Researchers at the University of California, San Diego School of Medicine have identified a key protein that is required for immune cells called B lymphocytes to divide and replicate themselves. The rapid generation of large numbers of these immune cells is critical to the body’s antibody defense mechanism. However, when B cells grow unchecked, it can lead to immune cell cancers such as multiple myeloma or, when they grow to attack the wrong targets, to autoimmune disease. By discovering the role of the CD98hc protein, scientists may find new therapy targets for such diseases.

The study from the laboratory of Mark H. Ginsberg, MD., professor of medicine, will be published online March 8 in advance of print in Nature Immunology. It describes why CD98hc is essential in order for B lymphocytes to transition into antibody-secreting cells. It also describes how this relates to the protein’s role in the signaling ability of integrins – a large family of adhesion molecules that transfer information between the inside and outside of a cell.

According to first author Joseph Cantor, PhD, UC San Diego School of Medicine, scientists have known for nearly 25 years that CD98hc, common to all vertebrates, probably played a role in their adaptive immune system, but it wasn’t known how this protein functioned.

“This protein was used as a marker of activation because it was found in low levels on resting lymphocytes,” said Cantor. “But when B or T lymphocytes were stimulated by antigens – for instance, to protect the body against bacteria – levels of CD98hc went up 20 fold.”

The scientists generated a mouse model lacking the CD98hc protein in B lymphocytes. When vaccinated, these mice were unable to mount a normal antibody response to the pathogen. Cantor says this was the first clue to the researchers of the protein’s importance.

“In purifying B lymphocytes without the CD98hc protein, we discovered that the lymphocytes couldn’t divide rapidly,” Cantor said, adding that this proved the protein was essential to expanding the number of immune cells, a necessary step in the immune response. While deletion of the protein didn’t impair early B cell activation, it did inhibit later activation of elements along the signaling pathway that push the cell forward to divide.

“Since B cells can’t rapidly divide and replicate without CD98hc, perhaps by blocking this protein we could stop the unchecked growth of B lymphocyte cells that can result in cancer or block misdirected B cell attacks that can cause certain autoimmune diseases,” said Ginsberg.

The CD98hc protein functions in cells by helping to transmit integrin signals, as well as transporting amino acids – the building blocks of proteins – into the cell. But the scientists didn’t know which, if either, of these functions was related to the protein’s role in the rapid division of immune cells. By replacing normal CD98hc in B cells with a version that lacked one or the other of these two functions, they discovered that the integrin-binding domain of this protein is required, but the amino acid transport function is dispensable for B cell proliferation.

“CD98hc interacts with certain integrin subunits to prompt signaling events that control cell migration, survival and proliferation. Our study shows that the rapid proliferation of B cells, necessary for the body to fight infection, is aided by the CD98hc protein’s support of integrin signaling,” Cantor said.

Notes:

Additional contributors to this paper include Cecille D. Brown and Robert C. Rickert of the Burnham Institute; Raphael Ruppert and Reinhard Fässler of the Max Planck Institutte, Germany; and Chloé C. Féral, Nice-Sophia Antipolis University, France.

This work was supported by National Institutes of Health grants; Joseph Cantor is a post-doctoral fellow of the National Multiple Sclerosis Society.

Idera Pharmaceuticals, Inc. (Nasdaq: IDRA), a biotechnology company engaged in the discovery and development of DNA- and RNA-based drug candidates targeted to Toll-like Receptors (TLR), today announced the publication of a paper entitled “Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-like Receptor 9″ in Clinical Cancer Research (2009, 15, 1575-84) co-authored by scientists from Idera and Merck & Co., Inc. The paper describes a preclinical study evaluating a TLR9 agonist as a vaccine adjuvant in combination with a HER-2/neu plasmid DNA electroporation/adenovirus vaccine candidate.

In this preclinical study, a novel TLR9 agonist was evaluated for its ability to enhance the effects of a HER-2/neu plasmid DNA electroporation/adenovirus vaccine. In a tumor model the combination of HER-2/neu genetic vaccine and TLR9 agonist showed potent antitumor activity associated with antibody isotype switch and antibody-dependent cellular cytotoxicity activities.

“Under our collaboration with Merck, we have created novel agonists of TLR7, 8 and 9 for use as adjuvants in candidate vaccines for cancer, infectious diseases and Alzheimer’s disease. We are pleased with this demonstration that an agonist of TLR9 enhances the activity of an investigational genetic cancer vaccine in preclinical studies,” commented Sudhir Agrawal, D.Phil., Chief Executive Officer and Chief Scientific Officer of Idera.

About the Collaboration

Idera Pharmaceuticals, Inc. entered into an exclusive license and research collaboration agreement with Merck & Co., Inc. in December 2006 to research, develop and commercialize vaccine products containing Idera’s agonist compounds targeting TLRs 7, 8, and 9 in the fields of oncology, infectious diseases and Alzheimer’s disease. As part of the agreement, the two companies engaged in a two-year research collaboration to generate novel agonists targeting TLR7 and TLR8 incorporating both Merck and Idera chemistry for use in the licensed fields. In November 2008, Merck extended its research collaboration with Idera for an additional year.

About Idera Pharmaceuticals, Inc.

Idera Pharmaceuticals develops drug candidates to treat infectious diseases, autoimmune and inflammatory diseases, cancer, and respiratory diseases, and for use as vaccine adjuvants. Our proprietary drug candidates are designed to modulate specific Toll-like Receptors, which are a family of immune system receptors that direct immune system responses. Our pioneering DNA and RNA chemistry expertise enables us to create drug candidates for internal development and generates opportunities for multiple collaborative alliances. For more information, visit http://www.iderapharma.com.

Idera Forward Looking Statements

This press release contains forward-looking statements concerning Idera Pharmaceuticals, Inc. that involve a number of risks and uncertainties. For this purpose, any statements contained herein that are not statements of historical fact may be deemed to be forward-looking statements. Without limiting the foregoing, the words “believes,” “anticipates,” “plans,” “expects,” “estimates,” “intends,” “should,” “could,” “will,” “may,” and similar expressions are intended to identify forward-looking statements. There are a number of important factors that could cause Idera’s actual results to differ materially from those indicated by such forward-looking statements, including whether products based on Idera’s technology will advance into or through the clinical trial process on a timely basis or at all and receive approval from the United States Food and Drug Administration or equivalent foreign regulatory agencies; whether, if the Company’s products receive approval, they will be successfully distributed and marketed; whether the Company’s collaborations with Novartis, Merck & Co., and Merck KGaA will be successful; whether the patents and patent applications owned or licensed by the Company will protect the Company’s technology and prevent others from infringing it; whether Idera’s cash resources will be sufficient to fund the Company’s operations; and such other important factors as are set forth under the caption “Risk Factors” in Idera’s Quarterly Report on Form 10-Q filed on November 13, 2007, which important factors are incorporated herein by reference. Idera disclaims any intention or obligation to update any forward-looking statements.

Telomeres, structures that cap the ends of cells’ chromosomes, grow shorter with each round of cell division unless a specialized enzyme replenishes them. Maintaining telomeres is thought to be important for healthy aging and cancer prevention.

By this measure, T cells, or white blood cells, from patients with the autoimmune disease rheumatoid arthritis are worn out and prematurely aged, scientists at Emory University School of Medicine have discovered.

Compared with cells from healthy people, T cells from patients with rheumatoid arthritis have trouble turning on the enzyme that replenishes telomeres, they found. Reversing this defect could possibly help people prone to the disease maintain a balanced immune system.

The results are published online this week in Proceedings of the National Academy of Sciences.

In rheumatoid arthritis, T cells are chronically over-stimulated, invading the tissue of the joints and causing painful inflammation. This derangement can be seen as a result of the loss of the immune system’s ability to discriminate friend from foe, says senior author Cornelia Weyand, MD, PhD, co-director of the Kathleen B. and Mason I. Lowance Center for Human Immunology at Emory University.

In childhood, new T cells are continually produced in the thymus, she says. But after about age 40, the thymus “involutes” – or shrinks and ceases to function. After that, the immune system has to make do with the pool of T cells it already has.

“What we see in rheumatoid arthritis is an aged and more restricted T cell repertoire,” she says. “This biases the immune system toward autoimmunity.”

Weyand, postdoctoral fellow Hiroshi Fujii, MD, PhD, and their colleagues were interested in mechanisms of T cells’ premature aging, because scientists had previously observed that in rheumatoid arthritis, T cells tend to shift the molecules on their surface and function differently.

They found the answer in telomerase, the enzyme that renews telomeres and is necessary to prevent loss of genetic information after repeated cell division.

Telomerase adds short repeated DNA sequences to the ends of chromosomes to protect them. The enzyme is active in embryonic development but is usually switched off in adult cells. Many cancer cells reactivate it to enable runaway growth.

T cells are some of the very few cells in adults that can turn on telomerase when stimulated, probably because they have to divide many times and stay alive for decades.

Weyand and Fujii found that T cells from patients with rheumatoid arthritis make 40 percent less telomerase enzyme when stimulated. The cells came from 69 patients, 92 percent female, with an average age of 50, and were compared with cells from healthy people with similar demographics.

Shutting off a gene encoding part of the enzyme made normal T cells vulnerable to programmed cell death, and transferring telomerase into patients’ T cells rescued them from dying.

The finding suggests that restoring defective telomerase to T cells could possibly help “reset” the immune system in rheumatoid arthritis, Weyand says.

Pharmaceutical industry researchers have been looking for drugs that could elevate or depress telomerase activity, with the goal of either prolonging life or treating cancer. However, turning on telomerase indiscriminately could lead to cancer, so any treatment would have to be targeted to the right cells, she says.

Notes:

The research was funded by the National Institutes of Health and the Diane Wolf Discovery Fund.

Fujii is now an assistant professor of hematology and rheumatology at Tohoku University School of Medicine in Japan.

Reference: H. Fujii, L. Shao, I. Colmegna, J. Goronzy and C.M. Weyand. Telomerase insufficiency in rheumatoid arthritis. http://www.pnas.org/cgi/doi/10.1073/pnas.0811332106

The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include schools of medicine, nursing and public health; the Yerkes National Primate Research Center; the Emory Winship Cancer Institute; and Emory Healthcare, the largest, most comprehensive health system in Georgia. The Woodruff Health Sciences Center has a $2.3 billion budget, 17,000 employees, 2,300 full-time and 1,900 affiliated faculty, 4,300 students and trainees, and a $4.9 billion economic impact on metro Atlanta.

ImmunoCellular Therapeutics, Ltd. (OTCBB: IMUC) (IMUC), a biotechnology company, today announced that the company has identified new peptide candidates that may significantly expand the potential target patient population for the company’s cancer stem cell vaccine product candidate, ICT-121. Many cancer therapies are limited by their ability to be used only in patients with certain human leukocyte antigen (HLA) types. Identification of the new peptides for use in IMUC’s vaccine should enable the use of IMUC’s product candidate in patients with many different HLA types.

“This is an encouraging finding for us, as it could dramatically increase the number of patients who may be able to someday benefit from our cancer stem cell therapies,” stated Manish Singh, Ph.D., president and chief executive officer of IMUC. “ICT-121 is an exciting product candidate given that it targets cancer stem cells-cancer cells at their very root-and it has been shown in preclinical studies to be highly targeted for destroying cancer stem cells present in brain tumors. This is a very unique approach, as active immunotherapy provides a high degree of selectivity to target primarily cancer cells while leaving the normal stem cells alone.”

Dr. Singh continued, “We’ve been pleased to see the high level of interest around cancer stem cell technologies of late as evidenced by the number of recent deals done by pharmaceutical companies in this area as well as by the September 2008 cover story in The Economist entitled ‘Cancer and Stem Cells-The Connection that Could Lead to a Cure.””

About ICT-121

ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs. It is designed as an “off-the-shelf” vaccine. IMUC will initially evaluate it in a Phase I clinical study for glioblastoma which, subject to FDA clearance, IMUC plans to commence in the third quarter of this year. While glioblastoma will be the initial target for ICT-121, CD133 is also overexpressed in colon cancer, breast cancer, liver cancer, prostate cancer, multiple myeloma and melanoma, providing many potential cancer targets for this CSC vaccine in the future.

About ImmunoCellular Therapeutics, Ltd.

IMUC is a Los Angeles-based clinical-stage company that is developing immune based therapies for the treatment of brain and other cancers. IMUC is currently evaluating a dendritic cell-based vaccine in a Phase I clinical trial for glioblastoma. The company’s “off the shelf” therapeutic vaccine product candidate targeting cancer stem cells for multiple cancer indications is expected to enter clinical trials during the third quarter of 2009. IMUC is in pre-clinical development of a monoclonal antibody product candidate for the treatment of small cell lung cancer and pancreatic cancer, and is also evaluating its platform technology for monoclonal antibody discovery using differential immunization for diagnosing and treating multiple types of cancer. To learn more about IMUC, please visit http://www.imuc.com.

Forward-Looking Statements

This press release contains certain forward-looking statements that are subject to a number of risks and uncertainties, including without limitation the risks associated with obtaining FDA clearance to commence clinical trials of the cancer stem vaccine on a timely basis or at all; the risks associated with adhering to projected preclinical or clinical timelines and the uncertainties of outcomes of development work for product candidates, including those based on destroying cancer stem cells as a potentially safe and effective treatment for various cancers; the need to satisfy performance milestones to maintain the vaccine technology licenses with Cedars-Sinai; the risks associated with generating data to support the provisional patent application for the CSC technology and of obtaining a patent that provides commercially significant protection for this technology; and the need for substantial additional capital to fund development of product candidates beyond their initial clinical or pre-clinical stages. Additional risks and uncertainties are described in IMUC’s most recently filed SEC documents, such as its most recent annual report on Form 10-KSB, all quarterly reports on Form 10-Q and any current reports on Form 8-K. IMUC undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

The National Institutes of Health’s National Cancer Institute (NCI) has awarded The City College of New York (CCNY) and Memorial Sloan-Kettering Cancer Center (MSKCC) a $15.9 million grant to implement a unique partnership in cancer research, education, and outreach. The five-year, renewable award is funded by NCI’s U54 program, an initiative created to develop partnerships between minority-serving institutions and NCI-designated cancer centers.

The Partnership for Cancer Research, Training, and Community Outreach will build upon a previous collaboration between the institutions. The grant will help support key research activities that provide a multidisciplinary, but unified approach to several objectives set forth by MSKCC and CCNY.

“We are looking forward to partnering with CCNY to improve cancer research, training, education, and outreach for underserved communities in the New York area,” said Dr. Tim A. Ahles, Director of MSKCC’s Neurocognitive Research Laboratory, and U54 Co-Principal Investigator. “We also want to have these successful approaches to address cancer disparities serve as new models for other minority-serving institutions and NCI-designated cancer centers.”

“By combining our talents and some of our resources, CCNY and Memorial Sloan-Kettering will be well equipped to build and nurture programs in areas such as cancer research and community outreach that will help address cancer disparities in underserved minority and economically disadvantaged communities,” said Dr. Karen Hubbard, Professor of Biology at CCNY, and U54 Co-Principal Investigator.

The Partnership for Cancer Research, Training, and Community Outreach includes four primary objectives:

* Investigators will work to develop translational research programs in cell biology, immunology, and biomedical research. Translational research is a concept in which basic science discoveries are applied in clinical practice and clinical observations are studied in the laboratory.

* MSKCC and CCNY will collaborate with diverse communities to help define and address cancer disparities. The proposed Partnership for Community Outreach Program (PCOP) will provide an infrastructure to work with members of the community to identify and prioritize specific areas for action. Other elements of this effort include at least two large-scale annual outreach events and several smaller, topical activities featuring experts on issues such as healthy eating, smoking cessation, and cancer screening.

* A collaborative effort will be made to recruit and retain students from high school to the post-graduate level, in particular those of minority backgrounds, who are interested in pursuing careers in cancer research. Enhanced education and training opportunities, as well as increased mentorship and support, will be made available.

* The partnership will recruit new faculty members at both institutions. U54 resources will help support appointments in key CCNY divisions. At MSKCC, faculty lines will add to the capacity to conduct community-based intervention research and to the development of the PCOP.

About The City College of New York

For more than 160 years, The City College of New York has provided low-cost, high-quality education for New Yorkers in a wide variety of disciplines. Over 15,000 students pursue undergraduate and graduate degrees in the College of Liberal Arts and Sciences; The School of Architecture, Urban Design and Landscape Architecture (SAUDLA); The School of Education; The Grove School of Engineering; and The Sophie Davis School of Biomedical Education. For additional information, visit http://www.ccny.cuny.edu.

About Memorial Sloan-Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center is the world’s oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Our scientists and clinicians generate innovative approaches to better understand, diagnose, and treat cancer. Our specialists are leaders in biomedical research and in translating the latest research to advance the standard of cancer care worldwide. For more information, go to http://www.mskcc.org.

Women who’ve had a breast biopsy know the anxiety of waiting for the results, but that stress may cause adverse health effects, according to a new study published in the March issue of Radiology.

“When women express how taxing it is to have to wait for results, the medical establishment may dismiss their feelings as psychological,” said the study’s lead author, Elvira V. Lang, M.D., associate professor of radiology at Harvard Medical School and radiologist at Beth Israel Deaconess Medical Center in Boston. “We were able to show that this state of not knowing the diagnosis goes along with biochemical changes which can have adverse effects on wound healing and the immune system.”

More than 1.2 million breast biopsies are performed in the U.S. annually, with 80 percent resulting in non-cancerous findings, according to the American Cancer Society. Women experience considerable anxiety while waiting to undergo breast biopsy and while waiting for the results. Dr. Lang and colleagues sought to establish a biochemical marker to assess the physical effects associated with the stress of extended waiting for a final diagnosis after breast biopsy.

For this study, the researchers used cortisol samples collected from the saliva of 126 women during an earlier clinical trial on patient stress during biopsy. Cortisol is a hormone produced by the adrenal gland and is often referred to as the “stress hormone.” The production of cortisol is part of the body’s natural response to stress. Stress-induced imbalances in cortisol secretion have been associated with impairments to immune response and wound healing.

“Cortisol helps us fight acute stress by adjusting blood pressure, blood sugar and immune response in a good way when needed,” Dr. Lang said. “But when stress becomes chronic, cortisol secretion either goes into continuous overdrive or dries up, leaving the immune system vulnerable and other body functions less well adapted.”

The women participating in the study underwent large-core breast biopsy and learned their diagnosis one to six days after the procedure. Salivary cortisol samples were collected on cotton swabs on the day of biopsy and each of the four days following biopsy.

During the period in which the samples were taken, the women learned whether their biopsy results were benign (non-cancerous), malignant (cancerous) or uncertain. By the fourth day after biopsy, 16 patients had learned they had cancer, 37 patients had benign findings and 73 patients had an uncertain diagnosis, because their results had not been communicated yet or they required further diagnostic procedures.

The results showed that cortisol secretion for the women with uncertain results was significantly different than that of the women with benign results and highly similar to secretion levels in the women with malignant results.

The researchers hope that these findings will encourage faster analysis and communication of biopsy results. They counsel women to speak to their doctors about communication procedures before undergoing breast biopsy.

“Women should ask who will communicate their results to them and how long it will take to receive them,” Dr. Lang said. “Then they should schedule the biopsy accordingly, taking into account delays over weekends and holidays.”

“It is no longer so easy for healthcare providers to overlook the effects of extended waiting and say ‘Oh, it’s just nerves,’” she added.

For patient-friendly information on breast biopsy, visit RadiologyInfo.org.

“Large-Core Breast Biopsy: Abnormal Salivary Cortisol Profiles Associated with Uncertainty of Diagnosis.” Collaborating with Dr. Lang were Kevin S. Berbaum, Ph.D., and Susan K. Lutgendorf, Ph.D.

Radiology is edited by Herbert Y. Kressel, M.D., Harvard Medical School, Boston, Mass., and owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)

RSNA is an association of more than 42,000 radiologists, radiation oncologists, medical physicists and related scientists committed to excellence in patient care through education and research. (RSNA.org)

University of California, Irvine infectious disease researchers have shown the effectiveness of a potential alternative to the existing smallpox vaccine that can replace the current biodefense stockpile for this lethal virus.

Philip Felgner and Huw Davies with the Department of Medicine found that the modified vaccinia virus Ankara (MVA) produced the same antiviral response in human and animal studies as the current smallpox vaccine, Dryvax. The study is part of a national effort to develop a replacement for the Dryvax vaccine, which causes serious complications in some people. The results are published in the Journal of Virology.

“Studies have shown MVA to be a much safer vaccine product that takes advantage of modern technology,” Felgner said. “We are pleased that our advanced analytical methods may help to bring an effective and safer vaccine to the public.”

Smallpox was declared eradicated worldwide in 1980; the last naturally occurring case in the world was in Somalia in 1977. Routine vaccination against smallpox in the U.S. stopped in 1972, and Dryvax production was halted in 1982.

Both Dryvax and MVA are strains of vaccinia virus, which is related to the smallpox virus. The antibodies created by vaccinia virus infection protect a person against a lethal smallpox infection, making it suitable for use as a vaccine. Unlike smallpox virus, vaccinia creates a very mild infection and is completely safe for healthy individuals.

Although Dryvax was effective during the eradication campaign in the 1960s and ’70s, its manufacturing methods are outdated by today’s standards, and it is also associated with significant risk of adverse reactions for immune-compromised individuals.

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, identified MVA as a possible candidate to replace Dryvax. MVA was first developed in the 1970s and has been administered to animal species and humans with little or no adverse side effects.

In the study, Felgner and Davies applied blood serum samples taken from both humans and animals given the MVA or Dryvax vaccines to “microarray” chips containing more than 200 vaccinia virus proteins, on which they simultaneously studied how the serum antibodies responded to all the vaccinia proteins.

The researchers found that these antibody responses were similar in both the animal and human subjects regardless whether they were given MVA or Dryvax, suggesting that MVA contains antiviral properties similar to those in Dryvax.

This similarity is vital, Davies says, because if a vaccine initiates an immune response in humans that matches the one in animals that are protected against lethal pox viruses, then public health officials will have more confidence that the vaccine will be effective in humans.

“This is particularly important for vaccines against lethal infections like smallpox, where human clinical trials cannot be done,” he added.

A research team at Weill Cornell Medical College in New York City has identified two genes that may be crucial to the production of an immune system cytokine called interleukin-10 (IL-10).

The discovery fills in an important “missing link” in a biochemical pathway that’s long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS.

“IL-10 production has to be kept in a delicate balance for health,” explains study senior researcher Dr. Xiaojing Ma, Professor of Immunology and Microbiology in the Departments of Microbiology and Immunology and Pediatrics at Weill Cornell. “Too much IL-10 can leave the body more vulnerable to killers such as viruses and cancer, and to certain antibody-driven autoimmune diseases such as lupus, while too little can lead to run-away inflammatory pathology. Therefore, a better understanding of IL-10 regulation moves us closer to understanding these illnesses and – potentially – how to better treat them,” he says.

The findings are reported in this month’s issue of Immunity (vol. 27).

Dr. Jianguo Liu, of Weill Cornell, and Dr. Elaine Y. Chung, formerly of Weill Cornell and now a post-doc at the University of Pennsylvania, were co-lead researchers on the study.

Every second, millions of the body’s cells undergo naturally programmed cell death – a process called apoptosis. In healthy individuals, these dying or dead cells are spotted and then quickly ingested and removed by immune system “scavenger” cells such as macrophages.

However, to prevent this type of clean-up from triggering a wider immune response, macrophages express the IL-10 cytokine in the presence of apoptotic cells.

IL-10 suppresses the activity of immune system T-cells that might otherwise run amuck, Dr. Ma explains.

“That can be a good thing, of course,” he says. “But on the other hand, when immune system T-cell activity is weakened too much, that can help encourage AIDS in those infected with HIV. Also, excessive T-cell suppression can keep the immune system from destroying rogue cancer cells in people battling malignancy.”

All of this means that “anything that we can learn about IL-10 production – and related T-cell suppression – is a boon to medical research,” Dr. Ma explains.

Prior studies had already shown that CD36 – a protein receptor lying on the surface of the macrophage – was important for the recognition of apoptotic cells by macrophages. In this work, the researchers observed that CD36 also helped to trigger IL-10 production whenever apoptotic cells were around.

The team then asked a deeper question: “What signals lead to IL-10 production from CD36 present at the cell surface?”

To find out, the Weill Cornell group first exposed macrophages to apoptotic (dying) cells. They then used sensitive assays to look for key biochemical changes occurring downstream of CD36 activation.

“We found proteins in the cell nucleus that were binding to a site we knew was critical for the production of IL-10 as macrophages encountered apoptotic cells,” Dr. Ma says. In subsequent biochemical experiments, the team identified the two genes responsible for the transcription (gene-directed production) of these proteins.

These genes – pre-B transcription factor 1(Pbx-1) and Pbx-regulating protein 1 (Prep-1) – are best known to scientists as partners for their role in embryonic development and several forms of leukemia, with Pbx playing a major part in hematopoeisis, the production of new and myriad blood cell types.

“In that sense, their presence as immune system transcription factors came as a big surprise to us,” Dr. Ma says. “In fact, we still haven’t figured out exactly how Pbx-1 and Prep-1 are involved in regulating IL-10 transcription. I really hope this study opens up new avenues for immunologists to find out whether there’s a brand new biochemical pathway to be discovered.”

The findings could also reveal exciting new information as to how aberrant IL-10 expression contributes to disease.

“Because IL-10 expression (and related T-cell suppression) are so important to the etiology of so many illnesses, discoveries like ours could point to molecular pathways that may become important new targets for drug discovery going forward,” Dr. Ma explains. “It’s these types of breakthroughs in the lab that – step by step – will end up bringing real hope to patients down the line.”

This work was supported by the U.S. National Institutes of Health and the Mary Kirkland Foundation for Lupus Research.

Co-researchers include Dr. Yoichiro Homma, Yunhua Zhang, Dr. Andrea Brendolan, Dr. Matilde Saggese, Dr. Jihong Han and Dr. Licia Selleri – all of Weill Cornell Medical College; and Dr. Roy Silverstein of the Cleveland Clinic Foundation.

Weill Cornell Medical College

Weill Cornell Medical College – Cornell University’s Medical School located in New York City – is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health – and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College – in its commitment to global health and education – has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances – from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial for gene therapy for Parkinson’s disease, the first indication of bone marrow’s critical role in tumor growth, and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. For more information, visit http://www.med.cornell.edu.

VGX Pharmaceuticals announced today the successful completion of its first study to assess the tolerability of VGX’s patented CELLECTRA™ electroporation device in humans. Ten healthy adult volunteers were treated with CELLECTRA™ device and were asked to report the level of discomfort they experienced immediately after electroporation and at various times thereafter. The procedure was generally well tolerated. On average, the patients reported a moderate level of discomfort during the procedure. However, the discomfort was short-lived, with comfort levels approaching baseline levels within 30 minutes following the procedure. Other complaints were mild and did not require any treatment.

Numerous preclinical efficacy studies have shown that delivery of VGX’s DNA products with the CELLECTRA™ device resulted in therapeutic and protective immune responses that are unachievable by other treatment or vaccine methods.

“The completion of this Human Tolerability Study is a major milestone for VGX Pharmaceuticals,” stated Dr. J. Joseph Kim, President and Chief Executive Officer. “This is just the first step in our aggressive strategy to develop a potent and prolific DNA-based drug and vaccine development platform.”

Over the years, VGX Pharmaceuticals has established itself as a leading developer and manufacturer of DNA plasmid-based vaccines and therapies. The Company has built extensive, vertically-integrated capabilities including SynCon™ DNA-based product candidates, the CELLECTRA™ delivery device, and efficient cGMP manufacturing facilities for its own product supplies and for contract manufacturing.

PENNVAX™-B, the first of VGX Pharmaceuticals SynCon™ DNA vaccine candidates, is already in Phase I clinical trials as a preventative vaccine for HIV infection. VGX Pharmaceuticals plans to file three additional INDs for its SynCon™ DNA vaccine candidates during the first two quarters of 2008: VGX-3100, a therapeutic vaccine for the treatment for cervical cancer; VGX-3200, a therapeutic based on human growth hormone releasing hormone (GHRH) for cancer-related cachexia (wasting or heavy weight loss); and VGX-3400, a pandemic avian flu vaccine. All of these vaccines are delivered by the CELLECTRA™ device.

VGX Pharmaceuticals operates a 500-liter scale cGMP DNA plasmid manufacturing facility in The Woodlands, Texas. In addition, the Company has initiated a project to build and operate a 3000-liter cGMP manufacturing facility in Korea with its affiliate, VGX International.

http://www.vgxp.com

Cornell researchers are using advanced genetic techniques to better understand the relationship between the bacteria that cause tuberculosis and the human immune system defense cells that engulf them.

The researchers have discovered that unlike many bacterial pathogens, Mycobacterium tuberculosis does not react when immune system cells called macrophages initially make contact; but the bacterium’s genes become activated minutes after the pathogen is enveloped by a macrophage and contained in one of its membrane-bound compartments called vacuoles.

David Russell, professor of molecular microbiology at Cornell’s College of Veterinary Medicine, and colleagues reported in a November issue of the journal Cell Host and Microbe, that increased acidity inside the vacuoles containing the bacteria serves as the trigger for M. tuberculosis genes to express proteins.

The study also compared the responses of M. tuberculosis to a live bacterial vaccine against tuberculosis known as Bacillus Calmette-Guerin (BCG). It found that the two bacteria may each respond differently to the same stimuli and that BCG appears less capable of protecting itself once inside a macrophage. The findings are consistent with the reduced virulence of BCG, which is key to its safety as a vaccine.

The study is a small part of a larger plan to understand the processes that allow the bacteria to survive within macrophages and then to use that knowledge to develop more effective drugs to fight tuberculosis, which currently kills 2 million people worldwide each year. Existing drugs require six to nine months to treat the active disease that invades and replicates within the lungs.

“What we propose is the exploitation of the data obtained from these basic science studies to develop a comprehensive program of drug development that targets bacterial processes critical to survival inside the human host,” said Russell.

Russell’s lab used gene chips, or microarrays, to identify genes activated under specific environmental conditions. This allowed them to generate real-time readouts of bacterial health and their response to stress. The researchers have also created real-time readouts that measure conditions within the tuberculosis-containing vacuole at any time during the immune system’s process.

“Our goal is to develop these bacterial fitness readouts to screen small molecule libraries for compounds that will kill M. tuberculosis inside the macrophage,” said Russell. “Unfortunately, Cornell does not have either the instrumentation or the chemical libraries necessary to do this work, so I am trying different, private funding agencies to get the support to purchase equipment and libraries.”