The underappreciated organ that could be key to longer life

 I can't see how any normal person could get tested to find out the health of their thymus.

The underappreciated organ that could be key to longer life

An organ once thought to become unimportant after childhood could actually be key to longer life, according to new research.

The thymus is a small organ located behind the sternum and is known to play a central role in the immune system. It acts as a training ground for the immune system’s T cells, which help the body recognise and fight infections.

It’s generally believed to become largely inactive after puberty as it shrinks with age and produces fewer new T cells. As a result, scientists say, its role in adult health remains less studied.

A new study at Mass General Brigham challenges the theory that the thymus grows unimportant after childhood.

Clinicians used artificial intelligence to review CT X-ray scans and found that adults with healthier thymus tended to live longer, with lower risks of heart disease and cancer.

Another study shows that the health of the thymus affects how well cancer patients respond to a key treatment.

“The thymus has been overlooked for decades and may be a missing piece in explaining why people age differently and why cancer treatments fail in some patients,” Hugo Aerts, an author of one of the two studies published in the journal Nature, said. “Our findings suggest thymic health deserves much more attention and may open new avenues for understanding how to protect the immune system as we age.”

AI model analyses CT scans to estimate thymic health. Image depicts a comparison between high, average, and low thymic health and corresponding CT images (Mass General Brigham/Nature)

One of the studies analysed data from over 25,000 adults who were part of a national lung cancer screening programme and over 2,500 participants in the Framingham Heart Study, a long-running group of generally healthy individuals.

The thymus of each participant was evaluated by measuring its size, structure and composition, creating a “thymic health” score.

Researchers found those with higher scores had roughly a 50 per cent lower risk of death, a 63 per cent lower risk of dying from heart disease, and a 36 per cent lower risk of developing lung cancer compared to those with lower scores.

These risk reductions held even after accounting for age and other health factors.

When the thymus function declines, researchers suspect the immune system becomes less effective at responding to new threats like cancer. They say chronic inflammation, smoking and higher body weight are linked to poorer thymic health.

The second study corroborates this.

It reviewed CT scans and outcomes from 1,200 patients treated with immunotherapy, a key treatment method for cancer involving the priming of one’s own immune system to fight cancerous cells.

Patients with better thymic health had a 37 per cent lower risk of cancer progression and a 44 per cent lower risk of death, even after adjusting for differences in patients, tumours, and treatments, the study found.

The findings point to a previously under-recognised role for the thymus in determining how patients respond to modern cancer therapies.

More studies are needed to confirm these findings, scientists say, adding that an improved understanding of thymic health can help physicians better assess disease risk and guide treatment decisions.

Rare Brain Cells Offer Clues to Aging and Rejuvenation

 Ask your competent? doctor how this will be used in your favor to slow down brain aging. NO knowledge; you DON'T have a functioning stroke doctor! RUN AWAY!

Rare Brain Cells Offer Clues to Aging and Rejuvenation

Summary: A study reveals how brain cell interactions influence aging, showing that rare cell types either accelerate or slow brain aging. Neural stem cells provide a rejuvenating effect on neighboring cells, while T cells drive aging through inflammation. Researchers used advanced AI tools and a spatial single-cell atlas to map cellular interactions across the lifespan in mice.

This work sheds light on how interventions, such as enhancing neural stem cells, might combat neurodegeneration. By understanding these cellular dynamics, scientists can explore tailored therapies to slow aging and promote brain resilience. The findings also offer insights into conditions like Alzheimer’s disease, highlighting the importance of cell-to-cell interactions.

Key Facts:

• Rejuvenating Role: Neural stem cells create a supportive environment that rejuvenates nearby cells, even outside their lineage.
• Aging Impact: T cells accelerate brain aging through pro-inflammatory signals, especially interferon-γ.
• Innovative Tools: Researchers used a spatial transcriptomic atlas and machine learning models to study brain aging at the cellular level.

Source: Stanford

Much like plants in a thriving forest, certain cells in the brain create a nurturing environment, enhancing the health and resilience of their neighbors, while others promote stress and damage, akin to a noxious weed in an ecosystem.

A new study published in Nature on December 18, 2024, reveals these interactions playing out across the lifespan. It suggests local cellular interactions may profoundly influence brain aging — and offers fresh insights into how we might slow or even reverse the process.

“What was exciting to us was finding that some cells have a pro-aging effect on neighboring cells while others appear to have a rejuvenating effect on their neighbors,” said Anne Brunet, the Michele and Timothy Barakett Endowed Professor in Stanford’s Department of Genetics and co–senior investigator of the new study.

These findings are important, says Zou, “because they highlight how cellular interactions — not just the intrinsic properties of individual cells — shape the aging process.” Credit: Neuroscience News

Specifically, Brunet said, “We were surprised to discover that neural stem cells, which we’ve studied for a long, long time, had a rejuvenating effect on the cells around them. In the future we want to understand the role of neural stem cells in providing a beneficial environment for resilience within the brain.”

Brunet collaborated with James Zou, an associate professor of biomedical data science at Stanford, to conduct the study, which was spearheaded by graduate student, Eric Sun.

Brunet’s lab, a leader in brain aging and neural stem cell biology, provided the biological expertise and experimental framework. Zou’s team brought cutting-edge AI techniques to analyze the data, while Sun, with a background in physics and quantitative analysis, acted as the bridge between these two worlds.

The research was supported by a Catalyst Award from the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute.

These findings open new avenues of research, including examining how rejuvenating interventions like exercise and reprogramming factors promote brain health, potentially by enhancing the brain’s natural resilience and repair mechanisms. Such insights may suggest new strategies to combat neurodegeneration and cognitive decline.

The findings may also help scientists understand how diseases such as Alzheimer’s disease change the way cells interact and drive brain aging.

Cells that age — and rejuvenate — the brain

The research team set out to tackle a fundamental question: How do cells in their native environment influence one another during the aging process?

Previous studies have focused on individual cells in isolation, overlooking the critical context of their “neighborhoods” — the cells surrounding them.

By preserving and analyzing these spatial relationships, the team aimed to uncover whether interactions between different cell types either drive or mitigate aging in the brain.

Their investigation revealed a striking finding: Out of the 18 different cell types the researchers identified, two rare cell types had powerful but opposing effects on nearby cells.

T cells, immune cells that infiltrate the aging brain, have a distinctly pro-inflammatory, pro-aging effect on neighboring cells that may be driven by interferon-γ, a signaling molecule that drives inflammation.

On the other hand, they found that neural stem cells, though rare, demonstrate a powerful rejuvenating effect, even on nearby cells outside the neural lineage.

During brain development, neural stem cells mature into the major cell types in the brain; in adults, they can also give rise to new neurons and are important for maintenance and repair of the nervous system.

Beyond their well-established ability to generate healthy new neurons, the new study suggests NSCs may help create a supportive environment for brain cells.

These findings are important, says Zou, “because they highlight how cellular interactions — not just the intrinsic properties of individual cells — shape the aging process.”

Building a map and models

At the heart of this research are three key innovations by the research team: a spatial single-cell atlas of gene activity in the mouse brain across its lifespan and two advanced computational tools, each essential for piecing together how cells influence one another as they age.

To map the complex neighborhoods of the brain, the researchers created a spatial single-cell transcriptomic atlas of the mouse brain, capturing gene expression data from 2.3 million cells across 20 stages of life, equivalent to human ages 20 to 95.

Unlike traditional methods that separate complex tissues, like the brain, into a collection of many disconnected cells, this experimental approach preserved the spatial relationships between cells, allowing the team to study how their spatial proximity shapes aging.

The atlas laid the groundwork for the first computational tool — a spatial aging clock. The clocks are machine-learning models designed to predict the biological age of individual cells based on their gene expression.

“For the first time, we can use aging clocks as a tool to discover new biology,” says Sun, instead of just using them to estimate biological age.

The second tool, built using graph neural networks, provided a powerful way to model these cell-to-cell interactions. By creating a kind of in silico brain, the researchers could simulate what happens when specific cell types are added, removed, or altered. This allowed them to explore potential interventions that would be nearly impossible to test in a living brain.

“This computational tool allows us to simulate what happens when we perturb individuals cell in the brain, which is something we can’t really test experimentally at scale,” says Zou.

To ensure the broader scientific community can build on their findings, Sun has made their tools and code publicly available, providing a valuable resource for studying cellular interactions across various tissues and organisms.

Implications and future directions

The study offers major insights into the drivers of aging, as well as rejuvenating factors that could help restore resilience and vitality to the aging brain.

“Different cells respond differently to rejuvenating interventions,” explains Brunet.

“Brain aging is exceptionally complex, so future therapies will need to be tailored not only to tissues but also to the specific cell types within those tissues.”

By demonstrating how spatial context and proximity influence cellular aging, the research builds on longstanding theories about the role of immune and senescent cells in the aging process. Looking ahead, the team hopes to move from observation to causation.

“If we prevent T cells from releasing their pro-aging factors or enhance the effects of neural stem cells, how does that change the tissue over time?” asks Brunet.

While the study focused on mice, the team also hopes to extend their approach to human tissues. “We’re working to make these tools broadly applicable to other tissues and biological processes,” adds Sun.

Funding

The research was supported by the the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute, the Stanford Knight-Hennessy Scholars Program, the National Institutes of Health (P01AG036695, R01AG071711), a National Science Foundation (Graduate Research Fellowship, CAREER award 1942926), P.D. Soros Fellowship for New Americans, Silicon Valley Foundation, Chan Zuckerberg Biohub–San Francisco Investigator program, Chan Zuckerberg Initiative, the Milky Way Research Foundation, the Simons Foundation, and a generous gift from M. and T. Barakett.

Competing Interests

Brunet is a scientific advisory board member of Calico.

About this genetics and neuroscience research news

Author: Nicholas Weiler
Source: Stanford
Contact: Nicholas Weiler – Stanford
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Spatial transcriptomic clocks reveal cell proximity effects in brain ageing” by Anne Brunet, et al. Nature

Interleukin-2 Mediated Expansion of T-Regulatory Cells as an Ischemic Stroke Therapy

 You do expect your competent? doctor and hospital  to get human testing going? OF COURSE NOT! They are way too fucking incompetent to even know about this research, much less do something about it!

Interleukin-2 Mediated Expansion of T-Regulatory Cells as an Ischemic Stroke Therapy

David A. Hurst and

Farida Sohrabji

Originally published24 May 2024https://doi.org/10.1161/STROKEAHA.124.047357Stroke. 2024;55:e159–e160

The inflammatory cascade(Call it what is really is: the neuronal cascade of death! Which your doctors are doing nothing about, leaving millions to billions of neurons to die in the first week!) that ensues following an ischemic stroke has been increasingly recognized(Known since the Rockefeller University report in Jan. 2009! So you're that fucking out-of-date?) as a driving force in the long-term disability associated with the disease. This synopsis will highlight recent preclinical studies that aimed to promote a robust Treg (T-regulatory cell) response via interleukin-2 (IL-2) signaling following an experimental stroke.

To elucidate the mechanism by which an expansion in Tregs following experimental ischemic injury promotes white matter integrity and functional recovery, Yuan et al (Regulatory T cell expansion promotes white matter repair after stroke. Neurobiol Dis. 2023;179:106063. doi: 10.1016/j.nbd.2023.106063) demonstrated that Treg augmentation via direct intravenous transfer of Tregs isolated from donor mice 2 hours after transient middle cerebral artery occlusion (tMCAO) resulted in improved white matter recovery when compared with splenocyte-treated mice poststroke. To determine whether promoting an endogenous Treg expansion poststroke would similarly result in a neuroprotective(Don't ever use the milquetoast word, neuroprotection. It doesn't signal urgency at all! Whereas your doctor telling you they failed to stop the neuronal cascade of death in the first week might engender a few medical malpractice suits. I suggest a payment of $1000 a dead neuron; in my case that would come to 5.571 billion dead neurons; Only 55 trillion dollars!) phenotype, wild-type mice were treated with either a consecutive intraperitoneal administration of IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or equal concentrations of isotype-matched antibody (IgG) at 6 hours, 1 day, 2 days, 3 days, 10 days, 20 days, and 30 days after stroke. At 14 days after stroke, IL-2/IL-2Ab mice displayed a significant increase in the CD25⁺CD4⁺Foxp3⁺ Treg cell population in the blood, spleen, and brain parenchyma when compared with IgG-treated controls. Importantly, IL-2/IL-2Ab treatment mitigated sensorimotor dysfunction at 35 days, but not at 7 days after stroke. To evaluate white matter integrity, longitudinal in vivo diffusion tensor imaging scans 14 and 28 days after tMCAO coupled with ex vivo diffusion tensor imaging scanning of brains 35 days after stroke were used to construct fractional anisotropy maps. Fractional anisotropy mapping showed that IL-2/IL-2Ab–treated mice exhibited improved white matter integrity at 28 and 35 days after stroke, indicating that Treg expansion promotes white matter integrity in the late phase of stroke. Delayed IL-2/IL-2Ab treatment remained protective even when administered as late as 5 days after stroke, as Luxol fast blue staining of coronal brain slices of treated mice showed increased myelin in the external capsule and striatum 21 days after tMCAO in IL-2/IL-2Ab–treated mice compared with IgG-treated mice.

To determine a precise signaling mechanism through which Tregs promote long-term tissue repair following ischemic stroke, Shi et al (Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity. 2021;54:1527–1542.e8. doi: 10.1016/j.immuni.2021.04.022) utilized single-cell RNA sequencing and flow cytometry to verify that Tregs are among the immune cell populations that infiltrate the brain poststroke at 3, 5, 7, 14, and 35 days after stroke. To confirm their role in improving white matter integrity after stroke, Tregs were selectively depleted via diphtheria toxin (DT) injections in Foxp3^DTR (DTR) transgenic mice that express the DT receptor under the control of the Foxp3 promoter. Treg depletion resulted in diminished functional recovery and drastically aggravated white matter lesions following an ischemic stroke. Comparative transcriptomic analysis of sorted CD4⁺CD25⁺Foxp3(GFP)⁺ Treg cells from the ischemic brain and blood of stroke and sham DTR mice identified differentially expressed genes between brain-infiltrating Treg cells and peripheral Treg cells; several genes upregulated in brain-infiltrating Treg cells encoded trophic factors known to stimulate oligodendrocyte precursor cell differentiation, such as Igf1, IL-1a, and Osm. Additionally, brain-infiltrating Treg cells displayed higher levels of transcripts encoding cytokines such as Spp1, Il1b, Il1a, and Il10, suggesting that Treg cell-mediated white matter repair may rely on immunomodulatory signals and cell-cell interactions. Treg-derived osteopontin was identified as a potential signaling molecule driving microglial-mediated white matter repair, as protein-protein interaction enrichment analysis via STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) identified interactions between Spp1, which encodes osteopontin, and Itgb1, Itga5, and Itgav, which encode the integrin subunits of the osteopontin receptor on microglia. To confirm the role of osteopontin signaling in vivo, Treg cells derived from wild-type or Spp1^−/− mice into DTR+DT mice 6 hours after tMCAO, and myelination was assessed via Luxol fast blue staining. Importantly, Spp1^−/− Treg cell-treated mice displayed a reduction in myelination when compared with wild-type Treg cell-treated mice. Lastly, this study showed that IL-2/IL-2Ab treatment boosted the number of osteopontin+ Treg cells in the ischemic brain 3 days after tMCAO, improved sensorimotor function, spatial learning, and mitigated white matter injury (fractional anisotropy mapping and dual staining for myelin basic protein).

Observing the capacity of IL-2 to drive Treg recruitment and infiltration into the brain following stroke resulting in improved functional recovery and white matter repair, Yshii et al (Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat Immunol. 2022;23:878–891. doi: 10.1038/s41590-022-01208-z) aimed to develop and validate a central nervous system–specific therapeutic strategy. The adeno-associated virus–based therapeutic delivery system detailed in this study utilized the GFAP (glial fibrillary acidic protein) promoter to drive IL-2 expression in astrocytes specifically while simultaneously avoiding expression in both the peripheral immune systems and astrocytes. The ability of the delivery system to drive astrocyte-specific expression of IL-2 and increase recruit of Tregs to the central nervous system was validated using ELISA, flow cytometry, immunofluorescent staining, and single-cell RNA-seq. The efficacy of the gene delivery was evaluated in various models of central nervous system injury, such as the controlled cortical impact model for traumatic brain injury, a distal middle cerebral artery occlusion model, the photothrombotic model stroke, and the experimental autoimmune encephalomyelitis model of multiple sclerosis. Cognitive recovery was then assessed 15 days after injury using the Morris water maze test and the novel object recognition test. Comparative assessments of tissue injury and lesion size were conducted using immunofluorescence staining of the cortical tissue and MRI 14 days after injury. Importantly, PHP.GFAP-IL-2 treatment before injury mitigated neuroinflammation and improved functional recovery in all models of central nervous system injury, including traumatic brain injury, stroke, and multiple sclerosis, and did not impact the peripheral immune system.

While preclinical studies have shown promising results in the use of IL-2 to amplify Tregs to mitigate white matter injury following ischemic stroke, the application of this method in clinical settings remains sparse. One major hurdle in applying IL-2–mediated Treg expansion in clinical trials is to do so without inadvertently activating other immune cells or causing broader side effects that come with IL-2 treatments.

Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells

New Scientist magazine has this to say about this research: 

Giving mice antibiotics can protect them from brain damage caused by stroke. Antibiotics change the make-up of the mice's gut bacteria, which in turn alters the immune cells that travel to the brain and would normally cause inflammation. The treatment appears to reduce cell destruction by around 60 percent. 

What is your doctor and hospital doing to ensure human testing gets done? Being incompetent like usual and doing nothing?

Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells

• Corinne Benakis,
• David Brea,
• Silvia Caballero,
• Giuseppe Faraco,
• Jamie Moore,
• Michelle Murphy,
• Giulia Sita,
• Gianfranco Racchumi,
• Lilan Ling,
• Eric G Pamer,
• Costantino Iadecola &
• Josef Anrather 

Nature Medicine volume 22, pages 516–523 (2016)Cite this article

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Abstract

Commensal gut bacteria impact the host immune system and can influence disease processes in several organs, including the brain. However, it remains unclear whether the microbiota has an impact on the outcome of acute brain injury. Here we show that antibiotic-induced alterations in the intestinal flora reduce ischemic brain injury in mice, an effect transmissible by fecal transplants. Intestinal dysbiosis alters immune homeostasis in the small intestine, leading to an increase in regulatory T cells and a reduction in interleukin (IL)-17–positive γδ T cells through altered dendritic cell activity. Dysbiosis suppresses trafficking of effector T cells from the gut to the leptomeninges after stroke. Additionally, IL-10 and IL-17 are required for the neuroprotection afforded by intestinal dysbiosis. The findings reveal a previously unrecognized gut-brain axis and an impact of the intestinal flora and meningeal IL-17⁺ γδ T cells on ischemic injury.

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Longitudinal Variations of CDC42 in Patients With Acute Ischemic Stroke During 3-Year Period: Correlation With CD4+ T Cells, Disease Severity, and Prognosis

Useless, you're predicting failure to recover using CDC42 levels. What survivor wants to hear that?

Longitudinal Variations of CDC42 in Patients With Acute Ischemic Stroke During 3-Year Period: Correlation With CD4⁺ T Cells, Disease Severity, and Prognosis

Xiao Cheng^1,2, Jianxin Ye^3*, Xiaolei Zhang¹ and Kun Meng¹

• ¹Department of Neurology, ShanXi Province People's Hospital of Shanxi Medical University, Taiyuan, China
• ²Shanxi Key Laboratory of Brain Disease Control, Shanxi Provincial People's Hospital, Taiyuan, China
• ³Department of Neurology, The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Fuzhou, China

Objective: Cell division cycle 42 (CDC42) modulates CD4⁺ T-cell differentiation, blood lipids, and neuronal apoptosis and is involved in the pathogenesis of acute ischemic stroke (AIS); however, the clinical role of CDC42 in AIS remains unanswered. This study aimed to evaluate the expression of CDC42 in a 3-year follow-up and its correlation with disease severity, T helper (Th)1/2/17 cells, and the prognosis in patients with AIS.

Methods: Blood CDC42 was detected in 143 patients with AIS at multiple time points during the 3-year follow-up period and in 70 controls at admission by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, blood Th1, Th2, and Th17 cells and their secreted cytokines (interferon-γ (IFN-γ), interleukin-4 (IL-4), and interleukin-17A (IL-17A)) in patients with AIS were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively.

Results: Compared with controls (p < 0.001), CDC42 was reduced in patients with AIS. CDC42 was negatively correlated with the National Institutes of Health Stroke Scale (NIHSS) score (p < 0.001), whereas, in patients with AIS (all p < 0.050), it was positively associated with Th2 cells and IL-4 but negatively correlated with Th17 cells and IL-17A. CDC42 was decreased from admission to 3 days and gradually increased from 3 days to 3 years in patients with AIS (P<0.001). In a 3-year follow-up, 24 patients with AIS recurred and 8 patients died. On the 3rd day, 7th day, 1st month, 3rd month, 6th month, 1st year, 2nd year, and 3rd year, CDC42 was decreased in recurrent patients than that in non-recurrent patients (all p < 0.050). CDC42 at 7 days (p = 0.033) and 3 months (p = 0.023) was declined in reported deceased patients than in survived patients.

Conclusion: CDC42 is used as a biomarker to constantly monitor disease progression and recurrence risk of patients with AIS.

Introduction

Stroke is a common cerebrovascular disease, which has affected nearly 104 million people worldwide in the past three decades and has climbed to the second leading cause of death (second only to ischemic heart disease), besides, stroke is also known for its high disability rate (nearly 33.4–71%) (1–4). Acute ischemic stroke (AIS) is the primary type of stroke (accounting for ~70% of all stroke cases), which is characterized by immune system disorder, severe neurological deficits, etc. (5–10). Gradually, diversified therapeutic strategies (including thrombolysis, antiplatelet treatment, anticoagulants, and neuroprotective agents) have been introduced in an attempt to eliminate arterial occlusion, restore blood flow to the brain, and improve the recovery of neurological function; however, AIS is disease prone to recurrence, which requires continuous attention (11–16). Therefore, it is imperative to develop objective biomarkers to help identify patients with AIS as soon as possible, predict their outcomes, and then adjust the treatment regimens accordingly.

Cell division cycle 42 (CDC42), a small hydrolase of guanosine triphosphate (GTPase), acts as a signal transduction convergence point that mediates many signaling pathways. Moreover, it is reported that CDC42 regulates blood lipids, blood vessel development, CD4⁺ T-cell differentiation, microglial process, and neuronal apoptosis in some cardiovascular and cerebrovascular diseases (including ischemic brain injury, coronary heart disease, and cerebrovascular malformations) (17–23). For instance, a study found that CDC42 can act as an upstream activator of the c-Jun N-terminal kinase (JNK) signaling pathway to govern neuronal apoptosis in ischemic brain injury (19). Another study explored the correlation between CDC42 and T helper (Th) 2 cells, Th17 cells, and blood lipids in patients with coronary heart disease (20). Interestingly, these CDC42-modulated biological processes (mentioned above) behave as underlying pathogenesis of AIS, implying that CDC42 might be implicated in the development of AIS (6, 8, 24). Additionally, an in vitro study reported that the activation of CDC42 promoted the migration of endogenous neural stem/progenitors cells after ischemic stroke, which facilitates the recovery of injured brain tissue (25). However, the detailed clinical role of CDC42 in patients with AIS remains unanswered.

In this study, the expression of CDC42 was detected in patients with AIS during a 3-year follow-up period with the aim of evaluating the longitudinal changes of CDC42 and its correlation with disease severity, Th1/2/17 cells, and the prognosis in patients with AIS.

More at link.

 

Johns Hopkins Breakthrough Opens the Door for Stem Cell Transplants to Repair the Brain

In mice, so your doctor and stroke hospital have followup to to to ensure this gets tested in humans. With tens of thousands of doctors and stroke hospital presidents calling for this research it would get done.  Their responsibility, if they fail at this, call the board of directors and ask when competent people will be employed. 

Johns Hopkins Breakthrough Opens the Door for Stem Cell Transplants to Repair the Brain 

TOPICS:BrainJohns Hopkins MedicineNeurobiologyNeuroscienceStem Cells

By Johns Hopkins Medicine September 16, 2019

GRPs confocol in brain. Credit: Johns Hopkins Medicine

Transplanted brain stem cells survive without anti-rejection drugs in mice. By exploiting a feature of the immune system, researchers open the door for stem cell transplants to repair the brain.

In experiments in mice, Johns Hopkins Medicine researchers say they have developed a way to successfully transplant certain protective brain cells without the need for lifelong anti-rejection drugs.
A report on the research, published today (September 16, 2019) in the journal Brain, details the new approach, which selectively circumvents the immune response against foreign cells, allowing transplanted cells to survive, thrive and protect brain tissue long after stopping immune-suppressing drugs.

The ability to successfully transplant healthy cells into the brain without the need for conventional anti-rejection drugs could advance the search for therapies that help children born with a rare but devastating class of genetic diseases in which myelin, the protective coating around neurons that helps them send messages, does not form normally. Approximately 1 of every 100,000 children born in the U.S. will have one of these diseases, such as Pelizaeus-Merzbacher disease. This disorder is characterized by infants missing developmental milestones such as sitting and walking, having involuntary muscle spasms, and potentially experiencing partial paralysis of the arms and legs, all caused by a genetic mutation in the genes that form myelin.
“Because these conditions are initiated by a mutation causing dysfunction in one type of cell, they present a good target for cell therapies, which involve transplanting healthy cells or cells engineered to not have a condition to take over for the diseased, damaged or missing cells,” says Piotr Walczak, M.D., Ph.D., associate professor of radiology and radiological science at the Johns Hopkins University School of Medicine.
A major obstacle to our ability to replace these defective cells is the mammalian immune system. The immune system works by rapidly identifying ‘self’ or ‘nonself’ tissues, and mounting attacks to destroy nonself or “foreign” invaders. While beneficial when targeting bacteria or viruses, it is a major hurdle for transplanted organs, tissue or cells, which are also flagged for destruction. Traditional anti-rejection drugs that broadly and unspecifically tamp down the immune system altogether frequently work to fend off tissue rejection, but leave patients vulnerable to infection and other side effects. Patients need to remain on these drugs indefinitely.
In a bid to stop the immune response without the side effects, the Johns Hopkins Medicine team sought ways to manipulate T cells, the system’s elite infection-fighting force that attacks foreign invaders.
Specifically, Walczak and his team focused on the series of so-called “costimulatory signals” that T cells must encounter in order to begin an attack.
“These signals are in place to help ensure these immune system cells do not go rogue, attacking the body’s own healthy tissues,” says Gerald Brandacher, M.D., professor of plastic and reconstructive surgery and scientific director of the Vascularized Composite Allotransplantation Research Laboratory at the Johns Hopkins University School of Medicine and co-author of this study.
The idea, he says, was to exploit the natural tendencies of these costimulatory signals as a means of training the immune system to eventually accept transplanted cells as “self” permanently.
To do that, the investigators used two antibodies, CTLA4-Ig and anti-CD154, which keep T cells from beginning an attack when encountering foreign particles by binding to the T cell surface, essentially blocking the ‘go’ signal. This combination has previously been used successfully to block rejection of solid organ transplants in animals, but had not yet been tested for cell transplants to repair myelin in the brain, says Walczak.
In a key set of experiments, Walczak and his team injected mouse brains with the protective glial cells that produce the myelin sheath that surrounds neurons. These specific cells were genetically engineered to glow so the researchers could keep tabs on them.
The researchers then transplanted the glial cells into three types of mice: mice genetically engineered to not form the glial cells that create the myelin sheath, normal mice and mice bred to be unable to mount an immune response.
Then the researchers used the antibodies to block an immune response, stopping treatment after six days.
Each day, the researchers used a specialized camera that could detect the glowing cells and capture pictures of the mouse brains, looking for the relative presence or absence of the transplanted glial cells. Cells transplanted into control mice that did not receive the antibody treatment immediately began to die off, and their glow was no longer detected by the camera by day 21.
The mice that received the antibody treatment maintained significant levels of transplanted glial cells for over 203 days, showing they were not killed by the mouse’s T cells even in the absence of treatment.
“The fact that any glow remained showed us that cells had survived transplantation, even long after stopping the treatment,” says Shen Li, M.D., lead author of the study. “We interpret this result as a success in selectively blocking the immune system’s T cells from killing the transplanted cells.”
The next step was to see whether the transplanted glial cells survived well enough to do what glial cells normally do in the brain — create the myelin sheath. To do this, the researchers looked for key structural differences between mouse brains with thriving glial cells and those without, using MRI images. In the images, the researchers saw that the cells in the treated animals were indeed populating the appropriate parts of the brain.
Their results confirmed that the transplanted cells were able to thrive and assume their normal function of protecting neurons in the brain.
Walczak cautioned that these results are preliminary. They were able to deliver these cells and allow them to thrive in a localized portion of the mouse brain.
In the future, they hope to combine their findings with studies on cell delivery methods to the brain to help repair the brain more globally.
###
Other researchers involved in this study include Byoung Chol Oh, Chengyan Chu, Antje Arnold, Anna Jablonska, Georg Furtmüller, Huamin Qin and Miroslaw Janowski of The Johns Hopkins University; Shen Li of the Dalian Municipal Central Hospital and The Johns Hopkins University; Johannes Boltze of the University of Warwick; and Tim Magnus and Peter Ludewig of the University of Hamburg.

Reference: “Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts” by Shen Li, Byoung Chol Oh, Chengyan Chu, Antje Arnold, Anna Jablonska, Georg J Furtmüller, Hua-Min Qin, Johannes Boltze, Tim Magnus, Peter Ludewig, Mirosław Janowski, Gerald Brandacher and Piotr Walczak, 16 September 2019, Brain.

Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

So followup is needed. Contact your stroke leaders to get this done.  Nothing will happen since we have NO stroke leadership. 

Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

• Minako Ito,
• Kyoko Komai,
• Setsuko Mise-Omata,
• Mana Iizuka-Koga,
• Yoshiko Noguchi,
• Taisuke Kondo,
• Ryota Sakai,
• Kazuhiko Matsuo,
• Takashi Nakayama,
• Osamu Yoshie,
• Hiroko Nakatsukasa,
• Shunsuke Chikuma,
• Takashi Shichita &
• Akihiko Yoshimura 

Nature (2019) | Download Citation

Abstract

In addition to maintaining immune tolerance, FOXP3⁺ regulatory T (T_reg) cells perform specialized functions in tissue homeostasis and remodelling^1,2. However, the characteristics and functions of brain T_reg cells are not well understood because there is a low number of T_reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T_reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T_reg cells are similar to T_reg cells in other tissues such as visceral adipose tissue and muscle^3,4,5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT₇. The amplification of brain T_reg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T_reg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T_reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.

Regulatory T Cells in Central Nervous System Injury: A Double-Edged Sword

I don't understand, but what is your doctor doing with this information? 

Regulatory T Cells in Central Nervous System Injury: A Double-Edged Sword

Walsh JT¹, Zheng J², Smirnov I³, Lorenz U⁴, Tung K⁵, Kipnis J⁶.

Author information

Abstract

Previous research investigating the roles of T effector (T_eff) and T regulatory (T_reg) cells after injury to the CNS has yielded contradictory conclusions, with both protective and destructive functions being ascribed to each of these T cell subpopulations. In this work, we study this dichotomy by examining how regulation of the immune system affects the response to CNS trauma. We show that, in response to CNS injury, T_eff and T_reg subsets in the CNS-draining deep cervical lymph nodes are activated, and surgical resection of these lymph nodes results in impaired neuronal survival. Depletion of T_reg, not surprisingly, induces a robust T_eff response in the draining lymph nodes and is associated with impaired neuronal survival. Interestingly, however, injection of exogenous T_reg cells, which limits the spontaneous beneficial immune response after CNS injury, also impairs neuronal survival. We found that no T_reg accumulate at the site of CNS injury, and that changes in T_reg numbers do not alter the amount of infiltration by other immune cells into the site of injury. The phenotype of macrophages at the site, however, is affected: both addition and removal of T_reg negatively impact the numbers of macrophages with alternatively activated (tissue-building) phenotype. Our data demonstrate that neuronal survival after CNS injury is impaired when T_reg cells are either removed or added. With this exacerbation of neurodegeneration seen with both addition and depletion of Treg, we recommend exercising extreme caution when considering the therapeutic targeting of T_reg cells after CNS injury, and possibly in chronic neurodegenerative conditions.

Antigen-specific immune reactions to ischemic stroke

I'm not sure how this will help us so ask your doctors what they will do with this information. Hopefully not scoff at you. Mine pretty much did when I asked about specific research articles. I doubt he had read anything new since medical school. That lack of acquiring knowledge needs to be brought up to the hospital president because that means the stroke department head is not setting proper goals and expectations. 

Antigen-specific immune reactions to ischemic stroke

http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00278/full?utm_source=newsletter&utm_medium=email&utm_campaign=Neuroscience-w41-2014
Xabier Urra^1,2, Francesc Miró², Angel Chamorro^1,2 and Anna M. Planas^2,3*

• ¹Functional Unit of Cerebrovascular Diseases, Hospital Clínic, Barcelona, Spain
• ²August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
• ³Department of Brain Ischemia and Neurodegeneration, Instituto de Investigaciones Biomédicas de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain

Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke.

Halting Immune Response Could Save Brain Cells After Stroke

Well, well, how much more proof is needed to utilize this? 

Halting Immune Response Could Save Brain Cells After Stroke

A new study in animals shows that using a compound to block the body’s immune response greatly reduces disability after a stroke.
The study by scientists from the University of Wisconsin School of Medicine and Public Health also showed that particular immune cells—CD4+ T-cells produce a mediator, called interleukin (IL)-21 that can cause further damage in stroke tissue.
Moreover, normal mice, ordinarily killed or disabled by an ischemic stroke, were given a shot of a compound that blocks the action of IL-21. Brain scans and brain sections showed that the treated mice suffered little or no stroke damage. 
“This is very exciting because we haven’t had a new drug for stroke in decades, and this suggests a target for such a drug,” says lead author Dr. Zsuzsanna Fabry, professor of pathology and laboratory medicine.
Stroke is the fourth-leading killer in the world and an important cause of permanent disability. In an ischemic stroke, a clot blocks the flow of oxygen-rich blood to the brain. But Fabry explains that much of the damage to brain cells occurs after the clot is removed or dissolved by medicine. Blood rushes back into the brain tissue, bringing with it immune cells called T-cells, which flock to the source of an injury.
The study shows that after a stroke, the injured brain cells provoke the CD4+ T-cells to produce a substance, IL-21, that kills the neurons in the blood-deprived tissue of the brain. The study gave new insight how stroke induces neural injury.

Similar Findings in Humans
Fabry’s co-author Dr. Matyas Sandor, professor of pathology and laboratory medicine, says that the final part of the study looked at brain tissue from people who had died following ischemic strokes. It found that CD4+ T-cells and their protein, IL-21 are in high concentration in areas of the brain damaged by the stroke.
Sandor says the similarity suggests that the protein that blocks IL-21 could become a treatment for stroke, and would likely be administered at the same time as the current blood-clot dissolving drugs.
“We don’t have proof that it will work in humans,” he says, “but similar accumulation of IL-21 producing cells suggests that it might.”
The paper was published in the Journal of Experimental Medicine.
Source: University of Wisconsin School of Medicine and Public Health

Tolerization to Brain and Vascular Antigens: Targeting Autoimmunity After Acute Brain Injuries and Preventing Stroke

No idea what this means.
link.springer.com/chapter/10.1007/978-1-4614-8915-3_16#page-1

• Kyra J. Becker,
• John Hallenbeck

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Abstract

The immune response can contribute to the risk of stroke as well as to brain injury following stroke. Directed modulation of the immune response to attenuate risk or injury is thus a potential therapeutic strategy for treating stroke. Inducing a population of antigen-specific regulatory T cells is one such strategy and can be used to locally modulate the immune response to the organs in which the antigen is present, thereby limiting potential side effects. This chapter addresses the use of mucosal tolerance to both prevent and treat ischemic stroke.