Couple of interesting MS articles:
sciencedaily.com
Enhanced White Blood Cells Heal Mice With MS-Like Disease
June 1, 2013 — Genetically engineered immune cells seem to promote healing in mice infected with a neurological disease similar to multiple sclerosis (MS), cleaning up lesions and allowing the mice to regain use of their legs and tails.
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The new finding, by a team of University of Wisconsin School of Medicine and Public Health researchers, suggests that immune cells could be engineered to create a new type of treatment for people with MS.
Currently, there are few good medications for MS, an autoimmune inflammatory disease that affects some 400,000 people in the United States, and none that reverse progress of the disease.
Dr. Michael Carrithers, assistant professor of neurology, led a team that created a specially designed macrophage -- an immune cell whose name means "big eater." Macrophages rush to the site of an injury or infection, to destroy bacteria and viruses and clear away damaged tissue. The research team added a human gene to the mouse immune cell, creating a macrophage that expressed a sodium channel called NaVI.5, which seems to enhance the cell's immune response.
But because macrophages can also be part of the autoimmune response that damages the protective covering (myelin) of the nerves in people with MS, scientists weren't sure whether the NaV1.5 macrophages would help or make the disease worse.
When the mice developed experimental autoimmune encephalomyelitis -- the mouse version of MS -- they found that the NaV1.5 macrophages sought out the lesions caused by the disease and promoted recovery.
"This finding was unexpected because we weren't sure how much damage they would do, versus how much cleaning up they would do,'' Carrithers says. "Some people thought the mice would get more ill, but we found that it protected them and they either had no disease or a very mild case."
In follow-up experiments, regular mice that do not express the human gene were treated with the NaV1.5 macrophages after the onset of symptoms, which include weakness of the back and front limbs. The majority of these mice developed complete paralysis of their hindlimbs. Almost all of the mice that were treated with the Na1.5 macrophages regained the ability to walk. Mice treated with placebo solution or regular mouse macrophages that did not have NaV1.5 did not show any recovery or became more ill. In treated mice, the research team also found the NaV1.5 macrophages at the site of the lesions, and found smaller lesions and less damaged tissue in the treated mice.
Because the NaV1.5 variation is present in human immune cells, Carrithers says, "The questions are, 'Why are these repair mechanisms deficient in patients with MS and what can we do to enhance them?' '' He says the long-range goal is to develop the NaV1.5 enhanced macrophages as a treatment for people with MS.
Carrithers is a neurologist who treats patients with multiple sclerosis at University of Wisconsin Hospital and Clinics and the William S. Middleton Veterans' Hospital in Madison. His research team includes Kusha Rahgozar, Erik Wright and Lisette Carrithers. The research was supported by a prior National MS Society research grant and a current VA Merit Award from the Biomedical Laboratory Research and Development service of the Department of Veterans Affairs (7784115).
healthcanal.com
NIH scientists find link between allergic and autoimmune diseases in mouse study
14 hours 1 minute ago
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Scientists at the National Institutes of Health, and their colleagues, have discovered that a gene called BACH2 may play a central role in the development of diverse allergic and autoimmune diseases, such as multiple sclerosis, asthma, Crohn's disease, celiac disease, and type-1 diabetes.
In autoimmune diseases, the immune system attacks normal cells and tissues in the body that are generally recognized as “self” and do not normally trigger immune responses. Autoimmunity can occur in infectious diseases and cancer.
The results of previous research had shown that people with minor variations in the BACH2 gene often develop allergic or autoimmune diseases, and that a common factor in these diseases is a compromised immune system. In this study in mice, the Bach2 gene was found to be a critical regulator of the immune system’s reactivity. The study, headed by researchers at the National Cancer Institute (NCI) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), both part of NIH, and their colleagues appeared online in Nature, June 2, 2013.
 The finding that a single component of the immune system plays such a broad role in regulating immune function may explain why people with allergic and autoimmune diseases commonly have alterations in the BACH2 gene, said NCI researcher Rahul Roychoudhuri, M.D. "This may be the first step in developing novel therapies for these disorders."
Schematic of balance between tolerance and inflammation mediated by BACH2
Studies known as genome-wide association studies, which analyze genetic variants among people to determine whether specific variants are associated with particular traits, were critical to the discovery. These studies showed that DNA from patients with diverse autoimmune disorders often had minor alterations in the BACH2 gene, which laid the foundation for this research.
“What was exciting was the opportunity to apply cutting-edge technology permitted by the completion of the Human Genome Project,” said NIAMS scientific director John O’Shea, M.D. “Using genome-wide approaches we were able to map the action of Bach2 across all genes. This enabled us to gain a clearer understanding of Bach2’s key role in the immune system.”
The immune system is comprised of a variety of cell types that must act in unison to maintain a healthy balance. White blood cells called CD4+T cells play a dual role within the immune system. Some CD4+T cells activate immune responses, whereas others, called regulatory T cells, function in the opposite direction by constraining immune responses. This duality is important because uncontrolled immune responses may result in immune system attacks against the body’s own cells and tissues, which occurs in allergic and autoimmune diseases. One of the hallmarks of uncontrolled immune responses is excessive tissue inflammation. Although tissue inflammation is a normal part of immune responses, excessive inflammation can lead to tissue and organ damage and may be potentially lethal. How CD4+T cells become either activating/inflammatory or regulatory is not well understood, according to the researchers.
“We found that the Bach2 gene played a key role in regulating the switch between inflammatory and regulatory cells in mice,” said NIAMS researcher Kiyoshi Hirahara, M.D. “The loss of the Bach2 gene in CD4+ T cells caused them to become inflammatory, even in situations that would normally result in the formation of protective regulatory cells.”
The team found that if mice lacked the Bach2 gene their cells became inflammatory and the mice died of autoimmune diseases within the first few months of life. When they re-inserted Bach2 (using gene therapy) into Bach2-deficient cells, their ability to produce regulatory cells was restored.
"Although genes have been found that play specific roles in either inflammatory cells or regulatory cells, Bach2 regulates the choice between the two cell types, resulting in its critical role in maintaining the immune system’s healthy balance," said NCI principal investigator, Nicholas P. Restifo, M.D., "It’s apt that the gene shares its name with the famous composer Bach, since it orchestrates many components of the immune response, which, like the diverse instruments of an orchestra, must act in unison to achieve symphonic harmony."
Restifo suggests that these findings have implications for cancer as well, since cancers co-opt regulatory T cells to prevent their own destruction by antitumor immune responses. He and his colleagues are now working toward manipulating the activity of the Bach2 gene, with the goal of developing a new cancer immunotherapy. Also, as this study was in mice, it must be replicated in humans before its findings can be applied in a clinical setting.
In addition to researchers from NCI and NIAMS, this research was supported by the JSPS Research Fellowship for Japanese Biomedical and Behavioural Researchers at NIH and includes contributions from scientists at the National Institutes of Allergy and Infectious Diseases, NIH; the Department of Transfusion Medicine, NIH; the Division of Veterinary Resources, NIH; the Center for Regenerative Medicine, NIH; the Sidra Medical and Research Centre, Doha, Qatar; and the Department of Biochemistry, Tohoku University, Sendai, Japan. |
