Tag: Medication

Immune tolerance has long been the holy grail in transplant medicine, a hoped-for end to the downsides of anti-rejection regimens for patients after they receive lifesaving organ transplants. A small, early-stage study now shows promise in taking cells from living donors — people giving a portion of their livers — to teach recipients’ immune systems to accept the foreign organs as their own and achieve the ultimate healthy outcome. 

Living donations take advantage of the liver’s ability to regenerate, meaning donors can part with a piece of their liver and later see it grow back. Recipients can regain enough liver function from the partial organs that also grow, replacing livers damaged by alcohol-associated liver disease, metabolic-associated liver disease, liver cancer, or other causes. Immunosuppression keeps their bodies from rejecting the new organs, but it also raises their vulnerability to infectious diseases and certain cancers. Serious side effects from the drugs include developing diabetes and kidney damage.

Cell therapy has been tried before to disarm the immune system’s attack by recruiting regulatory T immune cells taken from the donor. In the new study, whose results were published Friday in Nature Communications, different immune cells known as regulatory dendritic cells were obtained from donors’ white blood cells and generated in a lab. The idea behind both cell therapies is the same: to teach immune cells in the recipient’s body to treat the donated liver fragment as familiar tissue, not an invader be attacked.

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UCLA researchers have found that macrophages with a senescent phenotype may be actively driving progression of fatty liver disease. A study published today in Nature Aging reports that clearing this aging cell population in mice dramatically reduced liver inflammation and reversed damage even without any dietary changes. 

“Senescent cells are fairly rare, but think of them like a broken-down car,” said Anthony J. Covarrubias, PhD, assistant professor at the UCLA David Geffen School of Medicine and senior author of the study. “Just one stalled car can back up traffic for miles. Now imagine five or ten of them slowly accumulating. That’s what these cells do to a tissue: even a small number causes enormous disruption.”

As cells age and become senescent, they are known to drive chronic inflammation across a range of tissues. While previous research has shown that eliminating senescent cells can improve health and lengthen lifespan, there is still a limited understanding of which cells undergo the senescence process and how to distinguish them from healthy cells.

This is especially the case for cells that naturally share hallmark features with senescent cells, as is the case of macrophages; when activated, macrophages secrete a range of inflammatory cytokines and immunomodulatory metabolites that many senescent cells also produce when driving chronic, age-driven inflammation. 

The researchers found that no single biomarker was enough to identify senescent macrophages. Instead, they identified that this aging cell population was defined by the simultaneous expression of p21 and Trem2 proteins, together with altered nuclear morphology, lipid metabolism and type I interferon (IFN) hyperactivation.

In mice, senescent macrophages carrying this molecular signature were found to surge from 5% in young mice to up to 80% in older ones, correlating with a rise in chronic liver inflammation during normal aging. In addition, excess cholesterol was found to push macrophages into a senescent state where they stopped dividing, increased secretion of inflammatory proteins and activated expression of p21 and Trem2. 

“Physiologically, macrophages can handle cholesterol metabolism,” said Ivan A. Salladay-Perez, graduate student in the Covarrubias lab and lead author of the study. “But in a chronic state, it’s pathological. When you look at fatty liver disease, which is driven by overnutrition and too much cholesterol in the blood, that excess cholesterol appears to be a major driver of the senescent macrophage population.”

Experiments using a publicly available genomic dataset of patient liver biopsies found that the same senescent macrophage signature was increased in diseased livers compared to healthy ones, suggesting they also play a role in chronic liver disease in humans. 

In mice with a high-fat, high-cholesterol diet, a drug that selectively kills senescent cells was found to reduce overall body weight and make livers healthier—smaller and with a lower fat percentage. These findings suggest that clearing senescent macrophages from the liver does not just slow the progression of fatty liver disease, but can actually reverse it without changing the diet. 

Because the drug tested in mice is too toxic for humans, the researchers plan to begin drug screening studies to identify new compounds that can replicate these effects. They will also be exploring whether this therapeutic target could be expanded to a range of other age- and cholesterol-driven conditions where senescent macrophages have been observed.

“It all goes back to understanding how these cells arise in the first place,” said Salladay-Perez. “If you really understand the basic mechanisms driving inflammation with aging, you can target those same mechanisms to treat not just fatty liver disease, but atherosclerosis, Alzheimer’s and cancer.” 

The post Aging Immune Cells Linked to Fatty Liver Disease  appeared first on Inside Precision Medicine.

Scientists at Boston Children’s Hospital and Harvard Medical School have uncovered evidence that rare, localized genetic mutations may spark the onset of devastating brain diseases even when those mutations are present in only a tiny fraction of cells.

The Nature Genetics study, which focused on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), discovered that these conditions can start with somatic “mosaic” mutations that spread throughout the nervous system.

Despite the association of a handful of genes with these neurodegenerative diseases, 90–95% of cases arise sporadically, without a family history, leaving their origins unclear. Researchers genomically examined 1,787 postmortem tissue samples of various brain regions and spinal cords from hundreds of patients (144 control, 291 ALS, and 117 FTD) who died before the age of 45 but had no family history. The samples were taken from the NIH NeuroBioBank.

Using molecular inversion probe (MIP)-panel sequencing of 88 neurodegeneration-associated genes, they discovered that about 2.1% of sporadic cases carried damaging somatic mutations in one of these disease-related genes. These mutations were extremely rare within the tissue, often present in less than 2% of cells. What makes the discovery noteworthy is where those mutations appear: rather than being distributed throughout the brain, they were concentrated in disease-affected areas, such as the motor cortex and spinal cord in ALS. This pattern suggests that neurodegeneration may begin in a small cluster of genetically altered cells before spreading outward. That idea aligns with existing theories that ALS and FTD progression involve the movement of toxic proteins, particularly TDP-43, between cells in a prion-like manner. A single focal mutation could initiate this cascade, effectively “seeding” disease.

Senior author Christopher A. Walsh, MD, PhD, Howard Hughes Medical Institute investigator and professor at BCH and HMS, told Inside Precision Medicine, “Above all, it suggests that the genes, or at least some of the genes, that drive the disease don’t necessarily have their toxic effects only in the neurons carrying the mutation. Or that some neurons are impacted and that leads to a domino effect that somehow impacts neurons that don’t carry the mutation.”

The study also identified mutations in unexpected genes, including DYNC1H1 and LMNA, which are typically linked to severe childhood neurological disorders. Inherited versions of these mutations are often incompatible with long-term survival, but when present only in a subset of brain cells, they may allow normal early development followed by late-onset neurodegeneration. In another key finding, researchers detected spontaneous expansions in the C9orf72 gene—the most common genetic cause of inherited ALS and FTD—arising directly within brain tissue. This provides some of the first evidence that such disease-causing expansions can occur somatically rather than being inherited.

Together, the results point to a new model of disease: ALS and FTD may not always begin with widespread genetic risk but instead with rare, localized mutations that trigger broader neurodegeneration over time. The discovery also highlights a major challenge for diagnosis. Because these mutations can be confined to the brain and present at extremely low levels, they would likely be missed by standard genetic tests using blood or saliva.

According to Walsh, the results highlight the importance of creating a more sophisticated clinical strategy. “Clinically translating these findings immediately is a challenge, because most of the variants we find are likely limited to the brain and hence unavailable to clinical sequencing,” said Walsh.

The researchers believe that these findings pave the way for novel methods, both for identifying concealed genetic alterations in the brain and for creating treatments that target early, localized disease processes before they proliferate.

Walsh said, “If we see that gene-directed anti-sense oligonucleotide (ASO) therapies (like the ongoing FUS trial) are incompletely effective, it could reflect that the degeneration is a widespread process. Or it may suggest the importance of starting these ASO trials at the earliest possible stage to try to block secondary processes.”

While the proportion of cases explained by these mutations is still small, the work underscores a growing realization in neuroscience: even a handful of altered cells may be enough to set off widespread brain disease.

The post Neurodegeneration in ALS and FTD May Be Caused by Somatic “Mosaic” Mutations appeared first on Inside Precision Medicine.