RxPG News : Autoimmune Diseases

First mouse model for auto-inflammatory diseases reveals role for innate immunity

Sun, 07 Jun 2009 04:06:07 PST

( from http://www.rxpgnews.com ) Researchers at the University of California, San Diego School of Medicine have developed the first mouse model for auto-inflammatory diseases, disorders that involve the over-activation of the body's innate, primitive immune system. Their study, published early on-line in Cell Immunity on June 4, suggests that the innate – not adaptive – immune system drives auto-inflammatory diseases. The findings could open new therapeutic directions for research into disorders such as gout or inflammatory bowel disease.

"Auto-inflammatory diseases are a relatively new classification of diseases that are different from autoimmune diseases or allergies," said Hal Hoffman, MD, associate professor of medicine at UC San Diego School of Medicine. Hoffman studies a group of rare, inherited auto-inflammatory conditions called Cryopyrin-Associated Periodic Syndromes (CAPS), which includes Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

Autoimmune diseases arise from an overactive response of the body's adaptive, or acquired, immune system against substances and tissues normally present in the body. Allergies are also a product of the adaptive immune system, but in response to environmental substances. Both involve the action of lymphocytes such as B cells and T cells. The older innate immune system, on the other hand, recruits immune cells to sites of infection and inflammation, but doesn't confer long-time protection. Pathogens evoke an inappropriate response that doesn't involve antibodies or lymphocytes.

With CAPS, Hoffman had earlier discovered that mutations of the NLRP3 gene caused the auto-inflammatory disease symptoms because the gene causes alterations in the protein called cryopyrin. Cryopyrin regulates the release of interleukin-1, an important mediator of fever and systemic inflammation during the body's innate immune response, and alterations in cryopyrin lead to over-production of Il-1.

Mutations in the NLRP3 gene are thought to result in inappropriate activation of a multi-protein complex called an inflammasome, leading to excessive Il-1β release and manifestation of CAPS disease symptoms. Treatment with Il-1β inhibitors reduces the inflammation and symptoms in auto-inflammatory diseases; however, NLRP3 may have other effects in addition to increased Il-1β.

"Patients treated with the Il-1β inhibitors got much better, but still exhibited some symptoms," said Hoffman.

In order to examine the role of inflammatory mediators and adaptive immune responses in CAPS, the researchers developed two NLRP3 mutant knock-in mouse models. (In "knock-in" models, genetic information is inserted into a particular part of the genome; in contrast to "knock-out" mouse models, in which genetic information is removed.) These mice had systemic inflammation and poor growth, similar to some human patients.

By mating these mice to mice with various gene mutant backgrounds, the scientists showed that CAPS requires an intact inflammasome, is only partially dependent on Il-1β and is independent of T cells. Their findings may help lead to more effective treatments for CAPS syndromes.

"The data shows that CAPS are true inflammasome-mediated diseases and that the adaptive immune system is not necessary for this disease," said Hoffman.

"In the larger picture, our findings also suggest that innate and adaptive immune systems don't necessarily always 'cross talk' or communicate with one another."

According to the researchers, given the importance of IL-Β and the inflammasome to innate immunity, NLRP3 knock-in mice may be applied to the study of many diseases along the autoinflammatory-autoimmune spectrum.

NF-κB mediated bioluminescence- sensitive and early indicator in auto-immune diseases

Wed, 25 Mar 2009 16:06:32 PST

( from http://www.rxpgnews.com ) Current research describes a new method to track the development of autoimmune diseases before the onset of symptoms. The related report by Zangani et al, "Tracking early autoimmune disease by bioluminescent imaging of NF-κB activation reveals pathology in multiple organ systems," appears in the April 2009 issue of The American Journal of Pathology.

Autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis and diabetes are caused when the immune system attacks the body's own cells. Normally, immune cells are prevented from attacking normal cells; however, in patients with autoimmune disease, this "tolerance" is lost. The immediate causes of autoimmune diseases remain unknown, partially due to the inability to detect disease before the onset of symptoms. Early detection of autoimmune disease is critical for assessing new treatments.

The molecule NF-κB is activated by inflammation, which plays a key role in autoimmune disease development, making NF-κB a prime candidate to track autoimmune activity. Researchers at the University of Oslo led by Drs. Ludvig Munthe and Bjarne Bogen in collaboration with Rune Blomhoff engineered NF-κB such that it would emit light when activated. Using a mouse model of systemic autoimmunity with features of lupus, they found that NF-κB activation signals were present in affected organs several weeks before the clinical manifestations of disease. The light signal intensity correlated with disease progression. NF-κB tracking may therefore provide a new tool in the evaluation of early autoimmune therapies.

The article from Zangani et al "indicate[s] that NF-κB mediated bioluminescence is a very sensitive and early indicator of inflammation and disease", allowing precise identification of incipient disease sites for biomedical and pathogenetic studies. In future studies, Drs. Munthe, Bogen, and colleagues will utilize this new model "for studies on early intervention, e.g. drug treatment, to prevent or treat autoimmune disease", and for studies of the development of B cell lymphoma.

Thymus transplants gives hope to babies with DiGeorge syndrome

Tue, 15 May 2007 19:01:41 PST

( from http://www.rxpgnews.com ) "My baby is doing what other babies her age are doing -- she's feeding herself, putting on her own clothes and she loves to dance."

Lolita Harding is describing her daughter Dave'yana, who will turn three in September, thanks in large part to a thymus transplant she received at Duke University Medical Center in April 2005 to reconstitute her absent immune system. Dave'yana was the 31st baby to receive such a transplant at Duke to correct immune system deficiencies caused by a condition called DiGeorge anomaly. Duke is the only center in the world that performs the procedure.

The latest results of Duke's experience with this treatment of DiGeorge anomaly, published Tuesday, May 15, in the journal Blood, show that 75 percent of the babies who received a thymus transplant were alive after one year. The recipient of the first transplant, in 1994, is alive and well.

The current study was supported by the National Institutes of Health and the Food and Drug Administration.

DiGeorge anomaly is marked by the lack of a functioning thymus, a gland that is responsible for "teaching" immune system cells known as T cells how to attack and fight off infections. Babies with DiGeorge anomaly also can have a range of problems including heart defects and unusual facial features. However, about 1 percent of these babies have no thymus at all, a situation that ends in death, usually by infection. These are the patients who are candidates for thymus transplantation.

"We want people to know that when the diagnosis of complete DiGeorge anomaly is made, it is no longer a death sentence," said pediatric immunologist Louise Markert, M.D., Ph.D., who developed the procedure. "There is a treatment available -- thymus transplantation -- that has led to survival of most of the infants who otherwise would have died."

For the procedure, surgeons obtain thymus tissue that usually is discarded from babies undergoing heart surgery. Since the gland is large and covers the heart in infants, surgeons must remove all or part of it to gain access to the heart. The removed thymus tissue is grown in culture for several weeks in a laboratory while researchers ensure that there are no diseases present in the tissue. Strips of tissue are then implanted in the baby's thigh, where they attract a blood supply and begin to act like a thymus gland. Within three to four months, mature T cells begin to appear in the bloodstream.

The latest Duke analysis followed the first 54 children with DiGeorge anomaly referred to Duke for possible thymus transplantation. Of those, 44 received the procedure. So far, 32 of the children who received the transplant are alive, with a follow up of as long as 13 years.

Markert said the 12 deaths occurred within one year of the transplant. The deaths were caused by various infections and were not a result of the surgery itself, she said.

"These babies are very frail when they get here, so it is crucial that they are nourished and supported during this period after transplant to strengthen and maintain them as their immune systems rebuild," Markert said. "We have a remarkable team that takes care of these children in tightly controlled conditions during this important early period."

Typically, children remain in the hospital for two to three months after transplantation as physicians work to keep infections at bay as the child's immune system develops. In Dave'yana's case, Harding returned to the hospital in Missouri after about a month. She received treatment for a viral infection at the Children's Hospital of St. Louis for four months after which her immune system was strong enough to get rid of the virus and prevent other infections. Dave'yana then went home.

"If it wasn't for Dr. Markert and her team, my baby would not be here right now," Harding said. "They really fought for my baby to get the transplant."

Whether she likes it or not, later this month Dave'yana, because of her new immune system, gets to experience what other children her age face -- standard childhood immunization shots.

IGF-1R implicated in the pathogenesis of Grave's Disease

Fri, 16 Feb 2007 12:26:58 PST

( from http://www.rxpgnews.com ) Investigators at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) have found evidence that continues to implicate insulin-like growth factor receptor (IGF-1R) in the development of Graves disease.

In previous research published in the Journal of Immunology, Terry J. Smith, M.D. and Raymond Douglas, M.D., Ph.D. have identified the interaction between immunoglobulins and IGF-1R as a cause of inflammation and lymphocyte infiltration in both Graves disease and rheumatoid arthritis. The discovery of these mechanisms in a similar class of autoimmune diseases supports the belief that a single biological mechanism is activating a variety of autoimmune diseases. The identification of such a mechanism may lead to a common therapeutic strategy for these conditions.

According to Dr. Smith, "We continue to build a body of evidence that suggests that a single biological mechanism can activate a variety of autoimmune diseases. It is possible that these findings will allow us for the first time to interrupt the disease process before any lasting damage is done. It could be involved in other autoimmune disorders as well; we're thinking about a large number of diseases."

In the article appearing in the March 1, 2007 issue of the Journal of Immunology, Dr. Smith and his colleagues report that a disproportionately large fraction of peripheral blood T cells express IGF-1R in patients with Graves disease. The results support a potential role for IGF-1R as a determinant of immune responses through fibroblast and lymphocyte activation and expansion. This further implicates IGF-1R in the pathogenesis of patients with Graves disease.

Graves' disease, the most common cause of hyperthyroidism, can lead to severe swelling around the eye sockets. It is part of a class of autoimmune disorders in which cellular defense mechanisms mistakenly identify the body's own tissues as foreign and seek to destroy them. Other autoimmune disorders in the same class include rheumatoid arthritis, multiple sclerosis, and lupus. 37,000 new patients per year are diagnosed with Graves disease in the United States.

"Autoimmune diseases are among the most insidious and debilitating of human ailments," said LA BioMed President and CEO Kenneth P. Trevett, J.D. We are working closely with Dr. Smith and his colleagues to facilitate this work and promote its transfer to the patient bedside."

Pregnant women with lupus are at higher risk for complications

Sun, 12 Nov 2006 16:20:37 PST

( from http://www.rxpgnews.com )

Pregnant women with systemic lupus should be considered a high-risk population and should be monitored closely by both a rheumatologist and an obstetrician who specializes in caring for high-risk patients.

Women with systemic lupus who become pregnant are at significantly greater risk for death or other medical complications than are pregnant women without lupus, Duke University Medical Center researchers have found in a nationwide study of more than 18 million women.

The study, believed to be largest of its kind, suggests that pregnant women with systemic lupus should be considered a high-risk population and should be monitored closely by both a rheumatologist and an obstetrician who specializes in caring for high-risk patients, the researchers said.

"Pregnant women with lupus should never try to go through their pregnancy alone and simply hope for the best," said study leader Megan Clowse, M.D., M.P.H., assistant professor in the Division of Rheumatology. "They should stay in close contact with their doctors and report any problems immediately."

Clowse presented the findings on Sunday, Nov. 12, at the annual meeting of the American College of Rheumatology, in Washington, D.C. The study was funded by the National Institutes of Health's Building Interdisciplinary Research Careers in Women's Health program.

Lupus is an autoimmune disease in which the immune system loses its ability to distinguish between "self" and foreign substances and thus relentlessly attacks the body's own tissues and cells. Individuals with lupus often exhibit many different symptoms, including arthritis, kidney disease, rashes, fevers, anemia and sensitivity to light, among other problems.

Approximately 1.5 million Americans -- roughly 90 percent of them women -- have some type of lupus. Most patients are diagnosed during their reproductive years. Seventy percent of patients have systemic lupus, the most severe form of the disease.

All women with systemic lupus, pregnant or not, are at increased risk for death and medical complications compared to a healthy population, Clowse said. Other studies report that each year, between 0.8 percent and 3 percent of lupus patients die from the disease.

Previous research also has shown that pregnancy can increase the activity level of lupus, increasing the danger to the woman and sometimes causing problems in her fetus, according to Clowse. What was not certain, she said, is how much lupus increased a woman's health risk.

To help answer this question, Clowse's team analyzed data from more than 18 million pregnancy-related hospital admissions and discharges in the United States from 2000 to 2002. The study found that slightly more than 13,500 women with systemic lupus gave birth during this time, and 44 of the women -- 0.3 percent -- died, Clowse said.

Overall, women with systemic lupus showed a more than 20-fold greater risk of pregnancy-related death, compared with women without the disease, she said. Extrapolating this observed increase in risk to the general population suggests that for every 100,000 women with systemic lupus who would deliver a baby, approximately 325 of them would die, compared with approximately 14 deaths for every 100,000 women without the disease who would give birth, Clowse said.

"We don't want these results to scare women with lupus away from getting pregnant, especially if they have a mild form of the disease," Clowse said. "But these women really must plan their pregnancies. They may need to change their medications before they get pregnant, and they really shouldn't conceive when their lupus is active."

Clowse said patients whose lupus has been dormant for at least six months before conception are at low risk for developing active systemic lupus during pregnancy and therefore are at least somewhat less likely than women whose disease is active to experience health complications.

However, all women with systemic lupus do face elevated risks for pregnancy complications, she said. In the study population, women with systemic lupus, compared to women without the disease, were nearly six times more likely to suffer from deep vein thrombosis -- a blood clot -- and 3.5 times more likely to develop sepsis, a severe illness caused by an extreme infection of the bloodstream. Many women with lupus also were anemic or had low blood platelet counts at delivery and were three times more likely to need transfusions.

Additionally, almost 37 percent of women with lupus gave birth via cesarean section -- 15 percent higher than the national average of 22 percent. Women with lupus also were 2.5 times more likely to experience preterm labor and three times more likely to develop preeclampsia, or pregnancy-related high blood pressure, than women without lupus.

Clowse said the study's results are highly suggestive and should be taken seriously within the health care community, but she added that the study did have certain limitations.

On the plus side, the study examined a large number of patients, including patients from a variety of clinical environments, and it compared pregnancy results among women with and without lupus, she said.

However, she added, the study relied on analyzing hospital admission and discharge data, rather than on analyzing individual patient records or on examining the patients themselves.

Antibody-interleukin complexes stimulate immune responses

Thu, 23 Feb 2006 12:19:37 PST

( from http://www.rxpgnews.com ) The study, which was published in the February 16 issue of the online journal Science Express, showed that these injections caused a massive selective increase in the immune system's two main types of T cells.

The findings could also be significant for developing new ways to help patients with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or juvenile diabetes.

"Our study shows that different cytokine-antibody complexes such as IL-2/IL-2 mAb could be clinically useful to selectively boost or inhibit the immune response in vivo," said Onur Boyman, a member of the Scripps Research Department of Immunology and lead author of the study.

The type of monoclonal antibody that was injected was specific to interleukin-2 (IL-2), a naturally occurring protein and a known immunotherapy for metastatic melanoma and renal cancer. The researchers showed that the anti-IL-2 monoclonal antibody (IL-2 mAb) expands the proliferation of specific T cells in vivo by increasing the biological activity of naturally occurring IL-2 through the formation of immune complexes. When combined with recombinant IL-2, some IL-2/IL-2 mAb complexes cause more than a 100-fold proliferation in CD8+ T cells, which can target virally infected cells or tumor cells.

Interleukin-2 increases the number of a subset of CD8+ T cells (referred to as antigen-experienced or memory T cells) in circulation and is often used for tumor immunotherapy and vaccination. However, IL-2 also stimulates CD4+ T regulatory cells, which can suppress those same memory T cells. Therefore, the prevailing view was that administration of IL-2 mAb removes the IL-2-dependent CD4+ T regulatory cells, which in turn leads to an expansion of CD8+ T cells.

"In the study, however, we noticed that the enhancing effect of IL-2 mAb correlated with naturally occurring levels of IL-2," Boyman said. "We concluded that, despite its reported neutralizing effect, IL-2 mAb actually expanded the proliferation of CD8+ T cells simply by increasing the biological activity of pre-existing IL-2 through the formation of antibody-cytokine immune complexes in vivo. We next combined recombinant IL-2 with IL-2 mAb, which led to an even more dramatic expansion. This expansion effect also extended to other types of antibody-cytokine complexes, such as IL-4/IL-4 mAb and IL-7/IL-7 mAb."

Despite these findings, Boyman noted, no one yet knows why these antibody-cytokine complexes are such potent immune response boosters in vivo.

"A few studies have suggested that injecting a cytokine together with the right antibody increases the half-life of the cytokine in vivo, accompanied by a very mild immune activation," he said. "But our study suggests a different mechanism and that joining a cytokine to its specific antibody opens the way for selective and vigorous stimulation of T cell subsets. With some types of antibodies, injecting IL-2/IL-2 mAb complexes might be clinically useful for tumor immunotherapy and for expanding T cell numbers after bone marrow transplantation. On the other hand, expansion of CD4+ T regulatory cells by IL-2 combined with another type of IL-2 mAb might provide a basis for treating autoimmune disease."

Oral Contraceptives in Women with Lupus might be Safe

Sun, 25 Dec 2005 00:58:38 PST

( from http://www.rxpgnews.com ) In a major study funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), women with either inactive or stable systemic lupus erythematosus (lupus) a disease in which the bodys immune system mistakenly attacks and damages healthy tissues of the skin, joints and internal organs were able to take oral contraceptives without increased risk of flares, or periods of increased disease activity, that characterize the disease.

Safe and effective contraception is an issue that many women of childbearing age face. But for women with lupus, doctors have often been hesitant to prescribe one of the most effective forms of contraception oral contraceptives, or the pill for fear that it might increase disease activity.

In the 15-center study of 183 women with inactive or stable lupus, those taking oral contraceptives (triphasic 35 µg.ethinylestradiol/0.5-1 mg norethindrone for twelve 28-day cycles) had no statistically significant difference in the occurrence of flares than those taking a placebo. Severe flares occurred in about 7 percent of the women, regardless of whether they received oral contraceptives or placebo. A severe flare was defined by several criteria, including the presence of new or worsening central nervous system involvement; inflammation of the blood vessels (vasculitis), kidneys (nephritis) and/or muscles (myositis); and/or blood problems, including low platelet count (thrombocytopenia) and destruction of the red blood cells (hemolytic anemia).

Mild-to-moderate flares and disease complications were similar between the two groups over the 12-month follow-up as well. Mild-to-moderate flares included fevers and inflammation of the skin, joints, the sac of fibrous tissue that surrounds the heart (pericarditis), and mucous membranes lining the nose and mouth.

Reluctance to prescribe oral contraceptives and other hormones for women with lupus arose in part from the fact that lupus is far more common in women (women with the disease outnumber men 10 to 1), and that it typically begins during the childbearing years (after the onset and before the cessation of menstruation) when female hormone levels are at their peak. In mouse models of lupus, giving estrogen makes lupus worse and, depending on the genetic background, influences the activity of white blood cells called B cells that are believed to play a key role in the disease process.

But for most women with moderate lupus that is inactive or stable, taking estrogen whether as part of an oral contraceptive or hormone replacement therapy appears to have no detrimental effect on disease activity, say co-authors Jill Buyon, M.D., of New Yorks Hospital for Joint Diseases, and Michelle Petri, M.D., M.P.H., of the Johns Hopkins University, who jointly led the study. However, they note that oral contraceptives still are not advised for women who have a history of, or are at high risk for, blood clots, because estrogens have been associated with dangerous blood clots.

The recently published study on oral contraceptives is one of two separate randomized, placebo-controlled studies that comprise the Safety of Estrogens in Lupus Erythematosus, National Assessment (SELENA) Trial. The other study, which showed no increased risk of severe flares in postmenopausal women on hormone replacement therapy, was published earlier this year (Buyon JP, et. al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial, Ann Intern Med 2005; 142: 953-962).

There are settings in which estrogens might provide benefit, say the authors. Among women with lupus, they say, there is a high elective abortion rate approaching 23 percent of pregnancies which may reflect a failure of the birth control method used or the absence of an adequate birth control program.

Estrogen, as used in this study, appears to be safe in the majority of women with stable disease, says NIAMS Director Stephen I. Katz, M.D., Ph.D. This research brings us another step forward in improving quality of life for people with rheumatic disease.

Pro-inflammatory HDL (piHDL) is a potential biomarker for lupus atherosclerosis

Wed, 16 Nov 2005 19:26:38 PST

( from http://www.rxpgnews.com ) Groundbreaking research reported at the annual meeting of the American College of Rheumatology indicates that a certain form of the normally "good" high density lipoprotein (HDL) cholesterol linked to cardiovascular health plays a counterproductive role in people with systemic lupus erythematosus (SLE) and rheumatoid arthritis, promoting atherosclerosis (hardening of the arteries) and heart disease in many of these individuals.

The menacing HDL form is pro-inflammatory HDL (piHDL), according to research by Bevra H. Hahn, MD, Maureen McMahon, MD, and colleagues at the David Geffen School of Medicine at UCLA, and it can easily be measured and, most importantly, treated. Dr. Hahn is chief of the division of rheumatology, and Dr. McMahon is an assistant clinical professor of rheumatology.

"Traditional risk factors for atherosclerosis--including high blood pressure, increased cholesterol levels, diabetes mellitus, older age and postmenopausal status--have proved ineffective for predicting atherosclerosis in SLE patients," said Dr. Hahn, whose research is funded by the Lupus Research Institute (LRI). "Uncovering a potentially important role for pro-inflammatory HDL in the development of atherosclerotic disease in patients with SLE is an important first step toward developing strategies to prevent cardiovascular morbidity and mortality in these patients."

Dr. Hahn notes that "pro-inflammatory HDL, which is easily measured, may provide just the sign, known as a biomarker, to determine which patients are at increased risk. If this research is successful, in two years or sooner a test may be available to screen for piHD.

According to Dr. Hahn, women with lupus are about 7 to 10 times more likely than women without the disease to suffer a heart attack or stroke--just a few of the myriad serious health problems confronting the estimated 1.5 million Americans with this chronic autoimmune disease. In lupus, the body attacks its own healthy tissues and organs in a repetitive cycle of flare-ups and remissions.

In the study, Dr. Hahn measured the presence of pro-inflammatory and HDL in samples of blood plasma from 154 women with SLE, 73 age matched controls, and 50 women with rheumatoid arthritis. Compared to the control group, the HDL from those with SLE contained significantly more piHDL. "We found that almost 50 percent of SLE patients, versus approximately 4 percent of controls and 20 percent of rheumatoid arthritis patients, had piHDL," said Dr. Hahn.

In addition, piHDL was found in 8 of the 10 individuals with SLE determined to have actual atherosclerosis. The biomarker was similarly high in half of the 12 subjects with SLE that had suffered a stroke (cerebrovascular event).

"We can clearly see from these results that HDL function fails to protect against cardiovascular disease in many SLE and rheumatoid arthritis patients," Dr. Hahn concluded. "This discovery may lead to an effective test [a fluorescence assay] to identify those at increased risk for blockage of the coronary arteries so that we can start them on preventive treatments like cholesterol-lowering statins."

Chronic infections may create autoimmune response

Tue, 13 Sep 2005 04:57:38 PST

( from http://www.rxpgnews.com ) New research finds the human immune system has foregone evolutionary changes that would allow it to produce better antibodies in less time because the improved antibodies would be far more likely to attack the body's own tissues. The Rice University study finds the immune system has evolved a near-perfect balance for producing antibodies that are both effective against pathogens and unlikely to cause autoimmune disease.

The findings will be published in the journal Physical Review Letters. They are based on a new model of the immune system that is the first to simulate the hierarchical nature of the body's immune response. The model predicts that chronic infections may lead to autoimmune diseases, a scenario that has been proposed as a cause of some rheumatic diseases like arthritis.

"There are as many as a 100 million unique antibodies circulating through our bodies at any given time, but just three or four of these might be effective against any particular disease," said Michael Deem, the John W. Cox Professor in Biochemical and Genetic Engineering and professor of physics and astronomy. "When we get sick, the immune system identifies the particular antibodies that are effective, as it rapidly creates and mass produces mutant white blood cells called B cells that make only these antibodies."

Deem said prior research has identified a number of alternate strategies the immune system could use to reduce the time needed to create an effective B cell. In addition, these methods also could produce antibodies that are more apt to bind with disease cells. The upshot would be an immune system that responds faster and more effectively against disease.

"This should help us get well faster, so the question becomes, 'Why didn't we evolve that kind of adaptive response?'" Deem said.

Deem's analysis falls within a branch of physics called statistical mechanics, which uses a system's physical behavior at the molecular or atomic scale to build up a picture of the behavior at a larger level. In this case, Deem and postdoctoral researchers Jun Sun and David J. Earl studied the physical properties of fragments of DNA to determine the origins, behavior, and generation of antibodies.

Generating antibodies is one of the primary functions of the immune system. Antibodies are protein molecules that are made by B cells. Each antibody has a chemical signature that allows it to bind only with a particular sequence of amino acids.

"In our study, we first sought to understand the evolutionary rules that govern the way the immune system responds to an infection," Deem said. "With that framework in place, we identified a biologically-plausible strategy that would allow the immune system to react more quickly and with more effective antibodies. Our analysis revealed that such a system would be about 1,000 times more likely to produce antibodies that attack healthy tissues."

Antibodies that bind with something other than the antigen they evolved to attack are called cross-reactive, and some researchers believe cross-reactivity causes some autoimmune diseases.

For example, some scientists have found a correlation between chronic infection and an increased probability of autoimmune disease, but the strength and significance of the correlation is controversial. Rice's model suggests that a correlation does exist, but that the length of the infection prior to onset of autoimmune disease is highly variable.

"People have been looking for a clear, significant correlation in time, but a long distribution of onset times would lead to weaker statistical correlations, particularly in those cases where the infection persisted the longest," said Deem. "Searching for this distribution in health and medical statistics could shed light on this immunological puzzle and settle the scientific controversy."

The Rice analysis finds the human immune system evolved to minimize the risk of cross-reactivity. For example, each cell in our bodies contains about 100,000 proteins with an average of 500 amino acids apiece. Consequently, there are about one trillion potential docking sites, or epitopes, where antibodies could mistakenly attach themselves to proteins in a healthy cell. The mutation response method employed by our adaptive immune system seems keyed to this number, producing antibodies that are statistically likely to mistakenly bond with healthy proteins slightly less than one in a trillion times, meaning that on average, they recognize only invading pathogens.

Epratuzumab may Serve as a Potential Treatment Option for SLE

Mon, 06 Jun 2005 10:09:38 PST

( from http://www.rxpgnews.com ) Immunomedics Inc announced patient dosing has begun for the pivotal Phase III clinical trials to further evaluate the safety and efficacy of the Company's lead drug candidate, epratuzumab, for the treatment of patients with systemic lupus erythematosus (SLE), known as lupus.

Epratuzumab has been designated by the U.S. Food and Drug Administration ( FDA ) as a Fast Track product for the potential treatment of patients with moderate and severe SLE. Epratuzumab is a humanized monoclonal antibody that targets an antigen, known as CD22, found on the surface of a certain class of lymphocytes, a type of white blood cell.

Epratuzumab has shown activity in patients with SLE with mild depletion of circulating B-lymphocytes. This suggests epratuzumab may work by modulating B-cell function, as contrasted with other B-cell antibodies that appear to require depletion of B-cells. It also implies a possible reduction in the risk of infection, which is commonly associated with lupus, and can be life-threatening. We are pleased to advance our lead drug candidate, epratuzumab, into pivotal Phase III lupus trials, and to be at the forefront of lupus therapy research, commented Ivan D. Horak, M.D., Executive Vice President, Research and Development, and Chief Scientific Officer of Immunomedics.

There is a need for a new drug that addresses and improves the quality of life for the estimated 3 to 5 million patients worldwide afflicted with lupus, a debilitating and often life-threatening disease. We are pleased that Pharmaceutical Product Development, Inc. ( Nasdaq: PPDI ) will work with us to execute these pivotal trials, said Cynthia L. Sullivan, President and Chief Executive Officer of the Company. We continue to hold discussions with potential partners for epratuzumab in all indications, with the aim of securing the best possible agreement for further development of our product and to maximize value for our shareholders.

The pivotal trials are randomized, double-blinded, placebo-controlled, multi-center studies using the BILAG ( British Isles Lupus Assessment Group ) index to monitor and assess disease activity. A high BILAG score indicates increased disease activity. The trials have been named ALLEVIATE or Alleviate Lupus Affliction with Epratuzumab and Validate its Autoimmune Safety and Efficacy. One trial, ALLEVIATE A, is for patients with severe SLE flares, and the second trial, ALLEVIATE B, is for patients with moderately active SLE.

About Epratuzumab

Epratuzumab is Immunomedics' lead product candidate being evaluated in two pivotal Phase III trials for the treatment of moderate and severe SLE. The FDA granted a Fast Track designation to the clinical development program for epratuzumab for the treatment of patients with SLE. Epratuzumab has also demonstrated good safety, tolerability, and clinical efficacy in more than 340 patients with non-Hodgkin's lymphoma, resulting in reports published in The Journal of Clinical Oncology and Clinical Cancer Research.

About Systemic Lupus Erythematosus

Systemic lupus erythematosus ( SLE ) is a serious autoimmune disease affecting approximately 1.5 million Americans, according to the Lupus Foundation of America. In the U.S., women with SLE outnumber men by a ratio of nine to one, and 80% of female patients develop lupus between the ages of 15 and 45. At present, there is no cure for lupus and no new lupus drug has been approved in the U.S. for nearly 40 years. Lupus most often results in chronic inflammation and pain affecting various parts of the body, especially the skin, joints, blood, and kidneys. The disease can be serious and life threatening. Current treatments used in medical practice include corticosteroids, nonsteroidal anti-inflammatory drugs, immunosuppressives, and antimalarials.

The FDA has recently issued a draft guideline to industry on developing drugs for the treatment of SLE that is available at fda.gov/cder/guidance/6496dft.pdf.

How lupus T cells lose IL-2

Sun, 03 Apr 2005 13:10:38 PST

( from http://www.rxpgnews.com ) Lupus is a chronic, autoimmune disease that causes inflammation, particularly of the skin, joints, blood, and kidneys. Patients with lupus produce antibodies against their own proteins. Patients also have immune T cells that produce a protein called IL-2, which normally usually protects against infection, at lower than typical levels. In a study appearing in the April 1 print edition of The Journal of Clinical Investigation, George Tsokos and colleagues from the Walter Reed Army Institute of Research explore the mechanisms underlying this decreased IL-2 production.

The researchers find that sera from lupus patients contains antibodies that bind to T cells and activate a complex cellular signaling cascade that ultimately results in decreased IL-2 production. This deficiency in IL-2 could result in the autoantibody production that occurs in lupus.

In an accompanying commentary, Gary Kammer of Arthritis Associates, Inc points out "the contribution by Tsokos and his colleaguesprovides a new appreciation and insight into how the microenvironment in lupus can further impinge on a defective T cell to inhibit IL-2 production. From such studies will come the inspiration and novel approaches necessary to develop therapeutic tools to abate disease and improve the quality of life of our patients."