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IBD: How a class of killer T cells goes rogue in inflammatory bowel disease

IBD: How a class of killer T cells goes rogue in inflammatory bowel disease

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There are currently no permanent treatments for most patients with inflammatory bowel disease. PokPak05/iStock/Getty Images Plus

Between 6 and 8 million people worldwide suffer from inflammatory bowel disease, a group of chronic intestinal disorders that can cause belly pain, urgent and frequent bowel movements, bloody stools and weight loss. New research suggests that a malfunctioning member of the patient’s own immune system called a killer T cell may be one of the culprits. This discovery may provide a new target for IBD medicines.

The two main types of IBD are ulcerative colitis, which mainly affects the colon, and Crohn’s disease, which can affect the entire digestive tract. Researchers currently believe that IBD is triggered when an overactive immune system attacks harmless bacteria in the intestines. Although there are many treatments for IBD, for as many as 75% of individuals with IBD there are no effective long-term treatments. This leaves many patients without good options.

I am a physician-scientist conducting research in immunology and IBD and in a new study, my team and our colleagues specializing in immunology, gastroenterology and genomics examined immune cells from the blood and intestines of healthy individuals and compared them with those collected from patients with ulcerative colitis to gain a better understanding of how the immune system malfunctions in IBD. There are many reasons why current treatments aren’t permanent, but one reason is that scientists don’t fully understand how the immune system is involved in IBD. It is our hope that closing the current knowledge gap about how the immune system is involved in this disorder will eventually lead to new durable treatments for IBD that target the right immune cells.

Ulcerative colitis is a type of inflammatory bowel disease that results in chronic inflammation and damage to the large intestine. Graphic_BKK1979/iStock via Getty Images

Immunology 101

The immune system can be divided into innate and adaptive branches. The innate branch is our first line of defense and acts quickly – within minutes to hours. But this system senses changes caused by microbes generally. It does not mount a targeted response against a specific pathogen, which means that some invaders can be overlooked.

The adaptive branch is designed to detect specific threats, but is slower and takes a couple of days to get going. T cells are a part of the adaptive immune system and can be further subdivided into CD4⁺ and CD8⁺ T cells.

CD4⁺ T cells are helpers that aid other immune cells by releasing soluble molecules called cytokines that can induce inflammation.

CD8⁺ T cells can also release cytokines, but their main function is to kill cells infected by microbial invaders. This is why CD8⁺ T cells are often referred to as serial killers.

After the infection is cleared and the pathogen has been destroyed, cells called memory T cells remain. These memory T cells “remember” the pathogen they’ve just encountered and if they see it again, they mount a stronger and faster response than the first time. They and their descendants can also live for a long time, even decades in the case of certain infections like measles.

The goal of a vaccine is to provide a preview of the microbe so that the immune system can build an army of memory cells against an infectious agent, such as SARS-CoV-2, the virus that causes COVID-19. That way, if the virus attacks, the memory T cells will spring into action and activate an immune response including the production of antibodies from B cells.

Memory T cells that reside in organs

Immunologists further subdivide memory T cells into different classes depending on if and where they travel in the body. Circulating memory T cells are scouts that look for signs of infection by patrolling the blood, lymph nodes and spleen.

Tissue-resident memory cells, abbreviated TRM, are sentries stationed at key ports of entry into the human body – including the skin, lungs, and intestines – and act rapidly to counter an infectious threat. Intestinal TRM also function as peacekeepers and do not tend to overreact against the many harmless microbes living in the intestines.

In the new study, our team analyzed blood and intestinal samples to discover that intestinal CD8⁺ TRM come in at least four different varieties, each with unique features and functions.

We noticed that individuals with ulcerative colitis had higher numbers and proportions of cells belonging to one of these four varieties. This particular variety, which we’ll call inflammatory TRM here, carried instructions to make very large amounts of cytokines and other protein factors that allow them to kill other cells. High levels of certain cytokines can cause inflammation and tissue damage in the body.

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It seems that in individuals with ulcerative colitis, the balance of memory cells is shifted in favor of this rogue population of inflammatory TRM that may become part of the problem by causing persistent inflammation and tissue damage.

We also found evidence consistent with the possibility that these inflammatory TRM might be exiting the intestinal tissue and entering the blood. Other studies in mice and people have shown that TRM, despite being called “tissue-resident,” can leave tissues in certain circumstances.

By leaving the tissue and entering the blood, inflammatory TRM may be able to travel to other parts of the body and cause damage. This possibility may explain why autoimmune diseases that start in one organ, like IBD in the digestive tract or psoriasis in the skin, often affect other parts of the body.

The balance of memory T cell subtypes changes in individuals with ulcerative colitis. Illustrations created with BioRender.com. John Chang

IBD and other autoimmune diseases as a memory problem

The very features that make memory T cells so desirable for vaccines – their capacity to live for such a long time and mount a stronger response when they encounter a microbial invader for the second time – may explain why autoimmune diseases are chronic and lifelong.

It is important to point out that none of the current drug treatments for IBD specifically target long-lived memory cells, which might be a reason why these therapies don’t work long-term in many individuals. One therapeutic approach might be to target inflammatory TRM for destruction, but this could result in side effects like suppression of the immune system and increased infections.

Our findings build on previous studies showing that different TRM varieties, like the CD4⁺ subtype, may also be involved in IBD, while other studies show that TRM play a role in autoimmune diseases affecting other organs like the skin and kidneys.

The possibility that T cell memory is co-opted in IBD is exciting, but there is much that we still don’t understand about TRM. Can we selectively target inflammatory TRM for destruction? Would this be an effective treatment for IBD? Can we do so without causing major side effects? Further research will be needed to answer these important questions and to strengthen the link between TRM and IBD.

John Chang receives research grant funding from the National Institutes of Health, the Kenneth Rainin Foundation, Takeda, and Eli Lilly.

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International

Beloved mall retailer files Chapter 7 bankruptcy, will liquidate

The struggling chain has given up the fight and will close hundreds of stores around the world.

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It has been a brutal period for several popular retailers. The fallout from the covid pandemic and a challenging economic environment have pushed numerous chains into bankruptcy with Tuesday Morning, Christmas Tree Shops, and Bed Bath & Beyond all moving from Chapter 11 to Chapter 7 bankruptcy liquidation.

In all three of those cases, the companies faced clear financial pressures that led to inventory problems and vendors demanding faster, or even upfront payment. That creates a sort of inevitability.

Related: Beloved retailer finds life after bankruptcy, new famous owner

When a retailer faces financial pressure it sets off a cycle where vendors become wary of selling them items. That leads to barren shelves and no ability for the chain to sell its way out of its financial problems. 

Once that happens bankruptcy generally becomes the only option. Sometimes that means a Chapter 11 filing which gives the company a chance to negotiate with its creditors. In some cases, deals can be worked out where vendors extend longer terms or even forgive some debts, and banks offer an extension of loan terms.

In other cases, new funding can be secured which assuages vendor concerns or the company might be taken over by its vendors. Sometimes, as was the case with David's Bridal, a new owner steps in, adds new money, and makes deals with creditors in order to give the company a new lease on life.

It's rare that a retailer moves directly into Chapter 7 bankruptcy and decides to liquidate without trying to find a new source of funding.

Mall traffic has varied depending upon the type of mall.

Image source: Getty Images

The Body Shop has bad news for customers  

The Body Shop has been in a very public fight for survival. Fears began when the company closed half of its locations in the United Kingdom. That was followed by a bankruptcy-style filing in Canada and an abrupt closure of its U.S. stores on March 4.

"The Canadian subsidiary of the global beauty and cosmetics brand announced it has started restructuring proceedings by filing a Notice of Intention (NOI) to Make a Proposal pursuant to the Bankruptcy and Insolvency Act (Canada). In the same release, the company said that, as of March 1, 2024, The Body Shop US Limited has ceased operations," Chain Store Age reported.

A message on the company's U.S. website shared a simple message that does not appear to be the entire story.

"We're currently undergoing planned maintenance, but don't worry we're due to be back online soon."

That same message is still on the company's website, but a new filing makes it clear that the site is not down for maintenance, it's down for good.

The Body Shop files for Chapter 7 bankruptcy

While the future appeared bleak for The Body Shop, fans of the brand held out hope that a savior would step in. That's not going to be the case. 

The Body Shop filed for Chapter 7 bankruptcy in the United States.

"The US arm of the ethical cosmetics group has ceased trading at its 50 outlets. On Saturday (March 9), it filed for Chapter 7 insolvency, under which assets are sold off to clear debts, putting about 400 jobs at risk including those in a distribution center that still holds millions of dollars worth of stock," The Guardian reported.

After its closure in the United States, the survival of the brand remains very much in doubt. About half of the chain's stores in the United Kingdom remain open along with its Australian stores. 

The future of those stores remains very much in doubt and the chain has shared that it needs new funding in order for them to continue operating.

The Body Shop did not respond to a request for comment from TheStreet.   

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Government

Are Voters Recoiling Against Disorder?

Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super…

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Are Voters Recoiling Against Disorder?

Authored by Michael Barone via The Epoch Times (emphasis ours),

The headlines coming out of the Super Tuesday primaries have got it right. Barring cataclysmic changes, Donald Trump and Joe Biden will be the Republican and Democratic nominees for president in 2024.

(Left) President Joe Biden delivers remarks on canceling student debt at Culver City Julian Dixon Library in Culver City, Calif., on Feb. 21, 2024. (Right) Republican presidential candidate and former U.S. President Donald Trump stands on stage during a campaign event at Big League Dreams Las Vegas in Las Vegas, Nev., on Jan. 27, 2024. (Mario Tama/Getty Images; David Becker/Getty Images)

With Nikki Haley’s withdrawal, there will be no more significantly contested primaries or caucuses—the earliest both parties’ races have been over since something like the current primary-dominated system was put in place in 1972.

The primary results have spotlighted some of both nominees’ weaknesses.

Donald Trump lost high-income, high-educated constituencies, including the entire metro area—aka the Swamp. Many but by no means all Haley votes there were cast by Biden Democrats. Mr. Trump can’t afford to lose too many of the others in target states like Pennsylvania and Michigan.

Majorities and large minorities of voters in overwhelmingly Latino counties in Texas’s Rio Grande Valley and some in Houston voted against Joe Biden, and even more against Senate nominee Rep. Colin Allred (D-Texas).

Returns from Hispanic precincts in New Hampshire and Massachusetts show the same thing. Mr. Biden can’t afford to lose too many Latino votes in target states like Arizona and Georgia.

When Mr. Trump rode down that escalator in 2015, commentators assumed he’d repel Latinos. Instead, Latino voters nationally, and especially the closest eyewitnesses of Biden’s open-border policy, have been trending heavily Republican.

High-income liberal Democrats may sport lawn signs proclaiming, “In this house, we believe ... no human is illegal.” The logical consequence of that belief is an open border. But modest-income folks in border counties know that flows of illegal immigrants result in disorder, disease, and crime.

There is plenty of impatience with increased disorder in election returns below the presidential level. Consider Los Angeles County, America’s largest county, with nearly 10 million people, more people than 40 of the 50 states. It voted 71 percent for Mr. Biden in 2020.

Current returns show county District Attorney George Gascon winning only 21 percent of the vote in the nonpartisan primary. He’ll apparently face Republican Nathan Hochman, a critic of his liberal policies, in November.

Gascon, elected after the May 2020 death of counterfeit-passing suspect George Floyd in Minneapolis, is one of many county prosecutors supported by billionaire George Soros. His policies include not charging juveniles as adults, not seeking higher penalties for gang membership or use of firearms, and bringing fewer misdemeanor cases.

The predictable result has been increased car thefts, burglaries, and personal robberies. Some 120 assistant district attorneys have left the office, and there’s a backlog of 10,000 unprosecuted cases.

More than a dozen other Soros-backed and similarly liberal prosecutors have faced strong opposition or have left office.

St. Louis prosecutor Kim Gardner resigned last May amid lawsuits seeking her removal, Milwaukee’s John Chisholm retired in January, and Baltimore’s Marilyn Mosby was defeated in July 2022 and convicted of perjury in September 2023. Last November, Loudoun County, Virginia, voters (62 percent Biden) ousted liberal Buta Biberaj, who declined to prosecute a transgender student for assault, and in June 2022 voters in San Francisco (85 percent Biden) recalled famed radical Chesa Boudin.

Similarly, this Tuesday, voters in San Francisco passed ballot measures strengthening police powers and requiring treatment of drug-addicted welfare recipients.

In retrospect, it appears the Floyd video, appearing after three months of COVID-19 confinement, sparked a frenzied, even crazed reaction, especially among the highly educated and articulate. One fatal incident was seen as proof that America’s “systemic racism” was worse than ever and that police forces should be defunded and perhaps abolished.

2020 was “the year America went crazy,” I wrote in January 2021, a year in which police funding was actually cut by Democrats in New York, Los Angeles, San Francisco, Seattle, and Denver. A year in which young New York Times (NYT) staffers claimed they were endangered by the publication of Sen. Tom Cotton’s (R-Ark.) opinion article advocating calling in military forces if necessary to stop rioting, as had been done in Detroit in 1967 and Los Angeles in 1992. A craven NYT publisher even fired the editorial page editor for running the article.

Evidence of visible and tangible discontent with increasing violence and its consequences—barren and locked shelves in Manhattan chain drugstores, skyrocketing carjackings in Washington, D.C.—is as unmistakable in polls and election results as it is in daily life in large metropolitan areas. Maybe 2024 will turn out to be the year even liberal America stopped acting crazy.

Chaos and disorder work against incumbents, as they did in 1968 when Democrats saw their party’s popular vote fall from 61 percent to 43 percent.

Views expressed in this article are opinions of the author and do not necessarily reflect the views of The Epoch Times or ZeroHedge.

Tyler Durden Sat, 03/09/2024 - 23:20

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Government

Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The…

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Veterans Affairs Kept COVID-19 Vaccine Mandate In Place Without Evidence

Authored by Zachary Stieber via The Epoch Times (emphasis ours),

The U.S. Department of Veterans Affairs (VA) reviewed no data when deciding in 2023 to keep its COVID-19 vaccine mandate in place.

Doses of a COVID-19 vaccine in Washington in a file image. (Jacquelyn Martin/Pool/AFP via Getty Images)

VA Secretary Denis McDonough said on May 1, 2023, that the end of many other federal mandates “will not impact current policies at the Department of Veterans Affairs.”

He said the mandate was remaining for VA health care personnel “to ensure the safety of veterans and our colleagues.”

Mr. McDonough did not cite any studies or other data. A VA spokesperson declined to provide any data that was reviewed when deciding not to rescind the mandate. The Epoch Times submitted a Freedom of Information Act for “all documents outlining which data was relied upon when establishing the mandate when deciding to keep the mandate in place.”

The agency searched for such data and did not find any.

The VA does not even attempt to justify its policies with science, because it can’t,” Leslie Manookian, president and founder of the Health Freedom Defense Fund, told The Epoch Times.

“The VA just trusts that the process and cost of challenging its unfounded policies is so onerous, most people are dissuaded from even trying,” she added.

The VA’s mandate remains in place to this day.

The VA’s website claims that vaccines “help protect you from getting severe illness” and “offer good protection against most COVID-19 variants,” pointing in part to observational data from the U.S. Centers for Disease Control and Prevention (CDC) that estimate the vaccines provide poor protection against symptomatic infection and transient shielding against hospitalization.

There have also been increasing concerns among outside scientists about confirmed side effects like heart inflammation—the VA hid a safety signal it detected for the inflammation—and possible side effects such as tinnitus, which shift the benefit-risk calculus.

President Joe Biden imposed a slate of COVID-19 vaccine mandates in 2021. The VA was the first federal agency to implement a mandate.

President Biden rescinded the mandates in May 2023, citing a drop in COVID-19 cases and hospitalizations. His administration maintains the choice to require vaccines was the right one and saved lives.

“Our administration’s vaccination requirements helped ensure the safety of workers in critical workforces including those in the healthcare and education sectors, protecting themselves and the populations they serve, and strengthening their ability to provide services without disruptions to operations,” the White House said.

Some experts said requiring vaccination meant many younger people were forced to get a vaccine despite the risks potentially outweighing the benefits, leaving fewer doses for older adults.

By mandating the vaccines to younger people and those with natural immunity from having had COVID, older people in the U.S. and other countries did not have access to them, and many people might have died because of that,” Martin Kulldorff, a professor of medicine on leave from Harvard Medical School, told The Epoch Times previously.

The VA was one of just a handful of agencies to keep its mandate in place following the removal of many federal mandates.

“At this time, the vaccine requirement will remain in effect for VA health care personnel, including VA psychologists, pharmacists, social workers, nursing assistants, physical therapists, respiratory therapists, peer specialists, medical support assistants, engineers, housekeepers, and other clinical, administrative, and infrastructure support employees,” Mr. McDonough wrote to VA employees at the time.

This also includes VA volunteers and contractors. Effectively, this means that any Veterans Health Administration (VHA) employee, volunteer, or contractor who works in VHA facilities, visits VHA facilities, or provides direct care to those we serve will still be subject to the vaccine requirement at this time,” he said. “We continue to monitor and discuss this requirement, and we will provide more information about the vaccination requirements for VA health care employees soon. As always, we will process requests for vaccination exceptions in accordance with applicable laws, regulations, and policies.”

The version of the shots cleared in the fall of 2022, and available through the fall of 2023, did not have any clinical trial data supporting them.

A new version was approved in the fall of 2023 because there were indications that the shots not only offered temporary protection but also that the level of protection was lower than what was observed during earlier stages of the pandemic.

Ms. Manookian, whose group has challenged several of the federal mandates, said that the mandate “illustrates the dangers of the administrative state and how these federal agencies have become a law unto themselves.”

Tyler Durden Sat, 03/09/2024 - 22:10

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