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Saturday, February 12, 2022

Beijing’s ambitious Olympic COVID bubble

 For a country determined to keep out the virus that first emerged within its borders, bringing in more than 15,000 people from all corners of the world was a serious gamble. It appears to be working.

One week into the 17-day event, China seems to be meeting its formidable COVID-19 Olympic challenge with a so-called “bubble” that allows Beijing Games participants to skip quarantine but tightly restricts their movement so they don’t come in contact with the general population. There have been 490 confirmed cases — many of them positive tests on symptomless visitors — and no reports of any leaking out to date.

Inside the bubble, Olympic organizers are employing a version of the government’s zero-tolerance approach. Everyone is tested daily for the virus, and anyone who tests positive is rapidly isolated to prevent any spread. Athletes and others are required to wear N95 face masks when not competing.

“Arguably the riskiest thing they’ve done so far is to host the Games, and if they can get through that, then they can continue to use this strategy to keep localized outbreaks under control for a long time,” said Karen Grépin, a public health expert at the University of Hong Kong.

China has tight restrictions on who can enter China and requires those who do to quarantine at designated hotels for two to three weeks. It responds to even the smallest outbreaks with lockdowns of buildings and neighborhoods, followed by mass testing of all residents to root out and isolate positive cases.

The strategy is not without costs. In the run-up to the Olympics, China expanded its lockdowns to entire cities of more than 10 million people to stamp out outbreaks, forcing factories and nonessential shops to close and restricting people to their residential compounds.

A southwestern area of about 4 million people bordering Vietnam has been locked down this week because of an outbreak that has infected about 180 people. In Beijing, two residential neighborhoods remain locked down because of a handful of cases two weeks ago.

The closed loop, as the Olympics bubble is officially called, has created two separate worlds. Athletes and other participants aren’t able to visit Beijing’s tourist sites or restaurants and bars in their downtime. Their only glimpses of the city are from the windows of buses that shuttle them from lodging to venues and back.

Both their hotels and the competition venues are fenced off with temporary walls; guards are posted to keep people from going out or coming in.

Outside, life goes on as normal for most in the nation’s capital. Select groups — school children, corporate sponsors, winter sports groups, foreign diplomats and journalists among others — are being invited to fill the stands partially, but most follow the Games on their smartphones or TV.

“We don’t feel the Winter Olympics are far from our life,” said Yi Jianhua, a retiree from Hunan province visiting his daughter in Beijing. “We can watch it on TV and mobile phone. Although we cannot be there in the venue, we still pay close attention to it, because this is a grand event. Yes, there are regrets but it’s acceptable.”

China has had scattered outbreaks in the past month, but none related to the Olympics. On Friday, health authorities reported 22 new cases in an outbreak in Liaoning province, east of Beijing.

None of the 450 confirmed infections inside the loop have spread to others in the bubble, Huang Chun, a pandemic control official, said earlier this week. And there have been no reports of anything medically serious.

The possibility of a large outbreak inside the bubble, potentially sidelining athletes from competitions, has been a greater fear than any leakage into the rest of China.

“I feel all the protective measures are well in place,” said Fang Yanmin, a tourist taking photos with her friend in front of a statue of Bing Dwen Dwen, the Games’ panda mascot. “There is no need to panic.”

Guo Haifeng, waiting for friends at a nearby subway station, applauded the closed loop, saying it prevents the athletes and public from interrupting each other’s lives. Even if he were offered tickets, he said he wouldn’t go.

“Because of the pandemic, we should try to avoid going to the scene,” he said. “We should restrain ourselves and not affect others.”

The final test will come after the Games, when thousands of Olympic staff and volunteers from China exit the bubble. They are expected to be required to quarantine for a week or more before leaving to try to forestall the effects of any latent infections they might have.

China’s zero-tolerance policy has kept the virus at bay. Health authorities have reported 4,636 deaths since the start of the pandemic, a tiny fraction of those in other major nations. Most date from the initial outbreak in early 2020 that overwhelmed the health system in the city of Wuhan.

“For us, we achieved the goal of zero cases so we can travel with ease,” said Yi, the retiree.

Grépin believes the health and economic benefits of China’s approach have outweighed the costs, borne by those caught up in lockdowns and industries such as tourism, which has been damaged by on-and-off pandemic-related travel restrictions. Economic growth slowed to 4% at the end of last year but exports remain strong.

“They’ve had incredibly low mortality by any standard, and most of the country has lived a relatively normal life for the last two years,” she said.

China’s relative success may make exiting its zero tolerance strategy more difficult. Most of the nation’s 1.4 billion people have not been exposed to the virus, so they haven’t developed antibodies that way. And while the vaccination rate is high, the emergence of new variants such as omicron may make the vaccines in use less effective.

For at least the near future, that means anyone caught in an outbreak could face lockdowns and repeated testing — and those coming to China will be isolated in a hotel room for two weeks or more. The repercussions from the 2-year-old pandemic keep marching on.

https://apnews.com/article/winter-olympics-covid-pandemic-bubble-effectiveness-acb24560ea13174b94590c428dac29d9

A Third of Docs Saw a Patient Harmed by Prior Authorization

 One in three doctors said prior authorization led to one of their patients requiring hospitalization, being permanently disabled, or worse, according to a survey conducted by the American Medical Association (AMA).

In the sample of more than 1,000 practicing physicans, 24% said that a prior authorization led to a hospitalization, and 18% said a prior authorization led to a "life-threatening event" or an event that "required intervention to prevent permanent impairment or damage."

Another 8% saw one of their patients experience a disability or sustain permanent bodily damage, a congenital anomaly, a birth defect, or even death.

For physicians treating patients between the ages of 18 to 65, the majority said a prior authorization interfered with a patient's ability to do their job.

"Health insurance companies entice employers with claims that prior authorization requirements keep health care costs in check, but often these promises obscure the full consequences on an employer's bottom line or employees' well-being," explained AMA President Gerald Harmon, MD. "Benefit plans with excessive authorization controls create serious problems for employers when delayed, denied or abandoned care harms the health of employees and results in missed work days, lost productivity and other costs."

The AMA urged employers to ask insurers more questions about their plan requirements and to solicit feedback from employees about their own experiences with the insurer tool.

Rep. Suzan Delbene (D-Wash.) echoed Harmon's message in a press release: "The data is clear that the prior authorization status quo delays care, worsens health outcomes, and is an additional barrier for seniors, families, and medical providers."

Delbene urged passage of the Improving Seniors' Timely Access to Care Act , a bill she introduced and is pressing House leadership to advance. She argued it will "streamline" and "standardize" Medicare Advantage plans' prior authorization programs and require greater oversight and transparency of the requirements.

Multiple states including New YorkTexasIllinois, and Indiana either introduced or passed laws restricting insurance plans use of prior authorization.

Other grim feedback from the AMA survey found:

  • 93% said prior authorizations were linked to delays in patient care
  • 91% said prior authorizations had negative impacts on clinical outcomes
  • 82% said prior authorizations can at least "sometimes" lead patients to abandon recommended treatment
  • 30% said prior authorization criteria is "rarely" or "never" evidence-based (despite 98% of health plans claiming to use evidence-based studies to design their programs)

Only 7% of survey respondents said prior authorizations had no impact at all on patient outcomes.

On average, physician practices complete 41 prior authorizations each week -- accounting for more than two full business days of additional work. Two in every five physicians said they employ staff whose job it is to exclusively work on prior authorizations as well.

"Now is the time for employers to demand transparency from health plans on the growing impact of prior authorization programs on the health of their workforce," Harmon urged.

The survey was conducted online in December 2021 and completed by 1,004 practicing physicians drawn from the M3 Global Research Panel. All participants currently practice in the U.S. and provide at least 20 hours of patient care each week.

https://www.medpagetoday.com/practicemanagement/practicemanagement/97167

Friday, February 11, 2022

How China applicants could avoid the sintilimab scenario

 Farewell, sintilimab. This seems a realistic assessment of the Lilly/Innovent drug’s chances of gaining US approval in front-line lung cancer after yesterday’s 14-1 drubbing at an unusual advisory committee meeting.

Those hoping to see low-cost competition in the US anti-PD-(L)1 space will be disappointed, but the good news is that sintilimab might not necessarily set a broad precedent. Indeed, much of the panellists’ ire was directed at the way Lilly and Innovent had gone about the filing process, suggesting that other companies might avoid a similar fate as long as they engage the FDA early on and do as the agency says.

This became clear yesterday when Harpreet Singh, an FDA director of oncology, accused Lilly of being “incredibly misleading” in its characterisation of a 2020 meeting with the agency and the resulting guidance. This exchange went to the heart of how Orient-11, a first-line NSCLC trial of sintilimab conducted entirely in China, ended up backing a US filing.

Lilly and Innovent said Orient-11 had been designed to support Chinese approval, and they had no discussion over its design with the FDA until after data were reported. It was only then – and after Richard Pazdur, the director of the FDA's Oncology Center of Excellence, welcomed anti-PD-(L)1 drugs developed by Chinese companies as a means of lowering drug prices – that a US path forward emerged, and so a US filing was made.

Didn’t meet flexibility criteria

It is now abundantly clear that such a strategy will not do. Throughout the proceedings the agency stressed its flexibility regarding data generated outside the US, but said Lilly/Innovent failed to meet any of the criteria to warrant such flexibility, and the lack of early FDA interaction was a major black mark.

The FDA’s criticism centred on four key points: that Orient-11 might not be generalisable to the US population, that there were issues over lack of data integrity, that the trial had the wrong primary endpoint (progression-free survival), and that it used an outdated comparator (chemotherapy).

Lack of generalisability was relevant because Orient-11 was a single-country trial – not necessarily because it was conducted ex-US per se, and the FDA stressed the need for patient diversity. Data integrity came up at site inspections, where the FDA had found adverse event underreporting but “no evidence of fraud”.

Lilly/Innovent argued that PFS was a better primary endpoint than OS because it avoided the confounding effect of subsequent therapies, but this cut little ice. Other anti-PD-(L)1 projects with China trials in major indications like first-line NSCLC that also rely on PFS therefore now look like non-starters for US approval.

This could include Cstone/EQRX’s sugemalimab, Novartis/Beigene’s tislelizumab and Coherus’s toripalimab. However, the last two are pursuing a different approach: Coherus’s US filing is in the niche use of nasopharyngeal carcinoma, and could thus pass FDA muster; tislelizumab has been filed for oesophageal cancer on the basis of a global trial, and Novartis’s near-term NSCLC strategy targets second-line use.

What are US anti-PD-(L)1 latecomers relying on?
ProjectCompanyIndicationMajor US use?US statusSupporting studyStudy locationsComparatorKey primary
LibtayoSanofi/ Regeneron1L PD-L1 +ve (≥50%) NSCLCYesApproved 22 Feb 2021Empower-Lung-1Ex-USChemoOS & PFS
SintilimabLilly/ Innovent1L non-squam NSCLC (Alimta combo)YesFiled (22 Mar 2022 Pdufa date)Orient-11ChinaChemoPFS
PenpulimabAkeso/ Sino3L nasopharyngeal carcinomaNoFiled 24 May 2021NCT03866967ChinaNoneORR
ToripalimabCoherus/ Shanghai Junshi3L (& 1L chemo combo) nasopharyngealNoFiled (Apr 2022 Pdufa date)Polaris-02ChinaNoneORR
Jupiter-02AsiaChemoPFS
1L NSCLC (chemo combo)YesUnclear if for FDA filingChoice-01ChinaChemoPFS
TislelizumabNovartis/ Beigene2L oesophageal squamous cell carcinoma?Filed (12 Jul 2022 Pdufa date)Rationale-302GlobalChemoOS
1L non-squam NSCLC (chemo como)YesFDA filing will target 2LRationale-304ChinaChemoPFS
1L squam NSCLC (chemo combo)YesFDA filing will target 2LRationale-307ChinaChemoPFS
CosibelimabCheckpoint (Fortress)Cutaneous squamous cell carcinoma?Topline positive data Jan 2022NCT03212404Ex-USNoneORR
1L NSCLC (chemo combo)YesStudy started Dec 2021ConternoEx-USChemoOS
SugemalimabCstone/ EQRX1L NSCLC (chemo combo)YesPositive data Jan 2022Gemstone-302ChinaChemoPFS
EnvafolimabTracon/ Alphamab/ 3D1L biliary tract cancer (gemcitabine combo)NoPh3 trial ended Dec 2021NCT03478488ChinaChemoOS
ZimberelimabArcus (via Wuxi/ Gloriabio)1L PD-L1+ve NSCLC (+/- domvanalimab)YesPh3 trial ends Dec 2025NCT04736173Ex-USChemoOS & PFS
Source: company statements.

But a huge question for companies seeking approval in a major indication is what to give patients in the comparator cohort when an entrenched incumbent like Keytruda is available, as in the case of front-line NSCLC.

The adcom said that when Orient-11 enrolled its first patient (not under a US IND) in August 2018 Keytruda plus chemo was already the standard of care, based on the Keynote-189 study. Had the FDA been consulted it would likely have recommended a head-to-head comparison showing sintilimab to be non-inferior to an approved anti-PD-(L)1/chemo regimen, the panellists said.

Companies with first-line NSCLC trials that do test OS but which use chemo comparators include Arcus with zimberelimab, and the Fortress subsidiary Checkpoint with cosibelimab. These might today be sitting nervously, but will point in their defence to the Empower-Lung-1 trial that backed US approval of Sanofi/Regeneron’s Libtayo.

However, while Empower-Lung-1 did use a chemo comparator and was conducted ex-US it began in 2017, before Keytruda could be said to have become a standard of care in NSCLC. Lilly/Innovent argued that a head-to-head trial for sintilimab would have required 2,000 patients to be enrolled and taken over seven years to run.

For sintilimab a complete response letter now seems certain, leading some analysts to believe that Lilly will walk away from its deal with Innovent. But if the idea of low-cost anti-PD-(L)1 drug competition has been kicked down the road it has not been killed off entirely.

While pricing and competition were said to be outside the scope of the adcom, the panel meeting clearly had relevance beyond sintilimab. Other companies will have their work cut out persuading the FDA to be flexible in designing development paths but, with the agency apparently wanting to be flexible, early interaction holds the key.

Innovent today said the adcom had helped it gain tremendous experience, and the same surely applies to its peer companies too.

https://www.evaluate.com/vantage/articles/news/policy-and-regulation/how-china-applicants-could-avoid-sintilimab-scenario

Illuminate leaves Proqr in darkness

 Proqr had hoped that both doses of its gene therapy sepofarsen might prove effective in its pivotal phase 2/3 Illuminate trial in the rare eye disorder CEP290-mediated Leber’s congenital amaurosis 10 (LCA10). Today it admitted that neither was. The washout was total, with no significant difference between either dose, or between the doses and sham treatment, on the primary or any of the secondary endpoints, and the company’s stock plummeted 74%. On a call today Proqr did not rule out subgroup dredges, but it would be wildly optimistic to hope for anything here. The question for the company is what the failure means for the rest of its pipeline, and while it insisted that there was limited readthrough – and that it has cash to last until 2024 – it will have a nervous wait for readouts of its trials. Topline data from the phase 1/2 trial of QR-504a in Fuchs endothelial corneal dystrophy, as well as results of the phase 1 Aurora study of QR-1123 in retinitis pigmentosa, are expected this year. The remaining LCA10 pipeline is led by Editas with EDIT-101, but this has already proven a bit of a disappointment.

Leber’s congenital amaurosis projects in the clinic
ProjectCompanyMechanism of actionDetails
Phase 3
SepofarsenProqrCEP290 gene therapyFailed pivotal Ph2/3 Illuminate trial Feb 2022
Phase 2
EDIT-101EditasCrispr Cas9 CEP290 gene therapyInterim data from Ph1/2 Brilliance trial disappointed Sep 2021
SAR439483Atsena/SanofiGuanylate cyclase receptor inhibitorPh1/2 ongoing; primary completion Feb 2022
HORA-RPE65CoaveRetinoid isomerohydrolase gene therapyOnly active development is in retinitis pigmentosa
CEP290=centrosomal protein 290. Source: Evaluate Pharma

https://www.evaluate.com/vantage/articles/news/trial-results-snippets/illuminate-leaves-proqr-darkness

Eye provides clues to insidious vascular disease

 Researchers at the University and the University Hospital of Bonn have developed a method that could be used to diagnose atherosclerosis. Using self-learning software, they were able to identify vascular changes in patients with peripheral arterial disease (PAD), often at an early stage. Although these early stages do not yet cause symptoms, they are nevertheless already associated with increased mortality. The algorithm used photos from an organ not normally associated with PAD: the eye. The results have now been published in the journal Scientific Reports.

Poets consider the eyes a window to the soul. But more prosaically, they could also be called windows to our vessels. The fundus of the eye is very well supplied with blood. It has to be, so that the more than 100 million photoreceptors in the retina and the nerve cells connected to them can do their work. At the same time, the arteries and veins can be observed and photographed through the pupil without much effort.

It may be possible to detect early signs of atherosclerosis (hardening of the arteries) with such an examination in the future. In this case, chronic remodeling processes lead to narrowing of the vessels and hardening of the affected arteries. It is the main cause of heart attacks and strokes, the most frequent causes of death in western industrialized nations, as well as peripheral arterial disease (PAD).

More than four million people in this country suffer from PAD. "Because it usually does not cause any symptoms in the first few years, the diagnosis is often only made when secondary damage has already occurred," explains Dr. Nadjib Schahab, head of the angiology section and one of the authors of the study. "The consequences can be dramatic. In the long term, progressive circulatory problems in the legs and arms may even result in amputation. In addition, the risk of a fatal heart attack or stroke is significantly increased -- even in the early stages of the disease."

Early diagnosis is therefore very important in order to be able to treat those affected in time. The interdisciplinary project of the Department of Informatics at the University of Bonn and the Department of Ophthalmology and the Heart Center of the University Hospital Bonn starts exactly there. "We photographed 97 eyes of women and men who suffered from PAD," explains Dr. Maximilian Wintergerst from the University Eye Hospital in Bonn. "In more than half of them, the disease was still at a stage where it did not cause any symptoms." In addition, the team took camera images of the background of 34 eyes of healthy control subjects.

Neural network detects early vascular changes

They then used the images to feed a convolutional neural network (CNN). This is software that is modeled on the human brain in the way it works. If such a CNN is trained with photos whose content is known to the computer, it can later recognize the content of unknown photos. For this to work with sufficient certainty, however, one normally needs several tens of thousands of training photos -- far more than were available in the study.

"We therefore first carried out a pre-training with another disease that attacks the vessels in the eye," explains Prof. Dr. Thomas Schultz from the Bonn-Aachen International Center for Information Technology (b-it) and the Institute for Computer Science II at the University of Bonn. To do this, the researchers used a dataset of more than 80,000 additional photos. "In a sense, the algorithm learns from them what to pay particular attention to," says Schultz, who is also a member of the Transdisciplinary Research Areas "Modeling" and "Life and Health" at the University of Bonn. "We therefore also speak of transfer learning."

The CNN trained in this way was able to diagnose with remarkable accuracy whether the eye photos came from a PAD patient or a healthy person. "A good 80 percent of all affected individuals were correctly identified, if we took into account 20 percent false positives -- that is, healthy individuals whom the algorithm incorrectly classified as sick," Schultz explains. "That's amazing, because even for trained ophthalmologists, PAD can't be detected from fundus images."

In further analyses, the researchers were able to show that the neural network pays particular attention to the large vessels in the back of the eye during its assessment. For the best possible result, however, the method needed digital images with a sufficiently high resolution. "Many CNNs work with very low-resolution photos," Schultz says. "That is sufficient to detect major changes. For our PAD classification, on the other hand, we need a resolution at which details of the vascular structures remain discernible."

The researchers hope to further improve the performance of their method in the future. To do so, they plan to cooperate with ophthalmology and vascular medicine centers worldwide that will provide them with additional fundus images of affected individuals. The long-term goal is to develop a simple, rapid and reliable diagnostic method that does not require concomitant procedures such as the administration of eye drops.


Story Source:

Materials provided by University of BonnNote: Content may be edited for style and length.


Journal Reference:

  1. Simon Mueller, Maximilian W. M. Wintergerst, Peyman Falahat, Frank G. Holz, Christian Schaefer, Nadjib Schahab, Robert P. Finger, Thomas Schultz. Multiple instance learning detects peripheral arterial disease from high-resolution color fundus photographyScientific Reports, 2022; 12 (1) DOI: 10.1038/s41598-022-05169-z

Diabetes, metabolic syndrome in mice treated with novel class of compounds

 A study in mice -- led by researchers at Washington University School of Medicine in St. Louis -- shows that a new class of compounds the scientists developed can improve multiple aspects of metabolic syndrome. An increasingly common group of conditions that often occur together, metabolic syndrome includes type 2 diabetes, high cholesterol, fat buildup in the liver, and excess body fat, especially around the waist. This syndrome often leads to cardiovascular disease, the leading cause of death worldwide.

The study is published in the journal Nature Communications.

Testing one of the compounds referred to as SN-401, the researchers found it treats diabetes by improving the ability of the pancreas to secrete insulin and boosting the ability of other tissues to utilize that insulin to more effectively remove sugar from the bloodstream. In an effort to optimize the treatment, the researchers fine-tuned the compound -- creating a class of related compounds -- based on their studies of a key protein called SWELL1 (also LRRC8a). The gradual decline of this protein may have a central role in the development of diabetes and other aspects of metabolic syndrome.

"Our goal is to develop better therapies for cardiovascular disease, including diabetes and metabolic syndrome, which are major risk factors for worsening heart and vascular problems," said senior author Rajan Sah, MD, PhD, an associate professor of medicine. "We have many treatments for diabetes, but even with those therapies, cardiovascular disease remains a leading cause of death among patients with type 2 diabetes. There is a need for new treatments that work differently from the current standard-of-care therapies."

The protein Sah and his colleagues studied is called SWELL1 because of its role in sensing the size or volume of cells. Their new research reveals that the protein also helps to control insulin secretion from the pancreas and improve insulin sensitivity, including in skeletal muscle and adipose tissue, the body's fat stores.

Surprisingly, the researchers showed that SWELL1 does both of these seemingly independent tasks because the protein has a previously unknown double life. It acts as a signaling molecule, turning on cellular tasks that govern how well cells use insulin and also facilitates the pancreas' secretion of insulin into the bloodstream.

"This protein, SWELL1, has a sort of dual personality," Sah said. "The compound binds to SWELL1 in a manner that stabilizes the protein complex so as to enhance expression and signaling across multiple tissues, including adipose, skeletal muscle, liver, the inner lining of blood vessels, and pancreatic islet cells. This restores both insulin sensitivity across tissue types and insulin secretion in the pancreas."

Sah and his colleagues showed that the SN-401 compound improved multiple aspects of metabolic syndrome in two groups of mice that each developed diabetes from different causes, one because of a genetic predisposition and the other due to a high-fat diet. In addition to improving insulin sensitivity and secretion, treatment with the compound also improved blood sugar levels and reduced fat buildup in the liver. Most of these studies were conducted with an injected form of the compound, but the researchers showed evidence that it also could be effective if taken by mouth.

The researchers further showed that the compound does not have a big impact on blood sugar in healthy mice, which is important for its potential as a future possible therapy. Current medications for diabetes can result in blood sugar levels that are too low. The evidence suggests that this compound does not lower blood sugar in situations when it doesn't need to.

Sah worked with Washington University's Office of Technology Management to patent the class of compounds and co-found a startup company called Senseion Therapeutics Inc., which is developing small molecule drugs that act on SWELL1. The company was first supported through funding from the university's Leadership Entrepreneurship Acceleration Program (LEAP), and also recently received three Small Business Innovation Research (SBIR) grants totaling $4.5 million. SBIR grants are supported by the small business seed fund of the National Institutes of Health (NIH).

This work was supported by the National Institutes of Health (NIH), grant numbers P30CA086862, P30DK020579, T32GM008365, GM123496, GM128263, P30 DK056341, UL1 TR000448, T32 HL130357, R01DK115791, R01DK106009, R01DK126068, R01DK127080, R43 DK121598 and R44 DK126600; the John L. & Carol E. Lach Chair in Drug Delivery Technology; grants from the New York Stem Cell Foundation; a McKnight Foundation Scholar Award; a Rose Hill Innovator Award; a Sloan Research Fellowship; the Leadership Entrepreneurship Acceleration Program (LEAP) from the Skandalaris Center for Interdisciplinary Innovation and Entrepreneurship at Washington University in St. Louis; and the Roy J. Carver Trust, University of Iowa.


Story Source:

Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.


Journal Reference:

  1. Susheel K. Gunasekar, Litao Xie, Ashutosh Kumar, Juan Hong, Pratik R. Chheda, Chen Kang, David M. Kern, Chau My-Ta, Joshua Maurer, John Heebink, Eva E. Gerber, Wojciech J. Grzesik, Macaulay Elliot-Hudson, Yanhui Zhang, Phillip Key, Chaitanya A. Kulkarni, Joseph W. Beals, Gordon I. Smith, Isaac Samuel, Jessica K. Smith, Peter Nau, Yumi Imai, Ryan D. Sheldon, Eric B. Taylor, Daniel J. Lerner, Andrew W. Norris, Samuel Klein, Stephen G. Brohawn, Robert Kerns, Rajan Sah. Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetesNature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28435-0


Interleukin-2 promotes fate decisions in CD8 T cells for long- or short-term immune protection

 The immune system is a complex network of cells and proteins with a simple job. Defend the body against infection. To do that, the cells must recognize and destroy infecting viruses or bacteria. In addition, the system also has to keep a record of each pathogen it has defeated, so it can quickly remobilize if infected again.

A study in the journal Science Immunology now shows how two subsets of one type of immune cell -- the CD8 T cell -- develop to provide either short-term or long-term immune protection. The study focuses on one factor that guides that developmental bifurcation -- interleukin-2, or IL-2.

Understanding details of how naïve immune cells develop into effective infection-fighters or long-lived memory cells is important because it can help us understand which constituents of a complex response are necessary to provide protection against infections or cancers. It can also aid understanding of immune system dysfunction, or it can improve immunotherapy for cancer. Dysfunctions include autoimmune diseases, where the immune system attacks the body's own cells, and exhaustion, where the immune system loses its ability to fight off continuing infection or the ability to destroy a cancer.

Study senior author Allan Zajac, Ph.D., and co-first authors Shannon M. Kahan, Ph.D., and Rakesh K. Bakshi, Ph.D., all of the University of Alabama at Birmingham Department of Microbiology, used mouse models to follow the traits and fates of the two subsets of CD8 T cells, starting from the peak of their effector phase, eight days after an acute viral infection.

CD8 T cells are a type of white blood cell that has the ability to develop into effector T cells -- also known as cytotoxic T cells or killer T cells. These cells can destroy cancer cells or cells infected with viruses or bacteria. IL-2 is a cytokine, one of a large family of small signaling proteins that are released by cells to send messages to other cells, or act as an autocrine signal to the same cell that is making the cytokine. Cells receive the signal at the cell surface, where the cytokine binds to a receptor. The receptor transduces the signal to the cell interior, leading to changes in cell gene expression and phenotype.

Zajac and UAB colleagues were able to isolate and purify CD8 T cells from mice at the effector phase peak. Using fluorescence-activated cell sorting after cell stimulation with a viral antigen, they identified two subsets of this group -- a minority of the CD8 T cells that produced IL-2 and a majority that did not produce IL-2.

The two subsets turn out to be strikingly different in the short term, in terms of developmental transitions that lead to fate decisions. However, they then become more alike months later.

The cells that produced IL-2 developed like immune memory cells. They attained stem-like memory traits, resisted exhaustion and preferentially conferred protective immunity upon a secondary viral challenge. Counterintuitively, they did not respond to their own IL-2, which acts inside the cell through a complex called STAT5, or signal transducer and activator of transcription. Even though the IL-2-producing CD8 T cells had normal amounts of IL-2 receptor proteins on the cell surface, the level of phosphorylated-STAT5 inside the cell -- which is the activated form of STAT5 -- was greatly diminished. The researchers hypothesized several mechanisms acting inside the cell possibly acting to attenuate the ability to receive IL-2-dependent STAT5 signals, but the answer is not yet known.

In contrast to the IL-2-producing cells, the non-IL-2-producing effector cells did respond to IL-2 signals, and they then gained effector traits at the expense of memory formation.

The UAB researchers did RNA sequencing of the cell subsets during the effector phase, nine days after infection, and much later, during the memory phase, about 10 months after infection. The transcriptional profiles of the IL-2-producing and the IL-2-non-producing effector populations were unique and distinguishable from their memory counterparts. However, by the memory time point, the two populations were more related to each other in gene expression. Thus, despite having distinct properties during the effector phase, the IL-2-producing and ?nonproducing CD8 T cells appeared to converge as memory matured to form populations with equal recall abilities to respond to a second viral infection or chronic viral challenge.

"This bifurcation between the ability of IL-2-producing and -nonproducing CD8 T cells to respond to IL-2 couples functional competency with fate decisions, and it implicates IL-2 as a critical differentiation factor," Zajac said. Zajac notes that the salient findings of this study have not yet been confirmed for humans, and they are restricted to analyzing CD8 T cell responses to a single pathogen.

Co-authors with Zajac, Kahan and Bakshi in the study, "Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection," are Jennifer T. Ingram, R. Curtis Hendrickson and Elliot J. Lefkowitz, UAB Department of Microbiology; David K. Crossman, UAB Department of Genetics; Laurie E. Harrington, UAB Department of Cell, Developmental and Integrative Biology; and Casey T. Weaver, UAB Department of Pathology. These UAB departments are all part of the Marnix E. Heersink School of Medicine.

Support came from National Institutes of Health grants AI049360, AI156290 and TR003096; and the American Cancer Society award PF-16-150-01-LIB. Zajac is a professor in the Department of Microbiology.


Story Source:

Materials provided by University of Alabama at Birmingham. Original written by Jeff Hansen. Note: Content may be edited for style and length.


Journal Reference:

  1. Shannon M. Kahan, Rakesh K. Bakshi, Jennifer T. Ingram, R. Curtis Hendrickson, Elliot J. Lefkowitz, David K. Crossman, Laurie E. Harrington, Casey T. Weaver, Allan J. Zajac. Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protectionScience Immunology, 2022; 7 (68) DOI: 10.1126/sciimmunol.abl6322