cell signaling glitch leads to lupus progression
Immune cells that would normally die in healthy people accumulate in bodies of patients who have lupus and contribute to the disease, according to new research published in the Feb. 15 issue of Immunity.
Examining the blood from 14 lupus patients and 14 healthy people, Harris Perlman, PhD, associate professor of molecular microbiology and immunology at Saint Louis University, and his colleagues found those with lupus harbor a higher than normal number of immune cells that carry too much of the pro-survival or anti-apoptotic proteins that tells them to keep living past their prime. The more of these immune cells a patient had, the more severe was his or her disease.
Normally these cells should undergo "apoptosis," a natural process by which cells die so they don't spread infection or take away nutrients from healthy cells. The signal to die can come from inside the cell itself or from outside the cell.
Perlman and his colleagues found that the communications system that tells immune cells that it's time to die gets turned off in lupus patients and causes immune cells to accumulate in the body. This failure to delete these cells allows the disease to progress, Perlman says.
The team used that knowledge to create mice that had a defect in the two known “death pathways” that signal when they’re supposed to die. They showed that these mice displayed high numbers of immune cells that would normally die and that all of the mice developed very severe lupus.
“We showed it in patients and reproduced the result in mice,” Perlman says. “Now we can use this mouse model to do pre-clinical trials for therapies to fight lupus.”
The next step, Perlman says, is to test a therapy that blocks proteins that prevent cells from dying by mimicking the action of proteins that tell immune cells it’s time to die.
“We want to deliver a treatment that will target those proteins that keep these immune cells alive. This could induce a type of remission in patients,” he says.
Researchers discover a way to turn off immune system cells
Researchers at the University of Minnesota have discovered a new way to turn off genes in human T cells, a type of white blood cell that helps the immune system fight infection. They say their research, published in the February 1 issue of Molecular Cell, could potentially lead to the development of new drugs that turn off the immune system in people with autoimmune diseases such as rheumatoid arthritis and lupus. It could also prevent cancer cells from dividing.
Turning off genes, through a process known as messenger RNA (mRNA) decay, is important for regulating the body’s immune response after fighting infection. During an infection, T cells turn on and divide to help clear the infection from the body. After the infection is cleared, the cells need to turn off so the body can return to a stable condition. If the cells do not turn off, however, they can cause damage to the body and can potentially develop into cancer cells.
Researchers used a novel approach that combines molecular biology and computational analysis to identify the sequence of mRNA – a form of RNA that translates the DNA’s genetic code into the amino acids that make up proteins – responsible for turning off T cells.
Although this study analyzed T cells, the same pathway is present in all human cells, says Paul Bohjanen, MD, PhD, co-director of the university’s Center for Infectious Diseases and Microbiology Translational Research (CIDMTR) and principal investigator of the study. He says knowledge from this study can also be applied to help researchers better understand other types of cells and how they function.
Scientists find genetic variants that increase lupus risk
Scientists have pinpointed a set of common variations in human DNA that signal a higher risk for lupus in women who carry them. Some of these variations are more common in relatives of lupus patients, which may help future studies examining whether lupus is more prevalent among certain racial and ethnic groups, according to recent lupus news.
In a new study – the largest of its kind to date – the International Consortium for Systemic Lupus Erythematosus (SLEGEN) looked at the genomes of 6,728 people. They found several variations, which they believe may be linked to as many as 67 percent of all lupus cases in women, located on various chromosomes in women of European ancestry. The variants helped to identify those who had up to twice the risk of getting lupus compared to those who did not have the variants.
The findings point to various drug targets important to the search for cutting-edge lupus treatments, according to the study’s authors. In addition, the study will help in the understanding of the causes of lupus and in the development of new genetic tests to find those most at risk for the disease,” says Jeffrey Edberg, PhD, an associate professor of medicine in the UAB Division of Clinical Immunology and Rheumatology and co-author on the study.
Using the data from the study, the researchers are developing further studies to determine if the same gene variants signal higher lupus risks in certain ethnic or racial groups. Also, the scientists are examining how these genetic pathways contribute to developing lupus.
This new finding, published in the January 20 online issue of Nature Genetics, is one of three published by SLEGEN in the current issue of the journal underscoring the importance of genetic variants in diseases that affect immune function. Two other studies of lupus genetics were published in the New England Journal of Medicine and the journal Immunity. All of these new studies come just weeks after the identification of a gene called TNFSF4, one of the first genetic risk factors for lupus.
New approach for attacking lupus identified
Investigators at Hospital for Special Surgery have identified two new targets for drugs aimed at controlling lupus. If companies are able to develop drugs that home in on these targets, say the investigators, patients may be able to control their disease with few side effects.
The targets are two kinase enzymes in the calcium signaling pathway, CAMK and Pyk2, which the researchers have found could be manipulated to control a protein called STAT1. STAT1 mediates the autoimmune and inflammatory functions of a chemical called interferon that has been found in abnormally high levels in people with lupus.
While drugs exist to block interferon, blocking the chemical inhibits its wanted effects – protecting the body from viruses – along with its unwanted effects. Thus, giving a patient these drugs could leave them vulnerable to illnesses and infections, some of which could be deadly.
Blocking STAT1, however, could inhibit inflammation and autoimmunity without interfering with interferon’s ability to protect against infection, say the researchers. “Our idea is that if you block these calcium pathways, you could block the deleterious effects of the interferon, but maintain the antiviral effects,” says Lionel Ivashkiv, MD, director of Basic Research at Hospital for Special Surgery in New York City, who led the study.
This lupus news was published online this week in Nature Immunology and will appear in print in February.
Compounds may help doctors detect lupus kidney disease
New research funded by the Arthritis Foundation suggests that high urinary levels of four compounds may one day help doctors detect and possibly treat lupus nephritis, a potentially deadly kidney disease associated with lupus.
In studies of laboratory mice with lupus nephritis, researchers at the University of Texas Southwestern Medical Center found that the urine of the mice had elevated levels of the four compounds – VCAM-1, P-selection, TNFR-1 and CXCL 16 – particularly at the peak of their lupus-associated kidney disease. Further study showed that people with lupus nephritis had elevated levels of the same four compounds.
The researchers believe that testing the urine for the compounds could be a way to detect the nephritis early, so that kidney-sparing treatment may be initiated. Furthermore, they suspect that one or more of the compounds might be targets for potential drug therapies for the disease. The research is published online at the Journal of Immunology.
CellCept linked to pregnancy loss and birth defects
Mycophenolate mofetil (CellCept), a drug that suppresses the immune system, has been linked to an increased risk of first-trimester pregnancy loss, the FDA warned health-care professionals this week.
The warning, which was based on post-marketing data from the U.S. National Transplantation Pregnancy Registry and Roche worldwide adverse reporting system, also revealed an increased risk for congenital malformations.
CellCept is approved for use in organ transplant patients for preventing rejection of transplanted kidneys, hearts and livers. It is also used in the treatment of lupus to suppress the abnormal immune response in the disease.
Women of childbearing potential who must take CellCept should use two methods of contraception beginning four weeks before starting treatment and should have a negative pregnancy test during the week before the first dose. They should continue to use contraceptives for six weeks after they stop the drug. Because CellCept affects hormone levels, it could potentially reduce the effectiveness of oral contraceptives.
Vaccine-like treatment shows promise against lupus
Researchers at Perdue University have developed a vaccine-like treatment that shows promise for controlling lupus without the sometimes devastating side effects of current lupus treatments. In a study published in the September-October issue of Molecular Pharmaceutics, the treatment not only improved lupus symptoms but also extended the lives of laboratory mice with a disease comparable to human lupus.
The treatment, called folate-hapten-targeted immunotherapy, targets abnormal immune cells in a way that marks them for destruction by the body’s immune system without affecting healthy calls. The researchers say their study suggests the new therapy warrants further evaluation as a possible approach for treatment of lupus in people.
Researchers may have found a new form of lupus
New research published in the Journal of Experimental Medicine suggests there may be more than one type of lupus, explaining why some people with the disease don’t respond to therapies that target its suspected mechanism.
Current thinking about lupus is that it is a disease driven largely by cooperation between B cells and T cells, two types of cells that normally help fight infection or cancer, say the study’s authors. The new research suggests that, for at least some people, rogue B cells alone may responsible for the disease.
Research has shown recently that as many as a quarter of lupus patients have high blood levels of a molecule called BAFF, which is normally needed for B cells to mature and survive. In the new study, Australian researchers found that mice with high levels of BAFF, but without the capacity to develop T cells, develop a disease that is indistinguishable from the disease requiring collaboration of both types of cells.
While the research is preliminary, this lupus news suggests that for some people, new therapies to target rogue B cells – not the T-cell/B-cell collaboration – may be the most effective treatment for lupus.
Transplant drug may be useful for treating lupus
A drug similar to one used to prevent organ-transplant rejection in people attacks a key biochemical process in the faulty immune cells of mice prone to lupus, new research shows.
The drug, an analog of rapamycin (Sirolimus), was found to shut down specific biochemical processes in the B-cells of the mice. In human lupus, B cells produce abnormal antibodies that attack the person’s own tissues.
The drug was very effective in improving all aspects of the disease in lupus-prone mice, says Chandra Mohan, MD, PhD, professor of internal medicine at the University of Texas Southwestern Medical Center and author of the study appearing in the August issue of the Journal of Clinical Investigation. The next step will be to see if the same biochemical pathways exist in humans. If they do, this research and treatment could prove very significant, he says.
