Category: Immunology

Categories : Immunology New Compounds and TreatmentsTags :

New Compound Can Reduce Inflammation Without Dampening Immune Response

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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

Categories : Cancer ImmunologyTags :

New Biomarker Can Predict Response to Checkpoint Inhibitor Therapy

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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.

Categories : Diseases, Syndromes and Conditions ImmunologyTags :

New Bacteria-based Atopic Dermatitis Treatment Proves Effective

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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.

Categories : Immunology VaccinesTags :

Discovering Antibodies That Are Safe And Effective Against Zika

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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

Categories : COVID ImmunologyTags :

COVID Tracking in Space Company Employees Yields Antibody Clues

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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.

Categories : COVID ImmunologyTags :

COVID Antibody Drugs Work Best with Immune Cells

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Research into the current antibody-based drugs for COVID treatment shows that they need to be designed to work in concert with immune cells to be effective.

Three drugs using monoclonal antibodies are approved by the FDA to treat COVID, which provide the patient’s body with ready-made antibodies faster than can be produced by their own immune systems.

The distinctive Y shape of antibodies comes from their two short arms, which latch on to foreign molecules to clear them out, and a long effector arm which interacts with immune cells, inducing them to attack infected cells and release molecules that modulate the immune response.

In antibody-dependent enhancement, the long arm of antibodies can interfere with immune cells, such as in tropical dengue fever. Immunity against one strain against dengue fever causes life-threatening illness if infected with the other strain.

To investigate the possibility of this in COVID, some companies altered the long arm of their antibodies to prevent interaction with immune cells. Other companies took the opposite approach and strengthened antibody effector functions to boost the potency of their drugs.

“Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimise the effector functions,” said senior author Michael S Diamond, MD, PhD, the Herbert S Gasser Professor of Medicine. “Neither of these strategies is backed by data in the context of SARS-CoV-2 infections. Based on our findings, if you have a potently neutralising antibody without effector functions and you give it before infection, as a preventive, it will probably work. But if you give it after infection, it won’t work well; you need to optimise effector functions to get maximal benefit.”

“‘Effector functions’ refers to a complex set of interactions between antibodies and other elements of the immune system,” said Prof Diamond, who also is a professor of molecular microbiology and of pathology and immunology. “You can introduce different point mutations to augment certain kinds of effector functions, and some might be harmful to the immune response while others might be beneficial. There’s a lot of nuance. We are still learning how to harness effector functions so you get what you want but not what you don’t want.”

To find how antibody effectors work with COVID, the researchers took an antibody which was known to be effective against the virus and disabled the effector so it could not interact with immune cells.

They administered the original antibodies, the disabled antibodies and placebo antibodies each to a different group of mice, which were infected a day later with SARS-CoV-2. Both normal and disabled effector antibodies were able to protect against the disease. There were no signs of antibody enhancement of the disease, fortunately.

To find out whether the effector function was needed for treatment after infection, they infected mice with SARS-CoV-2 and administered one of the three sets of antibodies to mice  one, two or three days later. Only the original antibodies protected the mice from the disease. The tests were run in hamsters with the same results.

The researchers discovered in the study that losing effector functions changed the types of immune cells recruited to fight the COVID infection and the way they behaved.

Source: Medical Xpress

Journal information: Emma S. Winkler et al, Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection, Cell (2021). DOI: 10.1016/j.cell.2021.02.026

Categories : Cancer ImmunologyTags :

Immune Cells in Prostate Tumours Boost Survival with Immunotherapy

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A new Northwestern Medicine study discovered the reason why black men are more likely to survive prostate cancer when given immunotherapy. 

Black men die more often from prostate cancer, yet are more likely to respond to immunotherapy. The increased presence of a type of immune cell in the tumours of black men appears to be related to their increased odds of survival with immunotherapy. The findings will be published on February 10 in Nature Communications.

A research team by Dr Edward Schaeffer, chair of urology at Northwestern University Feinberg School of Medicine and Northwestern Medicine, found that men who survive prostate cancer with immunotherapy have been found to have more plasma cells. Plasma cells are a type of specially differentiated B cell, which secrete antibodies and play a key role in the adaptive immune response.

“If a man’s prostate cancer has numerous plasma cells, we found he had improved cancer survival,” Schaeffer said. “Our study suggests plasma cells are important in the body’s response to cancer.”

Recent studies have shown that black men with advanced prostate cancer have on average better response to immunotherapy than white men. However, there has been no way to determine which individuals would have a better response, regardless of race.

Schaeffer’s team went through the genomics of 1300 tumour samples classified to genetic ancestry or self-identified race, and found more plasma cells in the tumours of black men than those of white men. However, the finding was not unique to black men alone, as elevated plasma cells in all men raised the odds of cancer-free survival after surgery.

“The finding comes at a time as researchers are discovering plasma cells may play a greater role in cancer immunotherapy than previously thought,” said first author Dr. Adam Weiner, a Northwestern Medicine urology resident. “Testing for plasma cells in prostate cancer may help identify men who will benefit from immune-based treatments.”

Source: Medical Xpress

Categories : Gastrointestinal ImmunologyTags :

Jump-starting Macrophages to Help with IBD Tissue Repair

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A novel method which prompts immune cells to aid the repair of damaged intestinal tissues has been developed by researchers at KU Leuven and Seoul National University.

This new approach promises new treatments for inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease. Normally, the immune system defends against pathogens that enter the body. In conditions like IBD, the immune system instead attacks tissues that line the gut, creating ulcers. Some 3.9 million women and 3.0 million women suffer from IBD worldwide.

The origin of IBD is not known, so treatments typically dampen immune response, but at the same time this also obstructs the normal repair of damaged intestinal tissue by other parts of the immune system. Macrophages, for example, consume foreign bodies, clean out debris and direct other steps in inflammatory or repair response through released substances. 

Lead author Professor Gianluca Matteoli, an immunologist at the Translational Research Center for Gastrointestinal Disorders (TARGID) KU Leuven, explained the motivation behind the research. “Our idea is that the migration of macrophages to the damaged tissue in IBD is essential to stimulate its recovery.”

Examining macrophages in the intestines of a handful of people with IBD, the researchers found that a sub-group of cells responding to prostaglandin E2 (PGE2). Prostaglandins are messenger molecules involved in homeostatic functions and mediate pathogenic mechanisms, such as the inflammatory response, and are also involved in tissue repair.

“If the patients had acute disease, they had a lower amount of these beneficial cells, and if they went into remission, then amounts of macrophages went up. This suggests that they are part of the reparative process,” said Professor Gianluca Matteoli, immunologist, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven

In mice with ulcerative colitis (one the main forms of IBD), there were fewer macrophages responsive to prostaglandin than in healthy mice. However, when PGE2 levels were increased, those macrophages still responsive released a substance that stimulated tissue repair. When the researchers knocked out the PGE2 receptors on the macrophages, the level of tissue repair dropped.

Getting the macrophages to absorb a liposome containing a substance to trigger the repair stimulation agent restored the macrophages’ repairing effect. Liposomes are bubbles made of two layers of lipids enclosing an aqueous cavity, often used to hold substances for drug delivery.

“We already knew that prostaglandins were important for inducing proliferation of tissue cells, but this study shows that they are also important for controlling the inflammatory effect, so moving the body from the acute stage where inflammation dominates to the reparative stage,” Professor Matteoli said.

New treatments could involve liposomes being used to prompt macrophages into boosting tissue repair, a well-established experimental tool but which would require considerable work for this new application.

“This is one of the first times it has been used to produce a beneficial, therapeutic effect,” said Professor Seok. 

The next step is to closely examine human macrophages at different stages of IBD. “We want to identify other factors that trip the switch that turns macrophages from inflammatory cells to non-inflammatory cells,” said Professor Matteoli. “Then, using the liposome technology that Professor Seok has developed, these could be used to target the macrophages and so produce very precise drugs.”

Source: News-Medical.Net

Categories : ImmunologyTags :

Mystery Protein is an Immune System Component

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A protein called ITIH4, the function of which was largely a mystery, has been shown to a as a protease inhibitor, and a component of the innate immune system.

The discovery was made by Professor Steffen Thiel and PhD student Rasmus Pihl at Aarhus University, with the help of a mass spectrometry team led by Professor Jan J Enghild.

Proteases are enzymes which cleave other proteins, and usually occur in cascade networks where proteases cleave each other in a chain reaction. One example of this is blood clotting.

There is also the complement system in the body, which is responsible for eliminating pathogens, and cancerous or dying cells. Immunoglobin G (IgG) and M (IgM) antibodies activate complement proteins which work with them, hence the name “complement”. This system of enzymes is kept in check by protease inhibitors.

The researchers wanted to find out which other proteins in our blood the “MASP” proteases from the complement cascade interact with. They found to their surprise that two MASP proteases formed a strong complex with the ITIH4 protein, about which very little is known, especially its function.

“I was highly surprised when I saw the first data from our partners, showing that ITIH4 could form a complex with the MASP-1 and MASP-2 enzymes. At Biomedicine, we have been studying these two proteases for 25 years, and ITIH4 has simply never been on the radar. But it made good sense, as proteins similar to ITIH4 act as inhibitors of other proteases,” said Rasmus Pihl.

It was also discovered that when ITIH4 formed a complex with MASP-1 and MASP-2, they could still cleave small proteins, but when ITIH4 inhibited them, they could not cleave large proteins.The researchers discovered that ITIH4 performs an inhibitory enzyme function similar to that of one discovered in the 1980s called AM2, but it accomplished it in a new, entirely different manner.

“There is very little knowledge about ITIH4, but it is known that under various pathological conditions, the protein can be cleaved. Our results show that such a cleavage is absolutely necessary for the way ITIH4 can function as an enzyme inhibitor,” Professor Steffen Thiel explained.

Their colleague Gregers R Andersen added: “By using cryo-electron microscopy, we now try to understand in detail how ITIH4 inhibits MASP-1 and MASP-2 via this new inhibition mechanism. We already know that when ITIH4 is cleaved, it forms a complex with both MASP-1 and another ITIH4 molecule. We are very excited to see how it takes place.”

Source: Medical Xpress

Journal information: Rasmus Pihl et al, ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism, Science Advances (2021). DOI: 10.1126/sciadv.aba7381

Categories : COVID ImmunologyTags :

NSAIDs Suppress Antibodies in COVID Infections

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A new study has found that non-steroidal anti-inflammatory drugs (NSAIDs) suppress antibody counts as well as inflammatory levels in mice infected with the SARS-CoV-2 virus.

NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are needed for prostaglandin generation – lipid molecules involved in homeostasis and inflammation. The study used ibuprofen and meloxicam in mice infected with SARS-CoV-2. The researchers aimed to observe: viral infection through modified expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, effects on viral replication and modulated response of the immune system. However, they did not observe altered viral infection or replication.

“NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.

As well as taking NSAIDs for chronic conditions, eg arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” Dr Wilen explained.

“Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection. Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration,” said Dr Wilen. Dexamethasone, a potent anti-inflammatory but not an NSAID, is detrimental when administered at early stages of COVID but beneficial at later stages. NSAIDs may similarly be detrimental at the early stage because they counteract beneficial inflammation.

An antibody reduction by NSAIDs might not be harmful, but it could also reduce the immune system’s ability to mount a defence early on, or even reduce the length or magnitude of immunity or vaccination protection, Dr Wilen said. Antipyretics such as paracetamol have also been observed to blunt immune system response to vaccination.  

According to Dr Wilen, the original motivation from the study “was a twitter thread, suggesting NSAIDs should not be used during COVID-19. This seemed suspicious to us, so we wanted to investigate.”

Dr Wilen and his team believed there would be no effect of NSAIDs on viral infection, which turned out to be correct. However, they also thought there would be no effect on antibody response.

“In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong,” commented Dr Wilen.

Source: Medical Xpress

Journal information: Jennifer S. Chen et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection, Journal of Virology (2021). DOI: 10.1128/JVI.00014-21