Tag Archives: Cytokine

University of Louisville researchers receive $5.8 million to prevent immune system dysregulation

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Researchers at the University of Louisville have received $5.8 million in two grants from the National Institutes of Health to expand their work to better understand and prevent immune system dysregulation responsible for acute respiratory distress, the condition responsible for serious illness and death in some COVID-19 patients. A separate $306,000 NIH Small Business Innovation Research grant supports early testing of a compound developed at UofL as a potential treatment.

The three grants combined total $6.1 million.

During the pandemic, health care providers worked tirelessly to treat patients who became seriously ill with COVID-19. Some of those patients developed severe lung disease known as acute respiratory distress syndrome (ARDS) due to an excessive response of the immune system often called cytokine storm.

As they treated these critically ill patients, physicians and other providers at UofL Health shared their clinical insights and patient samples with researchers at UofL to discover the cause of the immune system overresponse.

At one time we had over 100 patients with COVID in the hospital. Once they were on a ventilator, mortality was about 50%. We were looking at this issue to see why some people would do well while some developed bad lung disease and did not do well or died.”

Jiapeng Huang, an anesthesiologist with UofL Health and professor and vice chair of the Department of Anesthesiology and Perioperative Medicine in the UofL School of Medicine

The UofL researchers, led by immunologist Jun Yan, discovered that a specific type of immune cells, low-density inflammatory neutrophils, became highly elevated in some COVID-19 patients whose condition became very severe. This elevation signaled a clinical crisis point and increased likelihood of death within a few days due to lung inflammation, blood clotting and stroke. Their findings were published in 2021 in JCI Insight.

With the new NIH funding, Yan is leading research to build on this discovery with deeper understanding of what causes a patient’s immune system to respond to an infection in this way and develop methods to predict, prevent or control the response.

“Through this fruitful collaboration, we now have acquired NIH funding for basic and translational studies and even progress toward commercialization of a potential therapy,” Yan said. “That’s why we do this research – eventually we want to benefit the patients.”

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Yan, chief of the UofL Division of Immunotherapy in the Department of Surgery, a professor of microbiology and immunology and a senior member of the Brown Cancer Center, will lead the new research, along with Huang and Silvia M. Uriarte, university scholar and professor in the Department of Oral Immunology and Infectious Diseases in the UofL School of Dentistry.

“COVID-19 continues to spotlight the impactful synergy between the clinical and research teams at the University of Louisville,” said Jason Smith, UofL Health chief medical officer. “Innovation is in the DNA of academic medicine. We collaborate to provide each patient the best options for prevention and treatment today, while developing the even better options for tomorrow.”

In addition to two research grants of $2.9 million each awarded directly to UofL, a $306,000 grant to a startup company will support early testing of a compound developed in the lab of UofL Professor of Medicine Kenneth McLeish that shows promise in preventing the dangerous cytokine storm while allowing the neutrophils to retain their ability to kill harmful bacteria and viruses. The compound, DGN-23, will be tested by UofL and Degranin Therapeutics, a startup operated by McLeish, Yan, Huang, Uriarte and Madhavi Rane, associate professor in the Department of Medicine.

“This is one more example of how UofL has led the charge in finding new and innovative ways to detect, contain and fight COVID-19 and other potential public health threats,” said Kevin Gardner, UofL’s executive vice president for research and innovation. “This team’s new research and technology could help keep people healthy and safe here and beyond.”

The knowledge gained through these studies may benefit not only COVID-19 patients, but those with other conditions in which immune dysregulation can occur, such as other types of viral and bacterial pneumonia and autoimmune diseases, and patients undergoing cancer immunotherapy and organ transplantation.

The grants

Grant 1 – $2.9 million, four-year grant to UofL. Investigators will study the new subset of neutrophils Yan identified to better understand how they contribute to acute respiratory distress and clotting. They also will determine whether a novel compound will prevent these complications. They will use lab techniques and studies with animal models that allow for manipulation of certain conditions that cannot be done in human subjects.

Grant 2 – $2.9 million, five-year grant to UofL. This work examines a more comprehensive landscape to characterize different subsets of neutrophils and measure their changes over the course of COVID-19 disease progression and how neutrophils contribute to immune dysfunction.

Grant 3 – $306,000, one-year grant to Degranin Therapeutics and UofL for early testing of DGN-23, a compound developed at UofL, to determine its effectiveness in preventing or reducing immune dysregulation.

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First clinical trial of GABA/GAD focused exclusively on children with recent onset Type 1 diabetes

For the first time, humans with newly diagnosed Type 1 diabetes, or T1D, have received two treatments called GABA and GAD that have shown promise in animal studies and in isolated human pancreas islets. This investigator-initiated clinical trial, published in Nature Communications, focused exclusively on children with recent onset T1D.

Diabetes is a disease affecting two pancreatic hormones -; insulin and glucagon. In healthy people, insulin helps cells take up glucose from the blood when glucose levels are high. In contrast, glucagon helps the liver release glucose into the bloodstream when glucose levels are low. Thus, levels of blood glucose remain steady.

In T1D, autoantibodies destroy the pancreatic beta cells, insulin release is diminished, and glucagon release is excessive relative to the insulin deficiency. This can cause a vicious cycle of escalating blood glucose levels. Strategies to ameliorate or cure T1D, therefore, target the preservation of insulin-secreting beta cells and/or attenuation of the relative excess of alpha cell glucagon. Most importantly, concerning the inhibition of alpha cell glucagon in this trial by GABA/GAD, recent studies in animals made diabetic have shown that inhibition of glucagon leads to expansion of insulin-secreting beta cells and improvements in hyperglycemia.

Researchers in the study, led by University of Alabama at Birmingham physicians, were able to enroll children within the first five weeks of diagnosis, before the near total eradication of beta cells. Forty percent of the study participants were younger than 10 years old. The study -; which was constrained to lower-dose GABA therapy by the United States Food and Drug Administration because it was the first human trial with GABA -; did not achieve its primary outcome, the preservation of insulin production by beta cells. However, it did meet the clinically relevant secondary outcome of reduced serum glucagon. Significantly, the trial confirmed the safety and tolerability of oral GABA. Additionally, in collaboration with the immunology team of Hubert Tse, Ph.D., at the UAB Comprehensive Diabetes Center, a separate manuscript under review will describe a salutary effect of GABA alone and in combination with GAD on cytokine responses in peripheral blood mononuclear cells from trial participants.

GABA is gamma aminobutyric acid, a major inhibitory neurotransmitter. In the endocrine pancreas, GABA participates in paracrine regulation -; meaning a hormone that acts on nearby cells -; on the beta cells that produce insulin and the alpha cells that produce glucagon. In various mouse model studies, GABA was able to delay diabetes onset, and restore normal blood glucose levels after diabetes had already commenced. GABA treatment also led to significant decreases in the inflammatory cytokine expression that participates in the pathogenesis of T1D.

GAD is glutamic acid decarboxylase, the enzyme that acts on glutamate to form GABA. Animal and pancreatic islet cell studies show that immunization with GAD alone may help preserve beta cells. Both GABA and GAD are highly concentrated in the pancreatic islet, which is the autoimmune target of T1D.

The study, which was conducted between March 2015 and June 2019, screened 350 patients and enrolled 97, whose ages averaged 11 years. Forty-one took oral GABA twice a day; 25 took the oral GABA in combination with two injections of GAD, one at the baseline visit and one at the one-month visit. The remaining 31 children received a placebo treatment. Analysis after one year of treatment included 39 in the GABA group, 22 in the GABA/GAD group and 30 in the placebo group.

Given that GABA reduces immune inflammation at higher doses in several diabetic rodent models, it is plausible that increased GABA doses, or longer-acting preparations, could offer sufficiently prolonged, above-threshold GABA concentrations to preserve islet cells, particularly during stage 1 diabetes.”

Gail Mick, M.D., UAB Professor in the Department of Pediatrics’ Division of Pediatric Endocrinology and Diabetes

Mick and Kenneth McCormick, M.D., who recently retired from UAB Pediatrics, co-led the trial.

Alexandra Martin and Mick, UAB Department of Pediatrics, are co-first authors of the study, “A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.”

Other authors are Heather M. Choat, Alison A. Lunsford and Kenneth L. McCormick, UAB Department of Pediatrics; Hubert M. Tse, UAB Department of Microbiology; and Gerald G. McGwin Jr., Department of Epidemiology, UAB School of Public Health.

Journal reference:

Martin, A., et al. (2022) A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes. Nature Communications. doi.org/10.1038/s41467-022-35544-3.

What are the major findings of long COVID research?

In a recent review published in Nature Reviews Microbiology, researchers explored existing literature on long coronavirus disease (COVID). They highlighted key immunological findings, similarities with other diseases, symptoms, associated pathophysiological mechanisms, and diagnostic and therapeutic options, including coronavirus disease 2019 (COVID-19) vaccinations.

Study: Long COVID: major findings, mechanisms and recommendations. Image Credit: Ralf Liebhold/Shutterstock
Study: Long COVID: major findings, mechanisms and recommendations. Image Credit: Ralf Liebhold/Shutterstock

Long COVID refers to a multisystemic disease among SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-positive individuals, with increasing prevalence rates by the day. Studies have reported on long COVID risk factors, symptoms, pathophysiology, diagnosis, and treatment options, with increasing similarities between long COVID and other diseases such as POTS (postural orthostatic tachycardia syndrome) and ME/CFS (myalgic encephalomyelitis/ chronic fatigue syndrome).

About the review

In the present review, researchers explored the existing data on long COVID immunology, symptoms, pathophysiology, diagnosis, and therapeutic options.

Key long COVID findings and similarities with other diseases

Studies have reported persistently reduced exhausted T lymphocytes, dendritic cells, cluster of differentiation 4+ (CD4+) lymphocyte and CD8+ lymphocyte counts, and greater PD1 (programmed cell death protein-1) expression. In addition, increase in innate cell immunological activities, non-classical monocytes, expression of interferons (IFNs)-β, λ1, and interleukins (IL)-1β, 4,6, tumor necrosis factor (TNF). Cytotoxic T lymphocyte expansion has been linked to gastrointestinal long COVID symptoms, and persistent increase in CCL11 (C-X-C motif chemokine 11) expression has been linked to cognitive dysfunction among long COVID patients.

Elevated autoantibody titers have been reported among long COVID patients, such as autoantibodies against ACE2 (angiotensin-converting enzyme 2), angiotensin II receptor type I (AT1) receptors, β2-adrenoceptors, angiotensin 1–7 Mas receptors, and muscarinic M2 receptors. Reactivation of Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6) has been reported in long COVID patients and ME/CFS. EBV reactivation has been linked to neurocognitive impairments and fatigue in long COVID.

SARS-CoV-2 persistence reportedly drives long COVID symptoms. SARS-CoV-2 proteins and/or ribonucleic acid (RNA) have been detected in cardiovascular, reproductive, cranial, ophthalmic, muscular, lymphoid, hepatic, and pulmonary tissues, and serum, breast, urine, and stool obtained from long COVID patients. Similar immunological patterns are noted between long COVID and ME/CFS, with elevated cytokine levels in the initial two to three years of disease, followed by reduction with time, without symptomatic improvements in ME/CFS. Lower cortisol levels, mitochondrial dysfunction, post-exertional malaise, dysautonomia, mast cell activation, platelet hyperactivation, hypermobility, endometriosis, menstrual alterations, and intestinal dysbiosis occur in both conditions.

Long COVID symptoms and underlying pathophysiological mechanisms

Long COVID-associated organ damage reportedly results from COVID-19-induced inflammation and associated immune responses. Cardiovascular long COVID symptoms such as chest pain and palpitations have been associated with endothelial dysfunction, micro-clotting, and lowered vascular density. Long COVID has been associated with an increased risk of renal damage and type 2 diabetes. Ophthalmic symptoms of long COVID, including altered pupillary responses to light, result from the loss of small nerve fibers in the cornea, increased dendritic cell density, and impaired retinal microvasculature. Respiratory symptoms such as persistent cough and breathlessness result from altered pulmonary perfusion, epithelial injury, and air entrapment in the airways.

Cognitive and neurological long COVID symptoms include loss of memory, cognitive decline, sleep difficulties, paresthesia, balancing difficulties, noise and light sensitivity, tinnitus, and taste and/or smell loss. Underlying pathophysiological mechanisms include kynurenine pathway activation, endothelial injury, coagulopathy, lower cortisol levels, loss of myelin, microglial reactivation, oxidative stress, hypoxia, and tetrahydrobiopterin deficiency.  Gastrointestinal symptoms such as pain in the abdomen, nausea, appetite loss, constipation, and heartburn have been associated with elevated Bacteroides vulgatus and Ruminococcus gnavus counts and lower Faecalibacterium prausnitzii counts. Neurological symptoms often have a delayed onset, worsen with time and persist longer than respiratory and gastrointestinal symptoms, and long COVID presents similarly in children and adults.

Diagnostic and therapeutic options for long COVID, including COVID-19 vaccines

The diagnosis and treatment of long COVID are largely symptom-based, including tilt tests for POTS, magnetic resonance imaging (MRI) to detect cardiovascular and pulmonary impairments, and electrocardiograms to detect QRS complex fragmentation. Salivary tests and serological tests, including red blood cell deformation, lipid profile, complete blood count, D-dimer, and C-reactive protein (CRP) evaluations, can be performed to assess immunological biomarker levels. PCR (polymerase chain reaction) analysis is used for SARS-CoV-2 RNA detection and quantification, and antibody testing is performed to assess humoral immune responses against SARS-CoV-2.

Pharmacological treatments include intravenous Ig for immune dysfunction, low-dosage naltrexone for neuronal inflammation, beta-blockers for POTS, anticoagulants for microclot formation, and stellate ganglion blockade for dysautonomia. Other options include antihistamines, paxlovid, sulodexide, and pycnogenol. Non-pharmacological options include cognitive pacing for cognitive impairments, diet limitations for gastrointestinal symptoms, and increasing salt consumption for POTS. COVID-19 vaccines have conferred minimal protection against long COVID, the development of which depends on the causative SARS-CoV-2 variant, and the number of vaccination doses received. Long COVID has been reported more commonly post-SARS-CoV-2 Omicron BA.2 subvariant infections.

Based on the review findings, long COVID is a multiorgan disease that has debilitated several lives worldwide, for which diagnostic and therapeutic options are inadequate. The findings underscored the need for future studies, clinical trials, improved education, mass communication campaigns, policies, and funding to reduce the future burden of long COVID.

Journal reference:

Microbes can easily share genes. Not only can different types of bacteria do this, there is also evidence …

Microbes can easily share genes. Not only can different types of bacteria do this, there is also evidence that entirely different branches of life – archaea and bacteria can also share genes. Some microbial genes can be found on small bits of DNA called mobile genetic elements, which are not a part of a microbe’s genome, but can still be expressed when they’re a microbial cell. These mobile genetic elements can move from one cell to another in a process known as horizontal gene transfer. Researchers have now found that bacteria in the maternal microbiome can share genes with bacteria in the infant microbiome, in the period just before birth until a few weeks after delivery – the perinatal period. Horizontal gene transfer enables maternal microbes to influence how bacteria in the infant microbiome are functioning, without actually moving the maternal microbes themselves. These findings have been reported in Cell.

Image credit: Pixabay

“This is the first study to describe the transfer of mobile genetic elements between maternal and infant microbiomes,” said senior study author Ramnik Xavier of the Broad Institute of MIT and Harvard. “Our study also, for the first time, integrated gut microbiome and metabolomic profiles from both mothers and infants and discovered links between gut metabolites, bacteria and breastmilk substrates. This investigation represents a unique perspective into the codevelopment of infant gut microbiomes and metabolomes under the influence of known maternal and dietary factors.”

The gut microbiome produces metabolites that can affect various aspects of infant development, such as immune system maturation and cognitive development during the perinatal period, a critical window. At birth, microbes move from the maternal microbiome to the infant microbiome, but we still have a lot to learn about how microbes are affecting development, and how they are developing into a microbiome themselves.

In this study, the researchers tracked the microbiomes and metabolites of 70 infant-mother pairs, from late pregnancy until the babies were one year old. This research showed that mobile genetic elements moved from microbes carried by moms and into microbes carried by infants. The mobile genetic elements that were transferred were often related to diet.

Infants were also found to have less diversity in their metabolomes compared to moms, however, there were metabolites, and links between microbes and metabolites that were identified exclusively by infants. Infants that got regular formula (that was not excessively hydrolyzed) also had metabolomes and cytokine signatures that were different from infants that were exclusively breastfed.

“The infant gut harbored thousands of unique metabolites, many of which were likely modified from breastmilk substrates by gut bacteria,” noted co-first study author Tommi Vatanen of the Broad Institute of MIT and Harvard. “Many of these metabolites likely impact immune system and cognitive development.”

This process seems to be a way for the maternal microbiome to exert an influence on the infant microbiome withouth transmitting specific species of bacteria.

Prophages, which are dormant bacteriophages, also seem to be involved in the movement of mobile genetic elements between the maternal and infant microbiomes, added Xavier.

Sources: Cell Press, Cell

Carmen Leitch

Novel immunotherapy offers a promising new strategy to fight hard-to-treat cancers

Scientists at UC San Francisco (UCSF) have engineered T cells to produce a potent anti-cancer cytokine, but only when they encounter tumor cells. The immunotherapy eliminated melanoma and pancreatic cancer in mice without major side effects, and it offers a promising new strategy for fighting these and other hard-to-treat cancers.

The cells deliver IL-2, a powerful inflammatory molecule that is naturally produced by the immune system. IL-2 supercharges T cells, immune cells that can kill cancer cells and also protect against infection. While oncologists have known for decades that IL-2 has potent anti-cancer activity, its use has been limited by the toxic response it produces when given systemically.

In the study, published Dec. 15, 2022, in Science, the researchers were able to keep the cytokine contained within the cancer by programming the tumor-infiltrating T cells to make their own IL-2 when they recognized a cancer cell.

We’ve taken advantage of the ability of these cells to be local delivery agents and to crank out their T-cell amplifiers only when they recognize they’re in the right place. I think this is a model for how we can use cell therapies to deliver many types of potent but toxic therapeutic agents in a much more targeted manner.”

Wendell Lim, PhD, the Byers Distinguished Professor in cellular and molecular biology, director of the UCSF Cell Design Institute and senior author on the study

Slipping past the barriers

Cellular therapies have been highly effective against many blood cancers, where the cells are easily accessible because they are floating freely. Solid tumors, however, build multiple defensive walls that prevent therapeutic T cells from entering. And even if the cells do get into the tumor, they often tire out before they’re able to finish off the cancerous cells.

Since the 1980’s, oncologists have known that high doses of IL-2 enable T cells to overcome these barriers, and the cytokine has been used as cancer therapy in challenging cancer cases. But simply infusing patients systemically with IL-2 can cause high fever, leaky blood vessels, and organ failure.

Lim and lead author Greg Allen, MD, PhD, adjunct assistant professor of medicine and a fellow at the Cell Design Institute, aimed to tame IL-2’s effects by engineering cells that enhance the cancer-killing immune response only where it’s needed: in the tumor.

They chose to go after notoriously difficult-to-treat tumors, like those of the pancreas, ovary and lung, that form nearly iron-clad barriers against T cells.

To engineer cells T cells that could sense when they were in the tumor, the researchers used a synthetic Notch (or synNotch) receptor, a flexible type of molecular sensor, which Lim’s lab developed several years earlier. These receptors span the cell membrane, with ends that protrude both inside and outside the cell. The outside portion recognizes and binds to tumor cells, triggering the inside portion to set the production of IL-2 in motion.

The team tested the synNotch cells on a number of deadly tumors, including melanoma and pancreatic cancer, and found that the cells worked exactly as planned.

“We were able to design these therapeutic cells to slip past the tumor’s defensive barriers. Once in the tumor, they could establish a foothold, and begin effectively killing cancerous cells,” said Allen. “We got on top of these tumors and in some cases cured them.”

A positive-feedback circuit

The approach owes its success to engineering a circuit in the cell that amplifies the immune response in a controlled way. This induces the cell to produce IL-2 only under the specific conditions it’s programmed to recognize.

“This induction circuit is really a positive-feedback loop, an important element behind making these designer T cells that are able to operate so effectively,” Allen said.

The circuit begins when the synNotch receptor tells the T cell to make IL-2. That IL-2 feeds back on the cell, causing it to divide, in turn creating more cells that make even more IL-2. The entire process is confined within the tumor, protecting the rest of the body from harm.

Allen, who is both a researcher and an oncologist, hopes to begin testing the therapeutic approach in clinical trials with pancreatic cancer patients in 2024.

“The most advanced immunotherapies are just not working in a lot of these difficult solid tumors,” he said. “We think this type of design can overcome one of the major barriers and do it in a way that’s safe and free of side effects.”

Journal reference:

Allen, G.M., et al. (2022) Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science. doi.org/10.1126/science.aba1624.

Chinese scientists reveal a previously undefined pathway by which Mtb counteracts host immunity

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a leading infectious threat to public health worldwide. It is estimated to have infected 2–3 billion people and causes ~1.5 million deaths each year.

Now, a group of Chinese scientists has described a previously undefined pathway by which Mtb counteracts host immunity. Specifically, the researchers identified the known Mtb protein tyrosine phosphatase PtpB as a phospholipid phosphatase that inhibits the host inflammasome-pyroptosis pathway by hijacking host ubiquitin.

The study, carried out by Prof. LIU Cuihua’s group at the Institute of Microbiology of the Chinese Academy of Sciences (IMCAS), in collaboration with Prof. QIU Xiaobo from Beijing Normal University, was published in Science.

Dr. LIU’s group has been investigating the molecular mechanisms underlying Mtb-host interactions, and previous studies from her group have provided potential targets for the development of anti-TB treatments based on pathogen-host interaction interfaces.

Mtb is an intracellular pathogen that has developed numerous intracellular survival strategies, and the intricate and dynamic interactions between Mtb and its host determine the occurrence, progression, and outcomes of TB. One interesting feature evolved by Mtb is a set of eukaryotic-like effectors, but their host targets and regulatory roles in pathogen-host interactions have been largely unexplored.

In this study, LIU’s group examined the whole genome of Mtb to predict secreted eukaryotic-like proteins possessing eukaryotic-like motifs or domains that might target host factors directly. These Mtb effector proteins were then subjected to further experimental analyses using an inflammasome reconstitution system for screening inhibitors of inflammasome-pyroptosis pathways.

Out of 201 predicted Mtb-secreted eukaryotic proteins, the scientists identified PtpB as a key bacterial effector that was abundantly secreted by Mtb to inhibit both NOD-like receptor protein 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasome pathways.

Subsequent experiments demonstrated that PtpB inhibited GSDMD-dependent cytokine release and pyroptosis to promote Mtb intracellular survival in macrophages. Mechanistically, Mtb-secreted PtpB targets and dephosphorylates host plasma membrane phosphatidylinositol-4-monophosphate (PI4P) and phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] to inhibit membrane localization of the N-terminal cleavage fragment of GSDMD (GSDMD-N), thus preventing GSDMD-mediated immune responses.

Interestingly, this phosphatase activity requires PtpB binding to ubiquitin via its unique ubiquitin-interacting motif (UIM)-like region. Disruption of phospholipid phosphatase activity or the UIM-like region of PtpB enhanced host GSDMD-dependent immune responses, thus reducing intracellular pathogen survival.

This study reveals a previously unrecognized strategy by which pathogens inhibit pyroptosis and counteract host immunity by altering host membrane composition. Its results might lead to the development of a potential TB treatment by targeting the PtpB-Ub-phospholipid-pyroptosis axis.

Journal reference:

Chai, Q., et al. (2022) A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin. Science. doi.org/10.1126/science.abq0132.