Category: Immunology

New Treatment may Regenerate Liver Scarring

Japanese researchers have come up with a new approach that could revolutionise the treatment and prevention of liver disease damage and possibly regenerate liver scarring.

This novel strategy involves small extracellular vesicles (sEVs), which are lipid-enclosed particles that are naturally released from a cell. The ones used in this study derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs).

Cirrhosis (scarring of the liver) and other chronic liver diseases result in up to 2 million deaths reported annually around the world, these in turn account for approximately 3.5% of annual deaths globally. As the only treatment for clinically advanced cirrhosis liver transplantation, targeted therapies for modulating fibrosis and aiding tissue regeneration.  The ability to control fibrosis–the growth of fibrous tissue in response to damage– is often lost in livers under advanced cirrhosis.  The research builds upon this.

One of the most popular approaches is cell therapy, where mesenchymal stromal cells (MSCs) and macrophages have shown the potential to reduce liver fibrosis. MSCs are able to transform into a number of different cells. They are cost-effective, being available not only from bone marrow, but also from medical waste such as umbilical cord tissue, adipose (fatty) tissue, and dental pulp.

Apart from the ease of availability, MSCs can also be lab-grown. MSCs don’t replace tissue but instead have been shown to be medical signaling cells that indirectly produce cytokines, chemokines, growth factors, and exosomes that are crucial for repairing and regenerating damaged tissue.

Previous research showed that MSCs have anti-inflammatory, anti-fibrotic, and anti-oxidative effects through these humoural factors. MSCs also have lower potential for provoking an immune response and therefore rejection, enabling their use in both within the same individual and another.

In a series of experimental mice studies, researchers pre-conditioned fat extracellular vesicles with interferon gamma (IFN-γ), an important immune system signaller. They showed that this increases the number of anti-inflammatory macrophages, which are the key players in tissue repair, reducing fibrosis and promoting tissue regeneration.

They reported that both MSCs derived from fatty tissue (AD-MSC-sEVs) and AD-MSC-γ-sEVs can boost macrophage motility and phagocytic activity. In addition, they also show that AD-MSC-γ- sEVs can effectively control inflammation and fibrosis in mice with cirrhosis.

They found thatAD-MSC-derived sEVs can affect the shape and function of macrophages, effectively recruiting them into damaged areas to initiate tissue repair.

In an interview, researcher Dr Atsunori Tsuchiya at Niigata University, explained that, “Both mesenchymal stromal cells and macrophages are reported to have therapeutic effects for liver cirrhosis, however relationship of both cells and mechanisms of action was not clear. We challenged this problem.”

He continued, “We found the important fact that extracellular vesicles from interferon-γ can induce the tissue repair macrophages, which can regress fibrosis and promote liver regeneration effectively.” 

Dr Suguru Takeuchi, another of the researchers at Niigata University, concurred: “In our previous study, we reported that intravenous administration of mesenchymal stromal cells migrated to the lung, can work as ‘conducting cells’ and affect to macrophages ‘working cells’ in the liver.

“In this study we first elucidated that extracellular vesicles from mesenchymal stromal cells are key molecules to affect the macrophages.”

This study, which complements macrophage therapy, holds potential as a strategy for treating liver diseases using small extracellular vesicles pre-conditioned with IFN-γ. However, further development is needed, as well as uncovering the mechanisms by which they increase Treg cell count.

“Our results showed that modified extracellular vesicles can become a new therapeutic strategy for liver cirrhosis,” said Professor Shuji Terai, Niigata University.

Source: News-Medical.Net

Journal information: Takeuchi, S., et al. (2021) Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis. npj Regenerative Medicine. oi.org/10.1038/s41536-021-00132-4.

Study Shows That Viral Infections Affect Immune System like Ageing


A study from the Buck Institute and Stanford University suggests that chronic viral infections leave an impact on the human immune system, similar to those seen during ageing.

Using systems immunology and artificial intelligence, researchers profiled and compared immune responses in a cohort of aging individuals, people with HIV on long-term antiretroviral therapy, and people infected with hepatitis C (HCV) before and after the virus was treated with sofosbuvir, a drug with a 97% cure rate. Shared immune system alterations include T cell memory inflation, upregulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells.

“Chronic inflammation stemming from immune system dysfunction is associated with many of the diseases of ageing,” said senior author David Furman, PhD, Buck Institute associate professor. “Whether chronic viral infection contributes to age-associated immune dysfunction is still an open question, but studies of this type provide a way to start getting answers. At this point it’s clear that both ageing and chronic viral infections leave profound and indelible marks on immunity.”

The body is normally able to clean out acute viral infections, such as the common cold. But some viruses besides just HIV and HCV can remain alive, setting up ‘host-parasite housekeeping’ in the body, without people’s awareness. Dr Furman said that, depending on geographic location, 70 to 90% of the population is infected with cytomegalovirus. In healthy people, this is harmless and problematic only for pregnant women or those with compromised immune systems. Various herpes viruses can also lead to chronic infections.

“Each of us has our own virome; it’s the collection of the viral infections you have during your lifespan,” Furman said. “You probably have been infected by 12 or 15, or even more viruses that you never knew you had. Fortunately technology now exists that allows us to profile these infections in the human population; it is helping us move these types of inquiries forward.” Dr He said this study is the first to fully incorporate the concept of systems immunology, holistically analysing the immune system with the same technological platforms across different cohorts of patients.

The study demonstrated that in patients with HIV, immune system dysregulations were evident despite having been on antiretrovirals for over ten years. However, clearing the HCV virus partially restored cellular sensitivity to interferon-a, which inhibits viral replication. “This plasticity means there is room for intervention in both chronic viral infections and in ageing,” said Dr Furman. “It’s just a matter of identifying and understanding the molecular pathways and networks involved.” The study also identified changes in STAT1, the primary transcription factor activated by interferons. STAT1 plays a major role in normal immune responses, particularly to viral, mycobacterial and fungal pathogens.

As for COVID, Dr Furman said that we are in the midst of an ongoing “living” experiment. Future studies are needed to determine whether the functional imprinting of the immune system is hardwired to only involve the chronic nature of specific infections, or whether short but vigorous ones such as COVID also leave a lasting mark on the immune system. “Has the immune system of those infected with the coronavirus taken a big hit? That’s a theory, but we don’t know what will happen,” says Furman, who is collaborating with Stanford University and the University of California, San Francisco on projects involving COVID-19 and immunity.

Source: Medical Xpress

Journal information: Cesar J. Lopez Angel et al., “Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.2022928118

Insights into How CAR T Cancer Treatment Works

Researchers have uncovered why some patients respond strongly to chimeric antigen receptor T-cell therapy (CAR T), 

CAR T is a new development in cancer therapy, a treatment approved to treat many types of aggressive B cell leukaemias and lymphomas. Moffitt Cancer Center researchers use mathematical modeling to help explain why CAR T cells work in some patients and not in others, with the response instead tapering off and the disease continuing its progression.

CAR T is a type of personalised immunotherapy that uses a patient’s own T cells to target cancer cells. Many patients have strong responses to CAR T; however, some have only a short response and develop disease progression quickly. The procedure involves T cells from a patient being genetically modified to include a specific receptor targeting cancer cells. 

hemotherapy then lowers some of the patient’s existing normal immune cells to help deal with the influx of CAR T cells that are infused back into the patient, where they can get to work and attack the tumour.

“Treatment success critically depends on the ability of the CAR T cells to multiply in the patient, and this is directly dependent upon the effectiveness of lymphodepletion that reduces the normal T cells before CAR T infusion,” explained co-lead author Frederick Locke, MD, Vice Chair, Blood and Marrow Transplant and Cellular Immunotherapy Department, Moffitt.

In their model, the researchers discovered that tumour eradication is effectively random, but can happen with high probability. The researchers showed that differences in the timing and probability of cures are determined largely by variability among patient and disease factors. The model confirmed that cures tends to happen 20 to 80 days before the CAR T cells decline, while disease tends to progress over a wider time range between 200 to 500 days after treatment.

“Our model confirms the hypothesis that sufficient lymphodepletion is an important factor in determining durable response. Improving the adaptation of CAR T cells to expand more and survive longer in vivo could result in increased likelihood and duration of response,” explained lead author Philipp Altrock, PhD, and assistant member of the Integrated Mathematical Oncology Department at Moffitt.

Source: News-Medical.Net

Journal information: Kimmel, G.J., et al. (2021) The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy. Proceedings of the Royal Society B: Biological Sciences. doi.org/10.1098/rspb.2021.0229.

Newly Discovered ‘Goldilocks’ Protein Keeps the Immune System in Check

A newly discovered ‘Goldilocks’ protein may be responsible for helping keep the immune system from running amok, according to researchers at the Lunenfeld-Tanenbaum Research Institute (LTRI).

This protein, known as WAVE2, is expressed in all immune cells and plays a critical role in keeping the immune system in balance. To test its role, researchers knocked out the WAVE2 protein in a subset of immune cells in mice, leading to severe autoimmunity and inflammation, as well as an inability to mount an immune response to a viral infection.

Senior author Dr Kathy Siminovitch, said the team also found that in the absence of WAVE2, another protein, known as mTOR, became overly active, sending the immune system into overdrive and leading to immune cell exhaustion.

“Much like Goldilocks, a proper immune response requires such a delicate balance,” said Dr  Siminovitch. “You have to get it just right. By developing a mouse strain in which T cells, key players in immunity, lack WAVE2, we have shown that this protein is absolutely required for balanced immune responses.”

The question of how to keep the immune system in balance is of key importance in the pandemic, where many deaths occur due to cytokine storms as the immune system overreacts, especially in the elderly. 
As part of her work exploring the mechanisms balancing the immune system, Dr Siminovitch helped trace the complex molecular steps that turn a rare gene mutation into Wiskott-Aldrich syndrome, a potentially lethal disease which impairs the immune system of boys.

Future research would look at how the contribution of the WAVE2-mTOR pathway to specific autoimmune, inflammatory and other conditions, such as Alzheimer’s disease.

Source: News-Medical.Net

Journal information: Liu, M., et al. (2021) WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. doi.org10.1126/science.aaz4544.

Common Preservative May Interfere with Immune Functions

A common preservative may hamper immune functions, along with other chemicals, warns the Environmental Working Group (EWG).

Using the Environmental Protection Agency’s Toxicity Forecaster, or ToxCast, the EWG assessed the potential human health impact of a number of chemicals including those commonly added to food and those that can be transferred to food from packaging.

Particularly concerning in the pandemic era, EWG’s analysis found that the preservative tertiary butylhydroquinone (TBHQ), has been found to harm the immune system both in both animal tests and in high-throughput in vitro toxicology testing.

“The pandemic has focused public and scientific attention on environmental factors that can impact the immune system,” said study lead author Olga Naidenko, PhD, and EWG Vice President for Science Investigations.”Before the pandemic, chemicals that may harm the immune system’s defense against infection or cancer did not receive sufficient attention from public health agencies. To protect public health, this must change.”

Using new non-animal test results from ToxCast, TBHQ was found to affect immune cell proteins at doses considered to cause harm. Previous studies have also found that TBHQ could influence flu vaccine effectiveness and may be associated with a rise in food allergies.

In the United States, the Food and Drug Administration often entrusts food companies to ensure that chemicals added to the foods they produce are safe. Additives such as TBHQ were approved decades ago, and the FDA does not consider new science.

Per- and polyfluoroalkyl substances (PFAS), which are used in food packaging, were found to be in many types of food packaging, and can migrate to food. Human epidemiological studies have found that PFAS is linked to reduced immune function and vaccine effectiveness. Recent research also links bloodstream PFAS levels to COVID severity. 

“Food manufacturers have no incentive to change their formulas,” explained Scott Faber, senior vice president for government affairs at EWG. “Too often, the FDA allows the food and chemical industry to determine which ingredients are safe for consumption. Our research shows how important it is that the FDA take a second look at these ingredients and test all food chemicals for safety.”

The EWG is calling on the FDA to close the food additive loophole, and to conduct immunotoxicity testing of chemicals in food and food packaging.

Source: News-Medical.Net

Journal information: Naidenko, O. V., et al. (2021) Investigating Molecular Mechanisms of Immunotoxicity and the Utility of ToxCast for Immunotoxicity Screening of Chemicals Added to Food. International Journal of Environmental Research and Public Health. doi.org/10.3390/ijerph18073332.

New Compound Can Reduce Inflammation Without Dampening Immune Response

Researchers from Nanyang Technological University (NTU), Singapore, have discovered a compound that is capable of dampening immune overactivity without the cost of reducing the immune response.

The new compound, ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes involved in immune response regulation. These enzymes have received attention in recent years as targets for drugs to treat immune system overactivity, and TYK2 is a possible therapeutic target for cancer treatment. A recent study found that high levels of TYK2 have been associated with severe COVID.

“Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes,” said Phan Anh, Professor and Interim Director, Institute of Structural Biology, NTU.

Co-lead author Dr Lim Kah Wai, NTU senior researcher, added: “With the UK-led study of critically ill COVID patients published in Nature linking high TYK2 expression to severe COVID, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential.”

The ASO-1 compound designed by the researchers is an antisense oligonucleotide (ASO), which targets messenger RNA (mRNA).  ASO-1 was identified from over 200 potentially effective ASOs designed by the team.  ASO-1 is designed to bind to TYK2 mRNA and prevent the cells from making the TYK2 protein. ASO-1 has to be highly selective for TYK in order to prevent side effects involving other JAK enzymes.

Through in vitro testing, the NTU scientists found that ASO-1 greatly reduced TYK2 levels over a sustained period and inhibited immune signalling pathways associated with autoimmune disorders. This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, There was also no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates under development.

The team plans academic collaboration for further development of ASO-1 and animal model testing.

Source: News-Medical.Net

New Biomarker Can Predict Response to Checkpoint Inhibitor Therapy

A team of researchers at Roswell Park Comprehensive Cancer Center have identified a biomarker that could be used to predict how well immune checkpoint inhibitors will be tolerated.

Immune checkpoint inhibitors (ICI) activate anti-tumour defences either through the disruption of inhibitory interactions between antigen-presenting cells and T cells at so-called checkpoints or else through the stimulation of activating checkpoints. Not all patients can tolerate ICI well; side effects can be severe, including colitis, which is one of the most common.

Pre-treatment biomarkers are of limited value in predicting response to ICI. Tumour biopsy shortly after ICI therapy is started can provide helpful information, but is invasive and difficult to do in some certain cancers.
Uncovering blood-based biomarkers that reflect the change of the tumour microenvironment and can predict a patient’s response to ICIs could improve current treatment regimens significantly, Dr. Ito notes. The team’s previous research indicates that T cells with varying levels of the chemokine receptor CX3CR1 responded differently to ICI therapy.

Based on those findings, the researchers sought to test CX3CR1 as a T cell biomarker in ICI therapy. They found that ICI therapy is linked to increased frequency and clonality of some CX3CR1-positive T cells; that the frequency of these CD8+ T cells stays high during ICI therapy; and that there are many genomic similarities between CD8+ tumour-infiltrating lymphocytes and this subset of CX3CR1-positive T cells.

Fumito Ito, MD, PhD, FACS, explained: “Although ICIs revolutionized the cancer treatment for significant numbers of people, many cancer patients do not respond to them, and some develop severe toxicity.”

“Currently, we are in need of a better biomarker to predict the response to immunotherapy, which is part of standard treatment in advanced and metastatic lung cancer,” said Hongbin Chen, MD, PhD. “This study sheds light on a promising blood-based biomarker that is potentially very useful in identifying which patients with lung cancer are most likely to benefit from immunotherapy. We look forward to investigating its utility in further clinical research.”

Source: News-Medical.Net

Journal information: Yamauchi, T., et al. (2021) T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nature Communications.doi.org/10.1038/s41467-021-21619-0.

New Bacteria-based Atopic Dermatitis Treatment Proves Effective

A skin bacteria-based treatment for atopic dermatitis (AD) was successful in clinical trials, with no serious adverse effects and indications that it reduces eczema symptoms as well.

Atopic dermatitis (AD) is a common, chronic skin disorder which can have great impacts on the lives of sufferers. The disorder seems to result from the complex interplay between the skin, environmental effects and the immune system. Treatment involves a multifaceted approach that involves education, optimal skin care practices, anti-inflammatory treatment with topical corticosteroids and/or topical calcineurin inhibitors, the management of pruritus, and the treatment of skin infections. Severe flare-ups or more difficult-to-control disease may be treated with systemic immunosuppressive agents. Topical corticosteroids are the first-line treatment of choice, and seem to be prophylactic against flareups.

AD is associated with S. aureus colonisation, which induces a proteolytic breakdown of the epidermal barrier and dermal immune dysregulation. Inflammation results in further dysregulation of the skin microbial system. Commensal, coagulase-negative staphylococci (CoNS) were observed to produce bacteriocins which inhibit bacteria such as S. aureus, and these were not seen in the skin of most patients with AD. They hypothesised that reintroduction of CoNS would improve AD in patients.

Patients treated with MSB-0221, which incorporated the naturally occurring skin bacteria S. hominis (ShA9), had fewer AD-related adverse events (AEs) as compared with patients treated with a topical placebo, reported Richard L Gallo, MD, PhD, of the University of California San Diego and co-founder of the company developing MSB-0221.

“Besides its effect on decreasing the redness and itch in a subset of patients, and dramatically and rapidly decreasing the colonisation by Staph aureus, one of the unique aspects of this is that it’s specific for this organism,” said Dr Gallo. “It was not detrimental to other members of the microbiome that could help restore balance.”

Applying MSB-0221 to 54 adults, they found a reduction in S. Areus, which was associated with a significant decrease in AD symptoms compared to placebo.

The next step would be a larger, 150 patient clinical trial over 12 weeks.

“We don’t fully understand all of the ramifications, but there seems to be at least a subset of patients with atopic dermatitis whose disease is influenced and exacerbated by certain bacteria, such as Staph aureus,” said Bruce Brod, MD, of the University of Pennsylvania. “There is still sort of a chicken-and-egg aspect to the relationship. Did the skin inflammation come first or the Staph aureus?“

“This is a proof-of-concept study that provides some evidence that shifting the balance of another bacteria that’s not pathogenic might have some therapeutic benefit in some patients with atopic dermatitis,” he added. “It provides support for larger studies looking at safe bacteria to shift the flora to a more favourable environment. At this point, it’s just another piece of a puzzle that could one day lead to different therapies. It’s probably not the whole picture, but in some patients, it may play a significant role.”

Source: MedPage Today

Journal information: Nakatsuji T, et al “Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase I randomized clinical trial” Nature Med 2021; DOI: 10.1038/s41591-021-01256-2.

Discovering Antibodies That Are Safe And Effective Against Zika

The Zika outbreak of 2015 and 2016 left lasting consequences for children who were in the womb when their mothers were infected with the virus, and now researchers are investigating a safe vaccine that will not negatively interact with certain other viruses.

Zika is a flavivirus, a family which includes dengue, West Nile, and yellow fever virus. In order to protect against these and other pathogens, “we have the ability to make a huge diversity of antibodies, and if we get infected or vaccinated, those antibodies recognise the pathogen,” explained first author Shannon Esswein, a graduate student at the California Institute of Technology.

However, when getting sick with a virus a second time, the body’s own immune response can worsen the situation. Known as antibody-dependent enhancement (ADE), this is when the antibodies stick to the outside of the virus but not neutralising its ability to lock onto cells. This can inadvertently help the virus to infect more cells by letting it enter cells the antibodies are sticking to. A recent study sought to investigate whether this could happen with monoclonal antibody treatments for COVID.

In order to prevent ADE when creating a vaccine, knowing how antibodies adhere to a specific virus is crucial for scientists. In the case flaviviruses, this is especially important as antibodies that protect against one flavivirus may also stick to, but not protect against other flaviviruses, raising the risk of ADE. Antibodies generated in response to a Zika virus vaccine could trigger ADE, if that person is exposed to other flaviviruses such as dengue.

To understand this, the researchers looked at a portion of the flavivirus called the envelope domain III protein, which has been shown to be an important target for protective antibodies fighting flavivirus infections. They studied how those antibodies changed over time as they matured and became better able to adhere to the Zika virus. They also looked at how the antibodies cross-reacted with other flaviviruses, including the four dengue virus types. Their results showed that the Zika antibodies also tightly stick to and defend against dengue type 1, but only weakly stick to West Nile and dengue types 2 and 4. “The weak cross-reactivity of these antibodies doesn’t seem to defend against those flaviviruses, but also doesn’t induce ADE,” Esswein said. These results suggest that the envelope domain III could be a useful basis for a safe vaccine. They also described structures demonstrating how two antibodies recognise Zika and West Nile envelope domain III.

The study results demonstrate how the body mounts “a potent immune response to Zika virus,” said Esswein. Insights gained on the antibodies involved in this immune response will aid the development of new vaccines.

Source: Medical Xpress

Journal information: Shannon R. Esswein et al. Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1919269117

COVID Tracking in Space Company Employees Yields Antibody Clues

SpaceX, an aerospace manufacturing company currently providing satellite launch services as well as transport of crew  to the International Space Station, collaborated with researchers from MIT to monitor the spread of COVID amongst its employees. 

Unusually, the paper included SpaceX CEO Elon Musk as a byline author. The technology entrepreneur is known to be quite hands-on in his company’s projects. However, he has also courted controversy by openly questioning COVID tests and saying he and his family would not take COVID vaccines, saying that achieving herd immunity naturally was a better strategy.

SpaceX was seeking data-driven methods to safeguard its essential workforce. The collaboration allowed the researchers to track the emergence of mild and asymptomatic cases in a cohort of adults as early as April, when data for such cases were rare.

“Essentially, this study indicates that it’s not simply the presence or absence of antibodies that matter; rather, the amount and type of antibodies may play a defining role in the development of a protective immune response,” said Professor Galit Alter, Harvard Medical School and Immunologist, Division of Infectious Diseases, Massachusetts General Hospital. 

The study was originally aimed at measuring antibody levels over time, but when reinfections began to be reported, the team realised their samples had some valuable information.

“In early spring, we weren’t sure if asymptomatic infection could drive long-lived antibodies,” said Prof Alter, “nor whether they possessed the capability to neutralise or kill the virus.”

The researchers knew that 120 participants had mild or asymptomatic COVID infections, resulting in their bodies producing antibodies. Using sophisticated techniques to analyse those antibodies, they found that individuals with stronger symptoms in mild COVID, had a larger number of antibodies and developed immune functions associated with natural immune protection. 

The study found that although the presence of antibodies was sufficient to determine whether an individual had experienced a COVID infection, they did not automatically mean that individual is protected against the virus in the long term.

Antibody effector functions (on the ‘long arm’ of the antibody) linked to long-term protection, such as T cell activation and virus neutralisation were only seen in certain immune responses. These involved high levels of antibodies targetting a part of the virus known as the receptor binding domain.

“Once you hit a certain threshold of these antibodies, it’s like a switch turns on and we can observe antibody effector functions,” said first author Yannic Bartsch, PhD. “These functions were not observed in individuals with lower antibody binding titers, and the level of protection from reinfections is uncertain in these individuals.”

Source: News-Medical.Net

Journal information: Bartsch, Y. C., et al. (2021) Discrete SARS-CoV-2 antibody titers track with functional humoral stability. Nature Communications. doi.org/10.1038/s41467-021-21336-8.