The Immune System Enables HIV-Infected T Cells To Transport The Virus Throughout The Body

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Main Category: HIV / AIDS
Also Included In: Immune System / Vaccines
Article Date: 03 Aug 2012 - 0:00 PDT Current ratings for:
The Immune System Enables HIV-Infected T Cells To Transport The Virus Throughout The Body

A new study has discovered one more way the human immunodeficiency virus (HIV) exploits the immune system. Not only does HIV infect and destroy CD4-positive helper T cells - which normally direct and support the infection-fighting activities of other immune cells - the virus also appears to use those cells to travel through the body and infect other CD4 T cells. The study from Massachusetts General Hospital (MGH) investigators, which will appear in the journal Nature and has received advance online release, is the first to visualize the behavior of HIV-infected human T cells within a lymph node of a live animal, using a recently developed "humanized" mouse model of HIV infection.

"We have found that HIV disseminates in the body of an infected individual by 'hitching a ride' on the T cells it infects," says Thorsten Mempel, MD, PhD, of the MGH Center for Immunology and Inflammatory Diseases, who led the study. "Infected T cells continue doing what they usually do, migrating within and between tissues such as lymph nodes, and in doing so they carry HIV to remote locations that free virus could not reach as easily. There are drugs that can manipulate the migration of T cells that potentially could be used to help control the spread of virus within a patient."

When HIV is introduced into blood or tissues, the virus binds to CD4 molecules on the surface of helper T cells, injecting its contents into cells and setting off a process that leads to the assembly and release of new virus particles. It has long been assumed that these free virus travel by diffusion through tissue fluids to encounter new cells that can be infected. But recent studies have suggested that HIV can also pass directly from cell to cell when structures called virological synapses form during long-lasting interactions between T cells. Since CD4 T cells usually migrate quickly and form only transient contacts with other cells, the current study was designed to examine whether HIV alters the migration of infected T cells, allowing the kind of persistent contact that facilitates the spread of infection.

The team's experiments used the humanized BLT mouse model, which has what is essentially a human immune system and is the only non-primate that can be infected with HIV. After first confirming that human T cells enter and normally migrate within the animals' lymph nodes - known to be important sites of HIV replication - the researchers injected the animals with HIV engineered to express green fluorescent protein (GFP), allowing them to track the movement of infected cells within living animals using a method called intravital microscopy. They first observed that, within two days, infected T cells continued to migrate and were uniformly distributed within lymph nodes but remained in nodes closest to the site of injection.

While the HIV-infected cells actively moved within lymph nodes, they did not move as quickly as comparable but uninfected T cells. In addition, 10 to 20 percent of the HIV-infected T cells formed abnormally long and thin extensions that appeared to trail behind moving cells, often exhibiting branches.

The researchers hypothesized that the HIV envelope protein, which is expressed on the surface of infected T cells before they release new virus particles, might cause infected cells to form tethering contacts with uninfected cells, producing these extensions. A series of experiments verified that the elongated shape of some infected cells requires the presence of the envelope protein and that many of the elongated cells contained multiple nuclei, suggesting they had been formed by the fusion of several cells.

To test the role of T cell migration in HIV infection, the researchers injected another group of BLT mice with HIV and at the same time treated them with an agent that prevents T cells from leaving lymph nodes. Two months later, levels of HIV in the bloodstream and in lymph nodes distant from the site of injection were much lower than in untreated HIV-infected animals, supporting the importance of T cell migration to carry virus throughout the body. Treatment with the migration-suppressing agent, however, did not reduce viral levels in animals with already established HIV infection.

"While our observation of tethering interactions between infected and uninfected CD4-expressing cells suggest that HIV may be transmitted between T cells by direct contact, we will have to clearly show this in future studies and explore how important it is relative to the transmission by free virus," explains Mempel, an assistant professor of Medicine at Harvard Medical School. He adds that the availability of the BLT mouse was instrumental in their ability to carry out this study. "This approach provides a new vantage point to investigate previously unexplored aspects of HIV pathogenesis."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our hiv / aids section for the latest news on this subject. Lead author of the Nature paper is Thomas Murooka, PhD, of the MGH Center for Immunology and Inflammatory Diseases (CIID). Additional co-authors are Maud Deruaz, PhD, Francesco Marangoni, PhD, Vladimir Vrbanac, DVM, Edward Seung, PhD, Andrew Tager, MD, and Andrew Luster, MD, PhD, MGH CIID; and Ulrich von Andrian, Harvard Medical School. The study was supported by grants from the National Institutes of Health and the Ragon Institute of MGH, MIT and Harvard.
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'The Immune System Enables HIV-Infected T Cells To Transport The Virus Throughout The Body'

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Ability Of Brown Fat To Burn Calories Linked To Immune Cells

Main Category: Obesity / Weight Loss / Fitness
Article Date: 15 Dec 2011 - 0:00 PST

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Throughout the interior spaces of humans and other warm-blooded creatures is a special type of tissue known as brown fat, which may hold the secret to diets and weight-loss programs of the future.

Unlike ordinary "white" fat, in which the body stores excess calories, brown fat can burn calories to heat up the body. It's one of the things that helps keep wild critters warm on cold nights.

Investigating how brown fat works in mice, a team of researchers at the University of California, San Francisco (UCSF) has uncovered what may be a holdover from our evolutionary past: in response to cold, tiny immune cells known as macrophages can switch on the brown fat, inducing it to burn energy to make heat.

Prior to this research, published last month in the journal Nature, scientists had assumed that brown fat metabolism was completely controlled by the brain. But the UCSF research suggests that the immune system plays a backup role in this process - a legacy, perhaps, of some ancient ancestral creature whose metabolic and immune systems were much more intertwined.

"This is a very important secondary system that the body uses to provide a backup for the thermal stress response," said Ajay Chawla, MD, PhD, an associate professor at UCSF's Cardiovascular Research Institute who led the research. "It raises the possibility that we can perhaps modulate this program and enhance it in humans to rev up metabolism."

Immune Cells Found Inside Brow

The modern human immune system relies on these macrophages to gobble up bacteria, helping protect us against infection. Macrophages were never known to play a role in metabolism, but the evidence Chawla and his colleagues gathered suggests otherwise.

Using brown fat to burn calories and produce heat is one of the ways that mammals maintain thermoregulation - an essential adaptation that defines warm blooded creature and enables them to thrive in the face of challenging environmental extremes. Not all animals share this ability.

Many animals, like lizards, are "cold blooded" or exothermic. They maintain their body temperature through completely external means, sunbathing at certain times of the day and huddling in warm, protective places at night. This naturally limits their range and explains why lizards, so abundant in tropical climates, are far rarer in cold climates.

Mammals, on the other hand, are "warm-blooded" or endothermic. They produce heat internally by a variety of means: shivering, sweating, regulating the size of their blood vessels and burning off excess calories in brown fat.

Scientists have known for years that brown fat burns calories in response to signals from the brain. These signals cause break down of molecules known as triglycerides in white fat, which are then released into the bloodstream as fatty acids. These circulating fatty acids are taken up by brown fat and burned to generate heat. Brown fat is full of blood vessels, and the heat warms the blood, which in turn circulates and warms the body.

The brain controls this process by monitoring the body's temperature and, in face of extreme cold, releasing a hormone called norepinephrine, which kick-starts the brown fat.

The work of the UCSF team showed that macrophage cells within the brown fat can also do this directly. Macrophages residing in brown and white fat produce an enzyme that makes norepinephrine when mice are exposed to the cold. This leads to the production, the breakdown and mobilization of stored fat, which is then burned in brown fat to produce heat.

What these results suggest, Chawla said, is that immune cells help facilitate the function of brown fat.

Mammals today have evolved to have separate systems for immunity and metabolism. But flies, for instance, have combined the equivalent functions of the human liver, fat and immune system into one organ: a tissue referred to as its fat body. Mammalian macrophages may have some functions related to this shared origin.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. The article, “Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis” by Khoa D. Nguyen, Yifu Qiu, Xiaojin Cui, Y. P. Sharon Goh, Julia Mwangi, Tovo David, Lata Mukundan, Frank Brombacher, Richard M. Locksley and Ajay Chawla appeared in the Nov. 20 issue of Nature.
In addition to UCSF, the authors of this study are affiliated with Stanford University and the University of Cape Town, South Africa.
This work was funded by grants from the National Institutes of Health and the Larry L. Hillblom Foundation; by an National Institutes of Health Director’s Pioneer Award; and by Stanford Graduate and
A-STAR Fellowships.
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Intestine Crucial To Function Of Immune Cells, Research Shows

Main Category: Immune System / Vaccines
Also Included In: GastroIntestinal / Gastroenterology;  Arthritis / Rheumatology;  Multiple Sclerosis
Article Date: 15 Dec 2011 - 0:00 PST

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Researchers at the University of Toronto have found an explanation for how the intestinal tract influences a key component of the immune system to prevent infection, offering a potential clue to the cause of autoimmune disorders like rheumatoid arthritis and multiple sclerosis.

"The findings shed light on the complex balance between beneficial and harmful bacteria in the gut," said Prof. Jennifer Gommerman, an Associate Professor in the Department of Immunology at U of T, whose findings were published online by the scientific journal, Nature. "There has been a long-standing mystery of how certain cells can differentiate between and attack harmful bacteria in the intestine without damaging beneficial bacteria and other necessary cells. Our research is working to solve it."

The researchers found that some B cells - a type of white blood cell that produces antibodies - acquire functions that allow them to neutralize pathogens only while spending time in the gut. Moreover, this subset of B cells is critical to health.

"When we got rid of that B-cell function, the host was unable to clear a gut pathogen and there were other negative outcomes, so it appears to be very important for the cells to adopt this function in the gut," said Prof. Gommerman, whose lab conducted the research in mice.

Textbook immunology - based mostly on research done in the spleen, lymph nodes or other sterile sites distant from gut microbes - has suggested that B cells develop a specific immune function and rigidly maintain that identity. Over the last few years, however, some labs have shown the microbe-rich environment of the gut can induce flexibility in immune cell identity.

Prof. Gommerman and her colleagues, including trainees from her lab Drs. Jörg Fritz, Olga Rojas and Doug McCarthy, found that as B cells differentiate into plasma cells in the gut, they adopt characteristics of innate immune cells - despite their traditional association with the adaptive immune system. Specifically, they begin to look and act like inflammatory cells called monocytes, while maintaining their ability to produce a key antibody called Immunoglobulin A.

"What intrigued us was that this theme - B cells behaving like monocytes - had been seen before in fish and in vitro. But now we have a living example in a mammalian system, where this kind of bipotentiality is realized," said Prof. Gommerman.

This B-cell plasticity provides a potential explanation how cells dedicated to controlling pathogens can respond to a large burden of harmful bacteria without damaging beneficial bacteria and other cells essential for proper function of the intestine.

It also may explain how scientists had failed to appreciate the multi-functionality of some B cells. "There are classical markers immunologists use to identify B cells - receptors that are displayed on their surface - and most of them are absent from plasma cells," said Prof. Gommerman. "So in some cases, what people thought was a monocyte could have been a plasma cell because it had changed its surface identity, although monocytes play an important role in innate immunity as well."

This transformational ability, the researchers also found, is dependent on bacteria called commensal microflora that digests food and provides nutrients. That relationship highlights the importance of the gut in fighting infection, and begs the question of whether plasma cells trained in the gut to secrete specific anti-microbial molecules can play a role in other infectious disease scenarios, such as food-borne listeria infection.

It also opens a line of investigation into whether a systemic relationship exists between those anti-microbial molecules and healthy cells in sites remote from the intestine. Understanding the nature of that relationship could improve understanding of inflammatory mechanisms in autoimmune disorders such as lupus, rheumatoid arthritis and multiple sclerosis, in which immune cells attack and eventually destroy healthy tissue.

But the next step, said Prof. Gommerman, is to look at human samples for the same type of multi-potentiality they saw in rodent plasma cells that acquired their anti-microbial properties in the gut.

"We're really at the early stages of understanding what we call the microbiome in the gut," said Prof. Gommerman. "There is a role for plasma cells in many autoimmune diseases, and B cells can do a lot more than just make antibodies. We need to understand the full spectrum of their effects within the immune response."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our immune system / vaccines section for the latest news on this subject. The study was funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the Ontario Research Fund, the Austrian Academy of Sciences and the National Institutes of Health.
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Immune Response To Multiple Myeloma Stimulated By Peptide 'Cocktail'

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Immune System / Vaccines
Article Date: 13 Dec 2011 - 4:00 PST

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Scientists at Dana-Farber Cancer Institute have created a "cocktail" of immune-stimulating peptides they believe could provoke the body's defenses to attack multiple myeloma in its early "smoldering" phase and slow or prevent the blood cancer.

Based on laboratory results (abstract 3990) presented at the annual meeting of the American Society of Hematology, the researchers say the immunotherapy approach merits testing in human clinical trials.

The combination of four antigenic peptides derived from myeloma cells sparked a stronger diverse response from immune defenses in laboratory culture than any of the individual peptides, according to the team, led by first author Jooeun Bae, PhD, and senior author Nikhil Munshi, MD.

"Thus, targeting multiple myeloma-associated antigens using a cocktail of specific peptides may provide an effective therapeutic application" in patients with the blood cancer and related diseases, the authors wrote.

Multiple myeloma, in which abnormal blood cells accumulate in bones and other organs, causing life-threatening malfunctions, will be diagnosed in about 20,520 Americans in 2011, according to American Cancer Society estimates, and there will be some 10,610 deaths.

Immunotherapy - getting the body's immune system to recognize cancer cells as "foreign" and then unleash a defensive reaction against them - has proven difficult in multiple myeloma. This type of therapy, also referred to as "cancer vaccines," relies on using a peptide - a piece of a protein from the myeloma cell itself - to spark an immune response.

But multiple myeloma, like many cancers, is a shape-shifting foe: Its tumor-associated antigens can appear and disappear, or undergo mutations that change their identity sufficiently to escape immune detection. For this reason, explained Munshi, previous efforts using a single myeloma antigen have failed to elicit effective immune responses against the disease.

In the new study, the Dana-Farber scientists reasoned that challenging the immune system with not just one, but several myeloma antigens would stand a better chance of prompting a strong reaction. So they identified four antigenic myeloma peptides and tested the ability of each of them to stir a reaction by immune T-cells in a laboratory dish.

Next, the researchers combined all four myeloma peptides into a cocktail: The combination prompted a greater multi-target defensive response against myeloma cells than any of the individual peptides.

Because the myeloma antigens they are studying are derived from human cells, the concept cannot be tested in animals, Munshi says, and therefore the next step will be to administer them in a clinical trial to patients with an early, or "smoldering," form of the blood cancer for which they are not receiving any treatment.

"Some of these patients won't develop the full-blown disease, or won't develop it for several years," Munshi explains. "We would like to find out if giving this peptide cocktail might prevent them from progressing.

"This is an exciting possibility," Munshi adds, "because these patients have good immune systems, and currently there's nothing we can do for them."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject. Funding for this work was provided by Dana-Farber Cancer Institute.
Co-authors include: Ruben Carrasco, MD, PhD, Weihua Song, MD, Rao Prabhala, PhD and Kenneth C. Anderson, MD, of Dana-Farber and Ann-Hwee Lee, PhD, of Harvard Medical School.
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Immune System Repaired In Leukemia Patients Following Chemotherapy

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Immune System / Vaccines
Article Date: 13 Dec 2011 - 0:00 PST

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A new treatment using leukemia patients' own infection-fighting cells appears to protect them from infections and cancer recurrence following treatment with fludarabine-based chemotherapy, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The new process is a step toward eliminating the harsh side effects that result from the commonly prescribed drug, which improves progression-free survival in patients with chronic lymphocytic leukemia (CLL) but destroys patients' healthy immune cells in the process, leaving them vulnerable to serious viral and bacterial infections. The drug's effects on the immune system tend to be so violent that it has been dubbed "AIDS in a bottle."

At the 53rd American Society of Hematology Annual Meeting, the research team presented results showing how they use a patient's own T cells to repair his or her immune system after fludarabine treatment. With a restored immune system, patients can stop taking prophylactic antibiotics and may have prolonged progression-free survival.

"Fludarabine is a double-edged sword," says Stephen J. Schuster, MD, an associate professor in the division of Hematology-Oncology and director of the Lymphoma Program at Penn's Abramson Cancer Center. "Although it is very active at killing CLL cells, it is also very active at killing normal cells in the immune system, particularly T lymphocytes, which are the master regulators of the immune system. So you rid the patient of their disease, but you also rid them of a normal immune system."

Thirty-four patients enrolled in the multicenter study. Prior to chemotherapy treatment, the researchers isolated healthy T lymphocytes from each patient's blood. When the patient finished chemotherapy, the team grew the T cells in Penn's Clinical Cell and Vaccine Production Facility using a technique that induces them to proliferate rapidly. The researchers then infused the expanded T cells back into the patient. "What we showed was that by giving them back their own T cells after treatment, we can restore patients' immune systems," Schuster said.

"Within four weeks of the T cell infusion, their T cell counts were within the normal range."

After chemotherapy and prior to T cell infusion, the median CD4 T cell count for fludarabine-treated patients was 119 cells/ml blood and the median CD8 T cell count was 80 cells/ml. Thirty days after the patients received the infusion of their own T cells, the median cell counts were in the normal range, at 373 cells/ml and 208 cells/ml for CD4 and CD8 cells, respectively. The T cell numbers remained in the normal range beyond 90 days, leading Schuster and colleagues to conclude that the autologous T cell transfer repaired the immune system of patients.

Although all of the patients' T cell counts returned to the normal range after treatment, not all patients responded equally well to the T cell therapy. Patients who had a complete response to chemotherapy had a more robust T cell recovery than did patients who had only a partial response. "We believe that having a complete remission of CLL seems to create a larger space for the normal immune cells to expand into," Schuster says. "Somehow, the cancer seems to interfere with recovery of the immune system."

In addition to quashing the complications ordinarily associated with treatment, the team hopes that the restored immune system will help keep the cancer in check. At a median follow-up of 14 months after T cell infusion, two-thirds of the patients remain progression-free. Longer follow up will be needed to compare treatment results for patients receiving T cells with published results for patients receiving similar chemotherapy without T cell support.

What is clear from the small trial is that patients can safely stop prophylactic antibiotic therapy after their T cell numbers rebound. Physicians regularly keep CLL patients on extended prophylactic antibiotic therapy to help stave off infections. In this study, though, patients stopped taking antibiotics about a month after receiving T cells without developing significant infections.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our lymphoma / leukemia / myeloma section for the latest news on this subject. In addition to the Penn researchers, investigators from the MD Anderson Cancer Center, the Baylor College of Medicine, Texas Children's Hospital, and the Methodist Hospital in Houston also participated in the study.
The study was funded by the CLL Global Research Foundation.
This research was presented Sunday, December 11, 2011 between 6 PM and 8 PM in Hall GH of the San Diego Convention Center.
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Promising Multiple Sclerosis Treatment Targets Immune Cells To Increase Neuroprotection

Main Category: Multiple Sclerosis
Article Date: 08 Dec 2011 - 0:00 PST

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Laquinimod is an orally available synthetic compound that has been successfully evaluated in phase II/III clinical studies for the treatment of relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of laquinimod has not been fully elucidated, but a study published in the January 2012 issue of The American Journal of Pathology suggests that laquinimod triggers immune cells within the central nervous system to produce and release brain-derived neurotrophic factor (BDNF), contributing to the repair or survival of neurons and thus limiting brain damage.

"Our data are indicative of a direct and sustained effect of laquinimod on the up-regulation of bioactive BDNF in patients with RRMS. Additionally, we demonstrate that laquinimod targets monocytes and skews the phagocyte population towards a regulatory phenotype, which in turn mediates immune modulation in vivo," explained Jan Thöne, MD, of the Department of Neurology at St. Josef-Hospital Bochum and Ruhr-University Bochum, Germany.

Neurotrophins, such as BDNF, are essential for the development and maintenance of neurons and axons in the central nervous system. Although BDNF is mainly produced by neurons, several types of immune cells also secrete BDNF, suggesting a role in neuroprotection.

To elucidate the mechanism of action of laquinimod, and to explore its potential neuroprotective capacity, the researchers evaluated levels of BDNF in the serum of RRMS patients treated with laquinimod in phase II clinical trials. A significant and robust BDNF increase occurred in 76% of the laquinimod-treated patients, with up to an 11-fold increase in BDNF serum levels observed in individual patients. BDNF elevation in individual patients was independent of relapse rate, and there was no correlation between BDNF levels and age, gender, or baseline disability. Yet, the source of serum BDNF subsequent to treatment remained questionable.

Experiments with animal models corroborated the findings in human patients. Experimental autoimmune encephalomyelitis (EAE; a model of MS) was induced in mice with a conditional BDNF deficiency in immune cells (LLF mice) and in wild-type (WT) control mice. Treatment with laquinimod resulted in a significant reduction in EAE incidence and disease severity in the WT mice. The effect of laquinimod was significantly reduced in the LLF-mice.

Further studies showed that WT mice treated with a suboptimal dose of laquinimod demonstrated a significant reduction in the inflammatory area and level of demyelination. These mice also displayed a reduction of macrophage infiltration and a significant preservation of axonal densities in comparison with laquinimod-treated LLF mice and controls. The data suggest a BDNF-dependent mechanism of action for laquinimod in autoimmune demyelination.

To investigate whether laquinimod-treated monocytes mediate immune modulation in vivo, laquinimod-stimulated monocytes were injected into WT mice at an early EAE disease stage. The mice showed less severe disease course than controls. Transfer of laquinimod-treated cells derived from LLF mice into WT mice with ongoing EAE did not influence disease course. The cells also secrete significantly less IL-10, an immunomodulatory cytokine that is associated with the generation of regulatory monocytes.

"Consistent with immunomodulatory properties, laquinimod skewed monocytes towards a regulatory phenotype and also acted via modulation of BDNF, which may contribute to neuroprotection in MS patients," said Dr. Thöne. "To date, selective targeting of monocytes has not been described for any other MS pipeline drug, highlighting an innovative mechanism of action of laquinimod."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our multiple sclerosis section for the latest news on this subject. The article is "Modulation of Autoimmune Demyelination by Laquinimod via Induction of Brain Derived Neurotrophic Factor," by J. Thöne, G. Ellrichmann, S. Seubert, I. Peruga, D-H. Lee, R. Conrad, L. Hayardeny, G. Comi, S. Wiese, R.A. Linker, R. Gold (doi: 10.1016/j.ajpath.2011.09.037). It will appear in The American Journal of Pathology, Volume 10, Issue 1 (January 2012) published by Elsevier.
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