Gene editing reverses Huntington's in mouse model

This is a concrete example, not yet clinical, of what can be done with CRISPR/Cas9 gene Read more

Urine tests for prostate cancer could reduce biopsies

Urine RNA tests could reduce the number of biopsies by giving a preview of a cancer's aggressiveness. Featuring Martin Sanda and Carlos Read more

Mitochondrial blindness -- Newman's Emory story

Neuro-ophthalmologist Nancy Newman’s 2017 Dean’s Distinguished Faculty Lecture and Award were unexpectedly timely. Her talk on Tuesday was a tour of her career and mitochondrial disorders affecting vision, culminating in a description of gene therapy clinical trials for the treatment of Leber’s hereditary optic neuropathy. The sponsor of those studies, Gensight Biologics, recently presented preliminary data on a previous study of their gene therapy at the American Academy of Neurology meeting in April. Two larger trials Read more

Immunology

Anti-inflammatory drug prevents neuron loss in Parkinson’s model

A lot of evidence has piled up suggesting that inflammation plays a big role in the progression of Parkinson’s.

Immune system genes are linked to disease risk. People who regularly take NSAIDs such as ibuprofen have lower risk. Microglia, the immune system’s ambassadors to the brain, have been observed in PD patients.

Malu Tansey and her postdoc CJ Barnum make a convincing case for an anti-inflammatory — specifically, anti-TNF– therapy to Parkinson’s. They’ve been working with the Michael J. Fox Foundation for Parkinson’s Research to push this promising approach forward. Please check it out.

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Cancer immunotherapy, meet chimera

697px-Chimera_d'arezzo,_fi,_03

In Greek mythology, the chimera was a monstrous fire-breathing creature composed of the parts of three animals: a lion, a snake and a goat.

Adoptive cell transfer is advancing as a cancer immunotherapy technique. It involves removing some of a patient’s immune cells, culturing them in the laboratory, and then infusing the cells back into the patient. The idea is to enhance the ability of the immune cells to attack the tumors far beyond what the immune system was able of doing on its own.

Two promising examples are the National Cancer Institute’s approach of treating advanced melanoma with IL-2-stimulated immune cells, and several investigators’ approach of genetically engineering T cells to attack leukemias or lymphomas.

Jacques Galipeau and colleagues at Winship Cancer Institute have developed a chimeric molecule for stimulating immune cells, which appears to have unique powers beyond simply the sum of its two parts. The molecule is called GIFT4, a fusion of the immune signaling molecules GM-CSF (often used in cancer treatment) and IL-4.

Read more

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Freezing stem cells disrupts their function

What applies to meat, vegetables and fish may also apply to cells for use in cell therapy: frozen often isn’t quite as good.

Ian Copland and colleagues from Emory’s Personalized Immunotherapy Center have a paper this week in Stem Cells Reports discussing how freezing and thawing stem cells messes them up. Specifically, it disrupts their actin cytoskeletons and impairs their ability to find their niches in the body. Culturing the cells for 48 hours after thawing does seem to correct the problem, though.

The findings have some straightforward implications for researchers planning to test cell therapies in clinical applications. The authors conclude:

Until such time as a cryopreservation and thawing procedure can yield a viable and fully functional MSC product immediately after thawing, our data support the idea of using live MSCs rather than post-thaw cryo MSCs for clinical evaluation of MSCs as an immunosuppressive agent.

Notably, the Emory Personalized Immunotherapy Center has built a process designed around offering never-frozen autologous (that is, the patient’s own) mesenchymal stem cells, as therapies for autoimmune disorders such as Crohn’s disease.

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Oink! — Glycan receptors for flu viruses

Pigs are natural hosts for influenza viruses that can infect humans, in particular the 2009 and, going way back, 1918 H1N1 flu strains. So to understand how influenza infections spread in the body, biochemists and virologists look at pigs.

Biochemistry chair Rick Cummings’ group has a paper in PNAS this week examining the carbohydrates or glycans on the surfaces of pig lung cells, using their “shotgun glycomics” library approach. MMG graduate student Lauren Byrd-Leotis is the first author.Piglung

“The results illustrate the repertoire of specific, endogenous N-glycans of pig lung glycoproteins for virus recognition and offer a new direction for studying endogenous glycan functions in viral pathogenesis,” the team reports.

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Whole exome sequencing in IBD

Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.

Subra Kugathasan, MD

Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.

The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.

As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.

The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:

Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].

Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.

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Two angles on cell death

One can take two very different angles when approaching Bill Kaiser’s and Ed Mocarski’s work on RIP kinases and the mechanisms of cell death. These are: the evolutionary where-does-apoptosis-come-from angle, and the anti-inflammatory drug discovery angle.

A pair of papers published this week, one in PNAS and one in Journal of Immunology, cover both of these angles. (Also, back to back papers in Cell this week, originating from Australia and Tennessee, touch on the same topic.)

First, the evolutionary angle.

Cellular suicide can be a “scorched earth” defense mechanism against viruses. Kaiser and Mocarski have been amassing evidence that some forms of cellular suicide arose as a result of an arms race of competition with viruses. The PNAS paper is part of this line of evidence. It shows that the cell-death circuits controlled by three different genes (RIP1, RIP3 and caspase 8) apparently can be lifted cleanly out of an animal. Mice lacking all three genes not only can be born, but have well-functioning immune systems.

Apoptosis is thought to be a form of cellular suicide important for the development of all multicellular organisms. That’s why, to cell and developmental biologists, it seemed rather shocking that researchers can mutate a group of genes that drive apoptosis and other forms of cellular suicide and have adult animals emerge.

Next, the drug discovery angle.

The J. Immunol paper makes that angle clear enough. Most of the authors on this paper are from GlaxoSmithKline’s “Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area.” Here, they show that a mutation in RIP1 inactivating the kinase enzyme protects mice against severe skin and multiorgan inflammation. They conclude their abstract with: “Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.”

Note: TNF-driven inflammatory diseases include rheumatoid arthritis, inflammatory bowel diseases and psoriasis, representing a multibillion dollar market.

 

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How CMV gets around

Human cytomegalovirus infects most people in the United States by the time they are 40 years old. HCMV is usually harmless in children and adults, but when pregnant women are infected for the first time, the infection can lead to hearing, vision or other problems in their babies once they are born. [It is also a problem for organ transplant recipients.] According to the Centers for Disease Control and Prevention, HCMV is usually transmitted by sexual contact, diapers or toys. Notably absent are references to needles. That means scientists who study how mouse CMV infection takes place by injecting the virus into the animal’s body are missing a critical step.

Postdoc Lisa Daley-Bauer, working with CMV expert Ed Mocarski, has a recent paper in the journal Cell Host & Microbe illuminating how the virus travels from sites of initial infections to the rest of the body. Defining the cells the virus uses to get around could have implications for efforts to design a HCMV vaccine.

The virus hijacks part of the immune system, the authors find. CMV emits its own attractant (or chemokine) for patrolling monocytes, a type of white blood cell that circulates in the skin and peripheral tissues. This attractant, called MCK2, is only important when mice are infected by footpad inoculation, not by systemic injection.

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Two heavy hitters in this week’s Nature

Two feature articles in Nature this week on work by Emory scientists.

One is from Virginia Hughes (Phenomena/SFARI/MATTER), delving into Kerry Ressler’s and Brian Dias’ surprising discovery in mice that sensitivity to a smell can be inherited, apparently epigenetically. Coincidentally, Ressler will be giving next week’s Dean’s Distinguished Faculty lecture (March 12, 5:30 pm at the School of Medicine).

Another is from Seattle global health writer Tom Paulson, on immunologist Bali Pulendran and using systems biology to unlock new insights into vaccine design.

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Souped-up method for iPS cell reprogramming

Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).

Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish “disease in a dish” models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.

Read more

Posted on by Quinn Eastman in Cancer, Immunology, Neuro Leave a comment

HIV discordant couples

On Thursday, NPR had a nicely done story on discordant couples (one partner is HIV positive, the other is HIV negative) in Kenya.

It provided a reminder of Susan Allen’s work in Rwanda and Zambia with discordant couples. It also very simply laid out the policy issues connected with treating discordant couples:

Medical workers are http://www.raybani.com/ extremely interested in discordant couples for two reasons. One is that almost half of new infections in Kenya happen in these relationships. It’s one place where HIV is spreading. The second reason is that when couples are open with each other about their HIV status, managing HIV is more successful…

The World Health Organization now recommends that any HIV-positive individual in a discordant relationship be supplied HIV treatment. But discordant couples are still being treated on an ad hoc basis in Kenya, primarily because the funding for the medication just isn’t there.

Allen’s research provided critical data about HIV Ray Ban outlet transmission and prevention methods, and led to the adoption of the WHO guidelines mentioned in the story. She has said that the WHO guidelines were designed to help partners in a stable relationship work together to prevent the uninfected person from getting the virus and that low-tech, inexpensive prevention methods like condoms are just as important as antiretroviral therapy in this effort.

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