US Pharm. 2022;47(3):34-37.

Could One Autoimmune Disease Lead to Another?

Researchers at the University of Colorado Anschutz Medical Campus have discovered that having one kind of autoimmune disease can lead to another. The scientists serendipitously found that mice with antibody-induced rheumatoid arthritis in their joints went on to develop spinal lesions similar to those in axial spondyloarthritis (AxSpA), which causes fusion of the vertebrate and curvature, or bending, of the backbone. The study was published in the journal Immune Network.

 “This interesting disease association may be due to the binding of anti-collagen autoantibodies to the spine, or to some alteration of the immune system that requires further investigation,” said the study’s lead author, Nirmal Banda, PhD, professor in the division of rheumatology at the University of Colorado School of Medicine.

These same anticollagen antibodies are also present in humans with arthritis. They directly attack joint cartilage, resulting in inflammation and pain. Dr. Banda noted that every mouse injected with collagen antibody–induced arthritis developed arthritis and then curvature of the spine consistent with AxSpA.

“I began to notice the proliferation of bone in the spine and fusing of the vertebrate,” he said. “The normal spaces between the spine vertebrate in certain locations were disappearing. This is similar to what happens to humans with AxSpA.”

The connection, he said, has not been made in any other study he has seen. But exactly how one autoimmune disease could trigger another remains a mystery, one that Dr. Banda hopes to investigate. “I want to know what the mechanism is,” he said. In the meantime, he suggested that those with an autoimmune disease be vigilant in case they develop another.


Common Virus May Pose Serious Threat to Transplant Patients

A common virus that causes no harm in most people may be a danger to organ-transplant recipients and other immunocompromised people, say researchers at Columbia University Irving Medical Center.

The researchers found that a human polyomavirus (HPyV9) was associated with the deaths of three solid-organ transplant recipients who developed a severe skin rash and then died about a year later from pulmonary and multiorgan failure.

The study, published in JAMA Dermatology, was led by Stephanie Gallitano, MD, assistant professor of dermatology at Columbia University Vagelos College of Physicians and Surgeons, and Nischay Mishra, PhD, assistant professor of epidemiology at Columbia’s Mailman School of Public Health and Center for Infection and Immunity.

The deaths of the organ-transplant recipients were initially a mystery. Some viruses can cause life-threatening diseases in transplant recipients and other immunocompromised people, but none of these were found in the three patients.

To identify a culprit, the researchers turned to VirCapSeq-VERT, a technique developed by researchers in the Center for Infection and Immunity, that detects all known vertebrate viruses. Using these techniques, the researchers detected HPyV9 and found that the virus was present in the skin, blood, and lungs of the three patients. Additional tests showed that the virus was not just present in the patients but was actively replicating, causing the initial skin rash and damaging the lungs.

Because of the newly identified risk, the researchers say organ-transplant recipients and other immunocompromised patients should be routinely tested for HPyV9 infection. (VirCapSeq-VERT recently received approval for clinical use from the New York State Department of Health.)

Although HPyV9 has been found in the blood of transplant recipients and may be present in up to 30% of the general population, it has not been previously linked to a human disease. “Since HPyV9 is not routinely tested in clinical settings, we may find it is more common than we realize,” says Dr. Mishra. “And as we begin to use VirCapSeq-VERT in clinical microbiology, we can anticipate finding other pathogenic viruses that we cannot otherwise predict.”

Earlier detection with the new technique may improve clinical outcomes. A fourth patient with HPyV9 identified by the researchers is currently being screened for viral load to monitor disease progression and is receiving treatment.

“Our study is the first to describe immunosuppressed transplant recipients infected with HPyV9, so the risk of developing HPyV9 infection is still unknown,” Dr. Gallitano says. “As we learn more about the pathogenesis of this disease, targeted novel forms of antiviral therapy and/or modification of immunosuppressive drug regimens may improve patient outcomes.”

“Kick and Kill” Strategy Aims to Eliminate HIV-Infected Cells

In a study using mice, a UCLA-led team of researchers have improved upon a method they developed in 2017 that was designed to kill HIV-infected cells. The advance could move scientists a step closer to being able to reduce the amount of virus, or even eliminate it, from infected people who are dependent on lifesaving medications to keep the virus from multiplying and illness at bay.

The strategy, described in Nature Communications, uses cells that are naturally produced by the immune system to kill infected cells that hide in the body, potentially eradicating them, said Dr. Jocelyn Kim, an assistant professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA.

“These findings show proof-of-concept for a therapeutic strategy to potentially eliminate HIV from the body, a task that had been nearly insurmountable for many years,” said Dr. Kim, the study’s lead author. “The study opens a new paradigm for a possible HIV cure in the future.”

Worldwide, there are currently 38 million people living with HIV, and an estimated 36 million have died of HIV-related diseases in the decades since HIV began circulating, according to UNAIDS.

Patients with HIV take antiretroviral medication to keep the virus at bay. But HIV has the ability to elude antiretrovirals by lying dormant in cells called CD4+ T cells, which signal another type of T cell, the CD8, to destroy HIV-infected cells. When a person with HIV stops treatment, the virus emerges from those reservoirs and replicates in the body, weakening the immune system and raising the likelihood of opportunistic infections or cancers that can lead to illness or death.

The UCLA-led study continues research on a strategy called “kick and kill,” which many of the same scientists first described in a 2017 paper. The approach coaxes the dormant virus to reveal itself in infected cells, so it can then be targeted and killed. In the earlier study, the researchers gave antiretroviral drugs to mice whose immune systems had been altered to mimic those of humans and then infected with HIV. They then administered a synthetic compound called SUW133, which was developed at Stanford University, to activate the mice’s dormant HIV. Up to 25% of the previously dormant cells that began expressing HIV died within 24 hours.

But a more effective way to kill those cells was needed. In the new study, while the mice were receiving antiretrovirals, the researchers used SUW133 to flush HIV infected cells out of hiding. They then injected healthy natural killer cells into the mice’s blood to kill the infected cells. The combination of SUW133 and injections of healthy natural killer immune cells completely cleared the HIV in 40% of the HIV-infected mice.

The researchers also analyzed the mice’s spleens because the spleen harbors immune cells and is a favorable place to look for latent HIV-infected cells. They did not detect the virus there, suggesting that cells harboring HIV were eliminated. In addition, the combination approach performed better than either the administration of the latency reversing agent alone or the natural killer cells alone.

Dr. Kim said the researchers’ next objective is to further refine the approach to eliminate HIV in 100% of the mice they test in future experiments. “We will also be moving this research toward preclinical studies in nonhuman primates with the ultimate goal of testing the same approach in humans,” she said.


Researchers Find Protein Trove That May Influence Cystic Fibrosis

Researchers at the University of Toronto (U of T) have identified hundreds of new proteins that could play a role in cystic fibrosis and which may shed light on why some patients respond better than others to current therapies.

Many of these proteins, part of a group of druggable molecules called membrane proteins, interact with the CFTR protein, which when missing or faulty leads to the buildup of mucos in the lungs and other organs that is often fatal in cystic fibrosis.

“We identified more than 400 proteins associated with either healthy or mutant CFTR and have shown that some of them could predict the variability seen in patient symptoms and treatment responses,” said Igor Stagljar, principal investigator on the study and a professor in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine.

“With a more comprehensive view of the CFTR protein interaction network, we can identify novel drug targets that should enable more patient-specific therapies,” Dr. Stagljar said. The journal Molecular Systems Biology published the findings.

To help identify protein-protein interactions involving CFTR, the researchers developed a new technology based on a platform they designed in 2014. The approach is a high-throughput version of their Mammalian Membrane Two-Hybrid system that allows for screening of many more membrane proteins associated with a specific protein.

“The earlier design was array-based, and we could only screen about 200 proteins at a time,” said Dr. Stagljar, who is also a professor of biochemistry and molecular genetics at U of T. “With this new technology, we’ve introduced several changes that allow us to screen thousands of protein targets simultaneously, in a pooled manner.”

Dr. Stagljar and his laboratory used the technology to find several overlooked proteins, including many membrane proteins that may play a role in CFTR function and cystic fibrosis. Membrane proteins account for roughly one-third of all proteins in cells and about 65% of all drug therapy targets.

One especially promising candidate the team found is the fibrinogen-like 2 protein, thought to play a role in hepatitis, liver disease, and immune function. Downregulation of this protein, the team showed, leads to increased expression of CFTR in organoids, 3D in vitro models that show how cells interact in an organ, in this case with patient-derived gut tissues.

“We think fibrinogen-like 2 protein is a valuable drug target for cystic fibrosis, and we’re now working with our collaborators to validate other proteins that turned up in this study and in genome-wide association studies,” Dr. Stagljar said.

Cystic fibrosis affects over 90,000 people globally. The disease can arise when children inherit two mutated CFTR genes, one from each parent, resulting in defective CFTR proteins on the surface of cells in the lungs and other organs.


Study Links Gut Fungi to Crohn’s Inflammation

Results of a new study by researchers at Case Western Reserve University represent a step toward improving our understanding of Crohn’s disease and the factors that cause its intestinal inflammation.

Crohn’s disease can lead to chronic inflammation of the entire digestive tract. Symptoms include diarrhea, pain and cramping, fatigue, weight loss, and more. There is no cure for Crohn’s disease, but patients can alleviate symptoms with current treatment options, and new treatment options for Crohn’s disease patients may be on the horizon thanks to the research linking a common fungal pathogen to inflammatory bowel disease.

The study recently appeared in Cellular and Molecular Gastroenterology and Hepatology. This new research from the Case Western Reserve School of Medicine focuses on the role of the fungus Candida tropicalis in triggering chronic inflammation within the gut microbiome. The gut microbiome is a complex ecosystem of fungus and bacteria found within the digestive tract.

Researchers introduced the fungi into animal models and induced colitis (inflammation of only the large intestine) through a chemical compound. The models infected with C tropicalis showed severe inflammation and significant imbalance of the gut microbiome with changes in bacteria levels.

Researchers say the findings show that this imbalance of fungi and bacteria can create a predisposition to inflammatory bowel disease. Past studies have shown that people with Crohn’s disease have higher levels of C tropicalis compared with healthy individuals.

Understanding the impact of C tropicalis on a person’s health, therefore, will play a role in developing treatments for Crohn’s disease.

Researchers Restore Function in Liver Cancer–Suppressing Gene

A team of researchers from Massachusetts General Hospital (MGH) and Brigham and Women’s Hospital (BWH) has reprogrammed the tumor microenvironment of liver cancer by using mRNA nanoparticles. This technology, similar to the one used in COVID-19 vaccines, restored the function of the p53 master regulator gene, a tumor suppressor mutated in not just liver but also other types of cancer. When used in combination with immune checkpoint blockade (ICB), the p53 mRNA nanoparticle approach not only induced suppression of tumor growth but also significantly increased antitumor immune responses in hepatocellular carcinoma (HCC) laboratory models. The results of the study were published in Nature Communications.

“The reprogramming of the cellular and molecular components of the tumor microenvironment could be a transformative approach for treating HCC and other cancers,” said cosenior author Jinjun Shi, PhD, with the Center for Nanomedicine at BWH, who developed the platform with MGH liver cancer biologist and cosenior author Dan G. Duda, DMD, PhD. “By using this new approach, we’re targeting specific pathways in tumor cells with mRNA nanoparticles. These tiny particles provide the cells with the instructions to build proteins, which, in the case of HCC, delayed tumor growth and rendered the tumor more responsive to treatment with immunotherapy.”

HCC is the most prevalent form of liver cancer, characterized by a high mortality rate and dismal prognosis. Immune checkpoint blockers, a revolutionary new class of drugs that enable the body’s immune system to recognize and attack cancer cells, have shown efficacy in treating HCC, but most patients do not benefit. To overcome this resistance, multiple strategies are being developed to improve ICBs by combining them with other existing therapies, such as anti-VEGF drugs and radiotherapy. However, even these approaches are expected to benefit only a small number of patients, creating an urgent need for new combination therapies.

Encouraged by the success of mRNA in COVID-19 vaccines, Dr. Shi decided to apply the technology (with certain modifications) to targeting cancer cells. He teamed up with Dr. Duda, whose MGH laboratory had already created sophisticated animal models to analyze the microenvironment of liver tumors in response to immunotherapy. They developed and optimized an mRNA nanoparticle strategy to restore loss of function of p53, a tumor-suppressor gene whose function is lost in more than one-third of HCC cases. In doing so, they uncovered evidence that p53 regulates the tumor microenvironment by modulating the interaction of cancer cells with immune cells as part of ICB therapy.

“In our previous work we had developed nanoparticles to target CXCR4—a chemokine receptor expressed by liver cancer cells—and selectively codeliver drugs such as kinase inhibitors,” explained Dr. Duda. “We’ve now adapted this platform to use CXCR4 as a kind of ZIP code to selectively target the tumor with nanoparticles encapsulating therapeutic mRNAs. When we combined this nanomedicine with anti–programmed death receptor 1 (PD-1) antibodies, a standard immunotherapy for HCC patients, it induced global reprogramming of the tumor microenvironment and tumor response by restoring p53 expression.”

How Exercise Could Help People With Asthma

Interventions aimed at promoting physical activity in people with asthma could improve their symptoms and quality of life, according to new research from the University of East Anglia (UEA).

Researchers looked at whether interventions such as aerobic and strength or resistance training had helped participants with asthma. Although they found that these interventions worked, patients with asthma may have had difficulty undertaking them because of their challenge of travel to fitness groups or because the interventions were not suitable for people with additional health conditions.

But the team say that digital interventions—such as video appointments, smartwatches, and mobile apps—could remove some of these barriers and enable patients to carry out home-based programs.

Dr. Andrew Wilson, from UEA’s Norwich Medical School, said, “Being physically active is widely recommended for people with asthma. Doing more than 150 minutes a week of moderate to vigorous physical activity has extensive benefits including improved lung function and asthma control. But research has shown that people living with asthma engage in less physical activity and are more sedentary than people without asthma.”

The team studied interventions that were designed to promote physical activity in adults with asthma. They looked at 25 separate studies from around the world involving 1,849 participants with asthma to see whether their symptoms and quality of life were changed thanks to the interventions.

Postgraduate researcher Leanne Tyson, also from UEA’s Norwich Medical School, said, “We found that interventions that promote physical activity had significant benefits in terms of increasing physical activity, decreasing time spent sedentary, improving quality of life, and decreasing asthma symptoms.

“This is really important because helping patients make significant behavior changes could really improve their outcomes in the long term. Our review also highlights the potential use of digital interventions, which were notably absent.”

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