‘Genetic doppelgangers:’ Emory research provides insight into two neurological puzzles

An international team led by Emory scientists has gained insight into the pathological mechanisms behind two devastating neurodegenerative diseases. The scientists compared the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) with a rarer disease called spinocerebellar ataxia type 36 (SCA 36). Both of the diseases are caused by abnormally expanded and strikingly similar DNA repeats. However, ALS progresses quickly, typically killing patients within a year or two, while the disease Read more

Emory launches study on COVID-19 immune responses

Emory University researchers are taking part in a multi-site study across the United States to track the immune responses of people hospitalized with COVID-19 that will help inform how the disease progresses and potentially identify new ways to treat it.  The study is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The study – called Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) – launched Friday. Read more

Marcus Lab researchers make key cancer discovery

A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes. The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates. The findings mark the first Read more

T cell exhaustion

Stem-like CD8 T cells stay in lymph nodes/spleen

In a mouse model of chronic viral infection, there are very few virus-specific killer T cells in the blood, Emory Vaccine Center scientists report in a new paper in PNAS. This has implications for efforts to enhance cancer immunotherapy, because in both chronic viral infection and cancer, the same types of exhausted T cells accumulate.

CD8 T cells in lymphoid tissue (spleen) – from Im et al Nature (2016)

Vaccine Center director Rafi Ahmed’s lab has learned a great deal about exhausted T cells by studying the LCMV (lymphocytic choriomeningitis virus) model. In this situation, virus-specific CD8 T cells accumulate in lymph nodes and in other organs, without circulating in the blood, because they acquire a residency program, the PNAS authors write. Postdoc Sejin Im’s 2016 paper defined these “stem-like” cells – he is the first author of the new one as well.

A related phenomenon can be seen in the Kissick lab’s recent paper on immune “outposts” in kidney and other urologic tumors. The stem-like cells stay within the tumor and give rise to similar progeny. One consequence may be that treatments aimed at reactivating those cells need to get inside the tumor.

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Revived T cells still need fuel

Cancer immunotherapy drugs blocking the PD-1 pathway – known as checkpoint inhibitors – are now FDA-approved for melanoma, lung cancer and several other types of cancer. These drugs are often described as “releasing the brakes” on dysfunctional T cells.

A new study from Emory Vaccine Center and Winship Cancer Institute researchers shows that even if the PD-1-imposed brakes are released, the tumor-specific T cells still need “fuel” to expand in numbers and restore effective immune responses. That fuel comes from co-stimulation through a molecule called CD28.

The results were published Thursday by the journal Science.

Despite the success of PD-1-targeting drugs, many patients’ tumors do not respond to them. The study’s findings indicate that CD28’s presence on T cells could be a clinical biomarker capable of predicting whether drugs targeting PD-1 will be effective. In addition, the requirement for CD28 suggests that co-stimulation may be missing for some patients, which could guide the design of combination therapies.

For the rest of our press release and quotes from authors Rafi Ahmed, Alice Kamphorst and Suresh Ramalingam, please go here. For some additional links and thoughts on PD-1 and CD28, read on:

Read more

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Dengue infection makes exhausted T cells?

An ongoing collaboration between the Emory Vaccine Center and the ICGEB (International Centre for Genetic Engineering and Biotechnology) in New Delh, investigating immune responses to dengue virus, is getting some attention.

A Journal of Virology paper published by the collaboration was highlighted by Nature Asia. In that paper, the researchers show that in dengue infection, the group of antiviral immune cells known as CD8+ T cells undergoes a massive expansion. That could be dangerous if all of the CD8 T cells were making inflammatory cytokines, but they do not. Only a small fraction are making cytokines.

The authors point out that this phenomenon is “somewhat reminiscent of T-cell exhaustion seen under the conditions of prolonged antigenic stimulus in chronic viral infections [which has been studied in detail by Rafi Ahmed and colleagues] or closely resembles the ‘stunned’ phenotype reported in febrile phase of other acute infections such as HIV and viral hepatitis… The IFN-γ unresponsiveness acquired during the massive antigen-driven clonal expansion is likely to ensure that these cells do not cause excessive inflammation at the time that their numbers are high during the febrile phase of dengue disease.” Read more

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Are you experienced?

Are you experienced? Your immune system undoubtedly is. Because of vaccinations and infections, we accumulate memory T cells, which embody the ability of the immune system to respond quickly and effectively to bacteria or viruses it has seen before.

Not so with mice kept in clean laboratory facilities. Emory scientists think this difference could help explain why many treatments for sepsis that work well in mice haven’t in human clinical trials.

Screen Shot 2016-08-24 at 1.42.21 PM

Mandy Ford has teamed up with Craig Coopersmith to investigate sepsis, a relatively new field for her, and the collaboration has blossomed in several directions

“This is an issue we’ve been aware of in transplant immunology for a long time,” says Mandy Ford, scientific director of Emory Transplant Center. “Real life humans have more memory T cells than the mice that we usually study.”

Sepsis is like a storm moving through the immune system. Scientists studying sepsis think that it has a hyper-inflammatory phase, when the storm is coming through, and a period of impaired immune function afterwards. The ensuring paralysis leaves patients unable to fight off secondary infections.

In late-stage sepsis patients, dormant viruses that the immune system usually keeps under control, such as Epstein-Barr virus and cytomegalovirus, emerge from hiding. The situation looks a lot like that in kidney transplant patients, who are taking drugs to prevent immune rejection of their new organ, Ford says.

Ford’s team recently found that sepsis preferentially depletes some types of memory T cells in mice. Because T cells usually keep latent viruses in check, this may explain why the viruses are reactivated after sepsis, she says. Read more

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