Category: Immunology

Categories : COVID ImmunologyTags :

COVID Antibody Drugs Work Best with Immune Cells

On By ModernMedia

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

On By ModernMedia

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

On By ModernMedia

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

On By ModernMedia

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

On By ModernMedia

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

Categories : COVID ImmunologyTags :

New “Double Antibodies” can Treat COVID Variants

On By ModernMedia

A new generation of “double antibodies” has been developed which can protect against all SARS-CoV-2 variants, as well as inhibiting mutations against the antibodies.

These “bispecific”  antibodies were created by the Institute for Research in Biomedicine (IRB; Bellinzona, Switzerland), which is affiliated to the Università della Svizzera italiana (USI).

While traditional antibody-based immunisation is able to offer protection against SARS-CoV-2, there is still a need to protect against variants which may achieve “vaccine escape”, as well as inhibiting mutations which give rise to resistance, as with antibiotic resistance in bacteria.

The researchers overcame these difficulties by splicing together a pair of antibodies to make a “bispecific” antibody that simultaneously targets two viral sites. The bispecific antibody treatment has proved effective in mouse models, which maintained body weight when infected with SARS-CoV-2, compared to infected controls, which lost 20-30% body weight before humane euthanisation. The paper is available on the bioRxiv preprint server.

Study author Luca Varani of USI explained: “We exploited our knowledge of the molecular structure and biochemical traits of the virus to fuse together two human antibodies, obtaining a single bispecific molecule simultaneously attacking the virus in two independent sites critical for infectivity. Supercomputing simulations allowed us to refine and validate the bispecific antibody design, which was later produced and tested in the laboratory. Although the virus can mutate and escape from the attack of a single first-generation antibody, we have shown that it cannot do so against the double action of the bispecific.

“A single injection of the bispecific antibody provides instantaneous protection against the disease in pre-clinical trials. The antibody effectively reduces viral burden in the lungs and mitigates inflammation typical of COVID-19”, said Daniel Ruzek from the Czech Academy of Sciences who led the antibody pre-clinical testing.

The effectiveness of the bispecific antibodies holds promise for human clinical trials, with the prospect of being both an effective prevention and treatment of COVID.

Source: News-Medical.Net

Journal information: Gasparo, R D., et al. (2020) Bispecific antibody prevents SARS-CoV-2 escape and protects mice from disease. bioRxiv.doi.org/10.1101/2021.01.22.427567.

Categories : Diseases, Syndromes and Conditions Gastrointestinal ImmunologyTags :

Taurine Boosts Microbiotic Defences in the Gut

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A new study has discovered that taurine has a role in triggering the gut’s microbiota to identify and destroy invading bacteria, such as Klebsiella pneumoniae, a bacteria commonly found in the gut and responsible for a variety of infections.

It is already known that gut microbiota can protect against infection, but it is not well understood how they accomplish this. A better of understanding of how they confer protection will aid the development of replacements for current antibiotic drugs, which currently harm gut microbiota and whose effectiveness is waning.

Taurine is a complementary (non-essential amino acid, involved in helping break down fats and is present in bile acid. Most taurine is produced by the body but some is also required in the diet. Certain seafoods, seaweed, poultry and beef are good sources of taurine.

The scientists believed that the taurine helped prevent against bacterial colonisation by producing hydrogen sulphide, but during their research they also discovered that a single infection was sufficient to prepare the gut microbiota to resist a second infection. The liver and gallbladder which produce and store bile acids, can develop long-term protection against infection.

While investigating further, the researchers discovered a particular type of bacteria, Deltaproteobacteria, which protected the gut against colonisation by infectious bacteria and which was activated by taurine. Taurine fed to mice in drinking water helped to shield against infection by boosting the function of the protective bacteria, but those fed bismuth subsalicylate (a common over-the-counter diarrhoea treatment), the infection protection diminished, because bismuth suppresses hydrogen sulphide production in the gut.

Source: News-Medical.Net

Categories : HIV ImmunologyTags :

HIV Vaccine Search is a Marathon

On By ModernMedia

While COVID vaccines have appeared in a record-breaking short time, an HIV vaccine is still yet to arrive – though not without good reasons, as The Daily Maverick reports.

Mitchell Warren, executive director of AVAC, a US-based HIV advocacy organisation explained: “There is still no conclusive research on what type of immune response an HIV vaccine should be trying to trigger.”

“With HIV, you’re trying to do better than nature,” continued Warren. “With a Covid-19 vaccine, the jab merely has to do what nature is doing already — in the form of an immune response — just faster. But with HIV, you’re trying to do better than nature because your body isn’t able to successfully fight off the virus.”

HIV mutates quite rapidly, to the point where there are now two distinct strains, HIV-1 and HIV-1, complicating the process. SARS-CoV-2 on the other hand uses a process called proofreading when it replicates, ensuring a lower rate of mutations.

There are currently three vaccines in development; HPX2008/HVTN 705: Imbokodo and HPX3002/HVTN 706: Mosaico both use adenoviruses to deliver protein fragments of the HIV virus to train the immune system to respond to it. The “Imbokodo” is being trialled with young women, and “Mosaico” is being trialled with transgender men and men who have sex with men, and expected to end in 2022 and 2024 respectively. 

The PrEPVacc vaccine uses DNA inserted into plasmids, which induce the body to produce the virus’ proteins, but not the virus itself. The two shots contain a cocktail of proteins and the plasmids to train the immune system. The trial is expected to end in 2023

Categories : ImmunologyTags :

Gut Microbiota Have Large Effects on Immune System

On By ModernMedia

For the first time, immune cells in the bloodstream have been shown to be affected by the makeup of gut microbiota.

In recent years, there has been increased interest in gut microorganisms and their influence on human health, partly as a result of improvements in the ability to study them. Much prior understanding of gut microbiota on the immune system comes from animal studies; this study was able to examine the effects in humans. This study used data from allogeneic stem cell and bone marrow transplants (BMTs), where the patient’s blood formation system is destroyed by radiation or chemotherapy and replaced with stem cells from a donor’s bone marrow. The patient is given antibiotics until the transplanted cells are able to re-establish the immune system, the gut microbiota being destroyed in the process and then re-establishing once the antibiotics are withdrawn. Over a period of ten years, a multidisciplinary team with the Memorial Sloan Kettering Cancer Center took blood and faecal samples from BMT patients.

Study author Dr Joao Xavier said, “Our study shows that we can learn a lot from stool—biological samples that literally would be flushed down the toilet. The result of collecting them is that we have a unique dataset with thousands of datapoints that we can use to ask questions about the dynamics of this relationship.”
“The parallel recoveries of the immune system and the microbiota, both of which are damaged and then restored, gives us a unique opportunity to analyse the associations between these two systems,” lead author Dr Jonas Schluter said.

A higher diversity of microbiota was shown to lower the risk of death following a BMT, and a lower diversity increased the risk of graft-versus-host disease, a potentially fatal condition where the transplanted marrow attacks the host’s body.

“Because experiments with people are often impossible, we are left with what we can observe,” Dr. Schluter noted. “But because we have so many data collected over a period of time when the immune system of patients as well as the microbiome shift dramatically, we can start to see patterns. This gives us a good start toward understanding the forces that the microbiota exerts on the rebuilding of the immune system.”

Source: Medical Xpress

Journal information: Jonas Schluter et al. The gut microbiota is associated with immune cell dynamics in humans, Nature (2020). DOI: 10.1038/s41586-020-2971-8