Tag Archives: Mouse Model

Microbiology

The right combination of bile salt hydrolases may offer a new approach to treat C. diff

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Reviewed by Emily Henderson, B.Sc.Mar 13 2023

Not all probiotics are created equal. In a new study, researchers found that certain enzymes within a class known as bile salt hydrolases (BSHs) can restrict Clostridioides difficile (C. diff.) colonization by both altering existing bile acids and by creating a new class of bile acids within the gut’s microbial environment. The work could lead to “designer” probiotics that protect against disease by introducing specific BSHs to the gut after antibiotic treatment.

Selecting the right suite of BSH-producing bacteria is critical, because the study found that interactions between BSHs and bile acids differ depending upon the type of bacteria the BSHs come from.

Certain bacteria within the gut microbiota contain BSH enzymes, which chemically modify bile acids. Bile acids are made in the liver and play an important role in modulating cholesterol levels, regulating fat absorption, shaping the immune system, and affecting which bacteria can colonize the gut.

Although researchers had long suspected a connection between BSHs from beneficial bacteria, the bile acid pool, gut microbial composition and host health, until now relatively little was known about how BSHs function and their potential impacts on host health.

The old dogma – that BSHs are needed for gut colonization because they render toxic bile acids non-toxic – oversimplified what’s actually happening.”

Casey Theriot, associate professor of infectious disease at North Carolina State University and co-corresponding author of the study

“The reality is that BSHs’ interactions are context-dependent, meaning they’re affected by the type of bacteria they come from,” Theriot says. “And they don’t just interact with bile acids produced by the host. BSHs in the microbiota can create and interact with a new class of bile acids called microbial conjugated bile acids (MCBAs) – bile acids that we didn’t even know existed until recently.”

In the new study, Theriot led a collaborative research team that included microbiologists, chemists, biochemists, and clinicians from NC State, the University of North Carolina at Chapel Hill, and the University of California, San Diego on a deep dive into BSHs.

Specifically, they looked at hundreds of BSHs from different Lactobacillaceae bacteria (which houses most probiotic strains) and then included BSHs from the gut microbiota (nearly 1,000 unique BSHs in total).

Matthew Redinbo, Kenan Distinguished Professor of Chemistry in UNC-Chapel Hill’s College of Arts and Sciences, and his departmental colleagues (led by then graduate student Morgan Walker) were instrumental in determining the structure of BSHs and how they “choose” to interact with bile acids, by either adding or taking away certain amino acids.

“We found the tiny molecular fingerprint that defined whether a BSH would ‘turn left’ or ‘turn right’ in terms of what they processed,” Redinbo says. “Knowing that allowed Casey’s team to steer the bile acid pool in whatever direction they wanted.”

The researchers used a cocktail of Lactobacillus BSHs to figure out if they could change the bile acid pool enough to alter C. diff colonization in both human stool samples collected from patients susceptible to C. diff infection (CDI) and in a mouse model of CDI. In both human stool samples and mice, the researchers saw that pre-treatment with BSH cocktails impacted C. diff colonization. Interestingly, the researchers noted elevated levels of MCBAs in the gut microbiota of the BSH-treated mice.

To determine whether the MCBAs were also involved in inhibiting C. diff germination and growth, they tested the MCBAs against C. diff in vitro. In most cases, the presence of MCBAs inhibited multiple steps of the C. diff life cycle.

“This is more evidence that BSHs are driving changes in the bile acid pool – including making MCBAs – that could serve to inhibit C. diff,” Theriot says. “We’ve uncovered a new function for BSH enzymes.”

“This work highlights the importance of BSHs as key intestinal enzymes and promising new therapeutics,” says Matt Foley, research scholar at NC State and co-first author of the study. “Using BSHs in combination with other strategies may offer a new approach to treat C. diff.“

The researchers see the work as the first step toward potential probiotics that could be customized to protect against a variety of bacterial infections and intestinal diseases. But first, more work must be done to determine how and why the BSHs decide which MCBAs to produce and/or target.

“This is an important illustration of how deciphering the biochemical and genetic basis for probiotic functionality both leads to a better understanding of how we can combat gut disease with novel modalities, and also practically design and formulate next-generation commercial probiotics,” says Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at NC State and co-corresponding author of the study.

The work appears in Nature Microbiology and was supported by the National Institutes of Health, the National Science Foundation, IFF Corporation and the U.S. Environmental Protection Agency. The MCBA detection work was done by Erin Baker, formerly of NC State and currently at UNC-Chapel Hill, Allison Stewart of NC State, and Emily Gentry and Pieter Dorrestein from UCSD.

Source:

North Carolina State University

Journal reference:

Foley, M. H., et al. (2023). Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut. Nature Microbiology. doi.org/10.1038/s41564-023-01337-7.

Microbiology

New discoveries made regarding autism onset in mouse models

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Reviewed by Emily Henderson, B.Sc.Mar 10 2023

Although autism is a common neurodevelopmental disorder, the multiple factors behind its onset are still not fully understood. Animal models of idiopathic autism, especially mice, are often used to help researchers understand the complicated mechanisms behind the disorder, with BTBR/J being the most commonly used mouse model in the world.

Now, an international research collaboration including Kobe University’s Professor TAKUMI Toru and Researcher Chia-wen Lin et al. have made new discoveries regarding autism onset in mouse models.

In their detailed series of experiments and analyses of BTBR/J mice and the other subspecies BTBR/R, they revealed that endogenous retrovirus activation increases a fetus’s susceptibility to autism. They also discovered that BTBR/R exhibits autistic-like behaviors without reduced learning ability, making it a more accurate model of autism than the widely-used BTBR/J model.

It is hoped that further research will contribute towards better classification of autism types, as well as the creation of new treatment strategies for neurodevelopmental disorders.

These research results were published in Molecular Psychiatry on March 7, 2023

Main points

  • The researchers analyzed BTBR/J, a widely used mouse model of autism, and its subspecies BTBR/Rusing MRI. This revealed that the corpus callosum, which connects the left and right hemispheres of the brain, was impaired in BTBR/J mice but not in BTBR/R mice.
  • Genome and transcription analysis showed that BTBR mice have increased levels of endogenous retrovirus genes.
  • Furthermore, single-cell RNA analysis of BTBR/R mice revealed changes in the expression of various genes (including stress response genes) that are indicative of endogenous retrovirus activation.
  • Even though BTBR/J and BTBR/R mice have the same ancestry, the results of various behavioral analysis experiments revealed differences in spatial learning ability and other behaviors between the two types of model mice.

Research background

Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapidly increasing number of patients. Reasons for this continuing increase in people diagnosed with autism include changes to diagnostic criteria and older fathers becoming more common. Autism is strongly related to genetic factors and can be caused by abnormalities in DNA structure, such as copy number variations. Animal models, especially mice, are often used in research to illuminate the pathology of autism. Among these models, BTBR/J is a mouse model of the natural onset of autism that is commonly used. Studies have reported various abnormalities in BTBR/J mice including impairment of the corpus callosum (which connects the left and right hemispheres of the brain) and excessive immune system signaling. However, it is not fully understood why this particular lineage displays autistic-like behavioral abnormalities.

The aim of the current study was to shed light on the onset mechanism of these autistic-like behavioral abnormalities by conducting comparative analysis on BTBR/J and its subspecies BTBR/R.

Research findings

First of all, the researchers conducted MRI scans on BTBR/J and BTBR/R mice to investigate structural differences in each region of the brain. The results revealed that there were differences between BTBR/J and BTBR/R mice in 33 regions including the amygdala. A particularly prominent difference discovered was that even though BTBR/J’s corpus callosum is impaired, BTBR/R’s is normal.

Next, the research group used the array CGH method to compare BTBR/R’s copy number variations with that of a normal mouse model (B6). They revealed that BTBR/R mice had significantly increased levels of endogenous retroviruses (ERV) in comparison to B6 mice. Furthermore, qRT-PCR tests revealed that these retroviruses were activated in BTBR/R mice. On the other hand, in B6 mice there was no change in the expression of LINE ERV (which is classified in the same repetitive sequence), indicating that this retroviral activation is specific to BTBR.

Subsequently, the researchers carried out single-cell RNA analysis on the tissue of embryonic BTBR mice (on the AGM and yolk sac). The results provide evidence of ERV activation in BTBR mice, as expression changes were observed in a group of genes downstream of ERV.

Lastly, the researchers comprehensively investigated the differences between BTBR/J and BTBR/R on a behavioral level. BTBR/R mice were less anxious than BTBR/J and showed qualitative changes in ultrasound vocalizations, which are measured as a way to assess communicative ability in mice. BTBR/R mice also exhibited more self-grooming behaviors and buried more marbles in the marble burying test. These two tests were designed to detect repetitive behavioral abnormalities in autistic individuals. From the results, it was clear that BTBR/R exhibits more repetitive behaviors (i.e. it is more symptomatic) than BTBR/J. The 3-chamber social interaction test, which measures how closely a mouse will approach another mouse, also revealed more pronounced social deficits in BTBR/R than BTBR/J mice (Figure 4i). In addition, a Barnes maze was used to conduct a spatial learning test, in which BTBR/J mice exhibited reduced learning ability compared to B6 (normal mice). BTBR/R mice, on the other hand, exhibited similar ability to B6.

Overall, the study revealed that retrovirus activation causes the copy number variants in BTBR mice to increase, which leads to the differences in behavior and brain structure seen in BTBR/J and BTBR/R mice (Figure 5).

Further developments

BTBR/J mice are widely used by researchers as a mouse model of autism. However, the results of this study highlight the usefulness of the other lineage of BTBR/R mice because they exhibit autistic-like behavior without compromised spatial learning ability. The results also suggest that it may be possible to develop new treatments for autism that suppress ERV activation. Furthermore, it is necessary to classify autism subtypes according to their onset mechanism, which is a vital first step towards opening up new avenues of treatment for autism.

Source:

Kobe University

Journal reference:

Lin, C-W., et al. (2023) An old model with new insights: endogenous retroviruses drive the evolvement toward ASD susceptibility and hijack transcription machinery during development. Molecular Psychiatry. doi.org/10.1038/s41380-023-01999-z.

Microbiology

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

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Reviewed by Emily Henderson, B.Sc.Feb 22 2023

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.

Source:

University of Alabama at Birmingham

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.

Microbiology

UTHSC researchers secure $308,000 grant from Department of Defense for dementia study

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Reviewed by Emily Henderson, B.Sc.Feb 19 2023

Repeated traumatic brain injuries (TBI) in soldiers and military personnel can cause behavioral, neurological, and cognitive effects and lead to dementia. There is currently no treatment for that type of dementia, but a $308,000 grant from the United States Department of Defense aims to help researchers at the University of Tennessee Health Science Center find one.

TBI can lead to the development of frontotemporal degeneration (FTD), a progressive process marked by atrophy of the frontal and temporal lobes. FTD is one of the most common causes of dementia in people under the age of 65.

Principal investigator Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology, and co-investigator Tayebeh Pourmotabbed, PhD, professor in the Department of Microbiology, Immunology, and Biochemistry, are working on a project to find the first therapeutic intervention to prevent frontotemporal dementia or slow its progression in a mouse model linked with the condition.

The team is aiming to use a novel gene therapy called DNAzymes to target pathological tau aggregates, which cause frontotemporal dementia and its resulting cognitive impairment and progressive neuropathological symptoms. The team is examining the effective dose, frequency, and duration of treatment as well as its potential in reducing neurodegeneration and behavioral deficits in mice.

Our preliminary data suggest that DNAzyme is a novel therapeutic approach and has a great potential for preventing the accumulation of pathological tau. The results of this proposal would be foundational for future studies examining the clinical use of DNAzyme for other neurological diseases associated with traumatic brain injury and other tauopathies.”

Dr. Mohammad Moshahid Khan, PhD, associate professor in the Department of Neurology

“DNAzyme is a powerful gene therapy technique that can be used to prevent production of proteins associated with diseases, like tau protein in Alzheimer’s disease and dementia,” Dr. Pourmotabbed said. “We have used DNAzyme as a potential therapy for breast cancer, glioma, and Huntington’s disease in preclinical animal models with great success. Hopefully, with the use of DNAzyme technology, we would be able to reduce the risk of dementia after traumatic brain injury in veterans and other individuals that deal with this debilitating disease.”

Source:

University of Tennessee Health Science Center

Microbiology

Researchers find a way to block anaphylaxis caused by peanut allergies

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Reviewed by Emily Henderson, B.Sc.Feb 9 2023

Researchers from Indiana University School of Medicine have found a way to block anaphylaxis caused by peanut allergies. The groundbreaking discovery could lead to life-saving therapeutics for people with severe peanut allergies.

There are treatments for symptoms in patients with food allergies, but few preventive therapies other than strict dietary avoidance or oral immunotherapy. Neither of those options is successful in all patients.”

Mark Kaplan, PhD, chair of the Department of Microbiology and Immunology and senior author of the study

The team details their findings in a newly published article in Science Translational Medicine. When someone is allergic to a food, it is a result of allergen proteins cross-linking allergen specific immunoglobulin E (IgE) on the surface of mast cells and basophils. Activation of these cells can lead to anaphylaxis, a severe, life-threatening allergic reaction that can occur very quickly after exposure to an allergen.

Researchers developed peanut-specific inhibitors called covalent heterobivalent inhibitor (cHBI), that successfully blocked mast cell or basophil degranulation and anaphylaxis in an animal model.

“The inhibitor prevented allergic reactions for more than two weeks when given before allergen exposure,” said Nada Alakhras, lead author and a graduate student in the Department of Biochemistry and Molecular Biology. “The inhibitor also prevented fatal anaphylaxis and attenuated allergic reactions when given soon after the onset of symptoms.”

“These new findings suggest that cHBI has the potential to be an effective preventative for peanut-specific allergic responses in patients,” said Basar Bilgicer, PhD, professor of chemical and biomedical engineering at the University of Notre Dame and co-senior author of the study.

The inhibitor has not been tested in human patients yet. Researchers are now doing further testing in animal models to evaluate efficacy and toxicity before moving to clinical trials.

The research was funded in part by the Falk Medical Research Trust Award. Other authors include Anthony L. Sinn, Wenwu Zhang, PhD, MS, and Karen E. Pollok, PhD from IU School of Medicine as well as Gyoyeon Hwang, Jenna Sjoerdsma, Emily K. Bromley, and Jaeho Shin from the University of Notre Dame and Scott A. Smith, MD, PhD from Vanderbilt University Medical Center.

Source:

Indiana University School of Medicine

Journal reference:

Alakhras, N.S., et al. (2023) Peanut allergen inhibition prevents anaphylaxis in a humanized mouse model. Science Translational Medicine. doi.org/10.1126/scitranslmed.add6373.

Microbiology

Altered gut microbiome plays a major role in the progression of endometriosis in animal model

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Reviewed by Emily Henderson, B.Sc.Jan 25 2023

About 196 million women worldwide suffer from endometriosis, a condition that typically causes pelvic pain and infertility. Endometriosis develops when lining inside the womb grows attached to surrounding tissues, such as the intestine or the membrane lining the abdominal cavity, causing bleeding, pain and other symptoms. Despite decades of research, little is known about the factors that contribute to the development of endometriosis.

Evidence suggests that the microbiome, a community of microorganisms living inside the body, is altered in women with endometriosis. In this study published in the journal Cell Death & Discovery, researchers at Baylor College of Medicine discovered that an altered gut microbiome plays a pivotal role in endometriosis disease progression in an animal model.

“To investigate the role of the microbiome in endometriosis we first implemented a novel mouse model of the condition in which we eliminated the microbiome using antibiotics,” said lead author Dr. Rama Kommagani, associate professor in the Departments of Pathology and Immunology and of Molecular Virology and Microbiology at Baylor.

The researchers found that mice lacking gut microbiome had smaller endometriotic lesions than mice with a microbiome. Furthermore, when gut microbiome-free mice received gut microbiota from mice with endometriosis, the lesions grew as large as those in mice retaining their microbiome. These findings suggest that altered gut bacteria drive disease progression. On the other hand, the uterine microbiome did not seem to affect disease progression.

The team also discovered a novel signature of microbiome-derived metabolites, products produced by the microbes, that were significantly altered in feces of mice with endometriosis. Supporting the role of microbiome metabolites in disease progression, Kommagani and his colleagues found that treatment of endometriotic cells and mice with the metabolite called quinic acid significantly enhanced the cellular proliferation and endometriotic lesion growth, respectively.

The findings suggest that certain microbiome communities and/or their metabolites can contribute to endometriosis progression and that modifying the composition of these communities could help control the condition in human patients. “We are currently investigating this possibility,” Kommagani said.

The findings also suggested that studying microbiome metabolites in human stool samples could be used as a diagnostic tool. “Endometriosis is typically diagnosed with ultrasound, and an invasive procedure is necessary to characterize the lesion well,” Kommagani said. “We are investigating whether microbiome metabolites in human stool samples could be a useful diagnostic tool and also whether some of these metabolites could be used as a treatment strategy.”

Women with endometriosis also tend to have bowel issues, such as colitis or inflammatory bowel syndrome.

We are interested in determining whether changes in the gut microbiome could affect bowel conditions and the possibility of controlling them by modifying the microbiome or with their metabolites.”

Dr. Rama Kommagani, Lead Author

Source:

Baylor College of Medicine

Journal reference:

Chadchan, S.B., et al. (2023) Gut microbiota and microbiota-derived metabolites promotes endometriosis. Cell Death Discovery. doi.org/10.1038/s41420-023-01309-0.

Microbiology

Targeting T cell iron metabolism may offer a new approach for treating lupus

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Reviewed by Emily Henderson, B.Sc.Jan 13 2023

Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) -; the most common form of the chronic autoimmune disease lupus.

A multidisciplinary team of investigators at Vanderbilt University Medical Center has discovered that blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE. The findings were published Jan. 13 in the journal Science Immunology.

Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation and tissue damage. Lupus most commonly affects skin, joints, brain, lungs, kidneys and blood vessels. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America.

Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.

It has been a real challenge to come up with new therapies for lupus. The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”

Jeffrey Rathmell, PhD, Professor of Pathology, Microbiology and Immunology and Cornelius Vanderbilt Chair in Immunobiology

Rathmell’s group has had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.

When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anemic.

“It was not clear why the T cells were high in iron, or what that meant,” said Voss, first author of the Science Immunology paper.

To explore T cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other investigators at VUMC:

  • Eric Skaar, PhD, and his team are experienced in the study of iron and other metals;

  • Amy Major, PhD, and her group provided a mouse model of SLE; and

  • Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples.

First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.

The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

“We see a lot of complications coming from that -; the mitochondria don’t function properly, and other signaling pathways are altered,” Voss said.

An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.

The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.

Skaar is the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. Major, associate professor of Medicine, and Ormseth, assistant professor of Medicine, are faculty members in the Division of Rheumatology and Immunology. Rathmell is the director of the Vanderbilt Center for Immunobiology.

Other authors of the study include Allison Sewell, Evan Krystofiak, PhD, Katherine Gibson-Corley, DVM, PhD, Arissa Young, MD, Jacob Basham, MD, Ayaka Sugiura, PhD, Emily Arner, PhD, William Beavers, PhD, Dillon Kunkle, PhD, Megan Dickson, Gabriel Needle, and W. Kimryn Rathmell, MD, PhD.

The research was supported by the National Institutes of Health (grants DK105550, AI153167, DK101003, AI150701, CA253718) and the Lupus Research Alliance William Paul Distinguished Innovator Award to Jeffrey Rathmell.

Source:

Vanderbilt University Medical Center

Journal reference:

Voss, K., et al. (2023) Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus. Science Immunology. doi.org/10.1126/sciimmunol.abq0178.