Eyewitness News reports that doctors at Groote Schuur Hospital have successfully performed Africa’s first incompatible kidney transplant. Known as ABO-incompatible (ABOi) transplants, these procedures are done when the donor’s blood type does not match the recipient’s – once a major contraindication.
The patient, a 35 year old woman named Chervon Meyer, received a kidney donation from her brother. She had been on dialysis for 10 years,
Incompatible living kidney transplants have long been contraindicated because of the presence of isohaemagglutinins, natural antibodies reacting with non-self ABO antigens. Due to the growing demand for transplant organs, incompatible donations were investigated in order to expand the pool of possible donors. This has changed with the development of new desensitisation regimens over the past decades. These include immunoadsorption and plasmapheresis and the immunosuppressive protocol.
The improvements have been so great that, despite a lack of randomised trials, recent meta analysis found that there is no difference in terms of graft and patient’s survival between ABOi and ABO compatible kidney transplant, even in the long term.
As nephrologist Dr Zunaid Barday explains, this procedure made use of a Glycosorb filter which reduced many of the risks associated with desensitisation, such as plasma exchange weakening the immune system. It works by binding anti-A and anti-B antibodies, reducing their levels in blood plasma. While expensive, the filter is a much cheaper alternative in the long run compared to years of dialysis.
A new study published in the Journal of Experimental Medicine provides a strategy for finding treatments optimally tailored for women and men to prevent cognitive decline in aging as well as progression of neurodegenerative diseases by leveraging sex differences in the brain.
Ageing is associated with cognitive decline and brain atrophy, and is a major neurodegenerative disease risk. Studying sex differences in brain aging and neurodegenerative diseases can reveal new candidate treatment targets tailored for women and men.
One new approach to identifying neuroprotective treatments lies in understanding the role of sex chromosome gene expression in the brain as sex hormones wane during the ageing process.
UCLA researchers Dr Rhonda Voskuhl, Professor, and Dr Yuichiro Itoh, Associate Researcher, in the Department of Neurology, have created a roadmap to identify novel neuroprotective treatments tailored for women and men that leverage known sex differences in brain aging and neurodegenerative diseases.
Previously, research pursuing treatments for neurodegenerative diseases ignored sex differences in the brain and pooled data together from males and females, taking a “one size fits all” approach. This could dilute out robust effects that exist in one sex but not the other at the clinical research level and fail to capitalize on known disease modifiers in the discovery of new treatment targets at the basic research level.
In their study Voskuhl and Itoh write that known sex differences in the brain as well as the effect of higher expression of certain X chromosome genes in females (XX) compared to males (XY) can be assessed for their role in neurodegeneration during aging, a stage of life characterised by loss of potentially neuroprotective hormones in females (namely oestrogen in menopause) and males (testosterone in andropause). The study offers a roadmap for disentangling the contribution of these sex-specific factors, which can yield treatments optimized and targeted for each sex.
In the future, this roadmap can be used by researchers to discover targets on the X chromosome gene for development of modulatory treatments that prevent neurodegeneration and promote neural repair during brain aging.
“Given the aging population and lack of treatments to prevent cognitive decline during health and to reduce the risk for developing neurodegenerative diseases, it is now imperative to apply new strategies to identify neuroprotective treatments,” said Voskuhl. “Leveraging what is known about sex differences in multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease can reveal candidate treatment targets tailored for women and men affected by these conditions. Sex chromosome effects remain understudied and represent a promising frontier for discovery, particularly in the context of declining levels of sex hormones during menopause and andropause.”
In patients with Huntington’s disease, neurons in a part of the brain called the striatum are some of the worst affected. Degeneration of these neurons contributes to patients’ loss of motor control, which is one of the major hallmarks of the disease.
Neuroscientists at MIT have now shown that two distinct cell populations in the striatum are affected differently by Huntington’s disease. Reporting their results in Nature Communication, they believe that neurodegeneration of one of these populations leads to motor impairments, while damage to the other population, located in structures called striosomes, may explain the mood disorders that are often see in the early stages of the disease.
“As many as 10 years ahead of the motor diagnosis, Huntington’s patients can experience mood disorders, and one possibility is that the striosomes might be involved in these,” says Ann Graybiel, an MIT Institute Professor and one of the senior authors of the study.
Using single-cell RNA sequencing to analyse the genes expressed in mouse models of Huntington’s disease and postmortem brain samples from Huntington’s patients, the researchers found that cells of the striosomes and another structure, the matrix, begin to lose their distinguishing features as the disease progresses. The researchers hope that their mapping of the striatum and how it is affected by Huntington’s could help lead to new treatments that target specific cells within the brain.
This kind of analysis could also shed light on other brain disorders that affect the striatum, such as Parkinson’s disease and autism spectrum disorder, the researchers say.
Neuron vulnerability
Huntington’s disease leads to degeneration of brain structures called the basal ganglia, which are responsible for control of movement and also play roles in other behaviors, as well as emotions. For many years, Graybiel has been studying the striatum, a part of the basal ganglia that is involved in making decisions that require evaluating the outcomes of a particular action.
Many years ago, Graybiel discovered that the striatum is divided into striosomes, which are clusters of neurons, and the matrix, which surrounds the striosomes. She has also shown that striosomes are necessary for making decisions that require an anxiety-provoking cost-benefit analysis.
In a 2007 study, Richard Faull of the University of Auckland discovered that in postmortem brain tissue from Huntington’s patients, the striosomes showed a great deal of degeneration. Faull also found that while those patients were alive, many of them had shown signs of mood disorders such as depression before their motor symptoms developed.
To further explore the connections between the striatum and the mood and motor effects of Huntington’s, Graybiel teamed up with Kellis and Heiman to study the gene expression patterns of striosomal and matrix cells. To do that, the researchers used single-cell RNA sequencing to analyze human brain samples and brain tissue from two mouse models of Huntington’s disease.
Within the striatum, neurons can be classified as either D1 or D2 neurons. D1 neurons are involved in the “go” pathway, which initiates an action, and D2 neurons are part of the “no-go” pathway, which suppresses an action. D1 and D2 neurons can both be found within either the striosomes and the matrix.
The analysis of RNA expression in each of these types of cells revealed that striosomal neurons are harder hit by Huntington’s than matrix neurons. Furthermore, within the striosomes, D2 neurons are more vulnerable than D1.
The researchers also found that these four major cell types begin to lose their identifying molecular identities and become more difficult to distinguish from one another in Huntington’s disease. “Overall, the distinction between striosomes and matrix becomes really blurry,” Graybiel says.
Striosomal disorders
The findings suggest that damage to the striosomes, which are known to be involved in regulating mood, may be responsible for the mood disorders that strike Huntington’s patients in the early stages of the disease. Later on, degeneration of the matrix neurons likely contributes to the decline of motor function, the researchers say.
In future work, the researchers hope to explore how degeneration or abnormal gene expression in the striosomes may contribute to other brain disorders.
Previous research has shown that overactivity of striosomes can lead to the development of repetitive behaviors such as those seen in autism, obsessive compulsive disorder, and Tourette’s syndrome. In this study, at least one of the genes that the researchers discovered was overexpressed in the striosomes of Huntington’s brains is also linked to autism.
Additionally, many striosome neurons project to the part of the brain that is most affected by Parkinson’s disease (the substantia nigra, which produces most of the brain’s dopamine).
“There are many, many disorders that probably involve the striatum, and now, partly through transcriptomics, we’re working to understand how all of this could fit together,” Graybiel says.
In October last year, Eastern Cape Health MEC Nomakhosazana Meth announced a three-phase plan to address key challenges with the province’s emergency medical services. PHOTO: Black Star/Spotlight
By Siyabonga Kamnqa for Spotlight
Gogo Nothembile Fanti (76) says she suffers from a heart condition and every time her grandchildren call an ambulance, they are told to wait, but it never arrives. She is one of about 40 patients – mostly older persons – sleeping on the floor and in chairs at All Saints Hospital in Ngcobo in the Eastern Cape during Spotlight’s visit on 30 January. They are all waiting for an ambulance to take them to referral hospitals such as Nelson Mandela Academic Hospital and Bedford Hospital about 60 kilometres away in Mthatha. They come from various villages around Ngcobo.
Fanti, like many other patients, says they are forced to sleep there overnight as the free transport provided by the hospital leaves at the crack of dawn.
“I had to call my neighbour to [bring] me here, otherwise I could have died waiting for the ambulance. They told me that I have to be taken to Mthatha to see a specialist, but having to sleep under these conditions at my age is a terrible experience,” she says.
An old problem
The challenges with patient transport, specifically emergency medical transport in the Eastern Cape, are not new. Spotlight has previously reported on the issue here, here, and here.
In October last year, Eastern Cape Health MEC Nomakosazana Meth in a response to a written question in the provincial legislature by DA MPL Jane Cowley said that there are 84 Emergency Medical Services (EMS) bases in the Eastern Cape – 16 of those are in the Chris Hani District where All Saints Hospital is situated.
Based on the numbers Meth provided, the district also has the highest vacancy rate – 65%. This means of the 796 posts available, there were 518 vacancies for EMS staff at the time of her response in October. Overall, for the whole province, the total posts were 3 269, but 1 202 were vacant at the time.
The province needs 671 ambulances based on its population but has 447 ambulances of which only 200 were rostered, meaning they were in service at the time. In Chris Hani District, they need at least 72 ambulances but only have 62 of which just 38 were rostered and on the road to provide a service.
Staff shortages and ambulances undergoing maintenance are among the reasons why there are not enough ambulances rostered in the province. Not one of the 84 EMS bases in the province complied with the national EMS regulations for personnel numbers.
According to the DA’s provincial health spokesperson, Jane Cowley, there are 150 ambulances at any given time in for repairs. “The average turnaround time for repairs is a shocking 100 days – this is because they use the Government Fleet Management Services, who are owed in excess of R300 million by the [provincial health department] so they really don’t prioritise ambulance repairs.” She says the DA has been calling for the decentralisation of ambulance repairs and the development of public-private partnerships, which the party believes would speed up repair turnaround times dramatically.
Shouldering the burden
Providing some perspective on the impact this has on services and patient lives, a doctor says there are some districts where, at times, there is only one paramedic on duty per shift (the doctor spoke to Spotlight on condition of anonymity given the risks of reprisals from the health department). “When there is a serious call from opposite ends of the district, then you have to wait for the paramedic to deal with the one case, then come to the second. Patients in hospitals are deemed ‘less serious’ than if they are on the roadside. So, patients can wait for hours in a district hospital before being referred to a tertiary hospital. We recently had an elderly man with wet gangrene on his foot who waited in a casualty for two days. Then he died,” the doctor says.
The doctor says they often have a full casualty unit on Saturday nights. At times there may be four patients waiting for a referral. They may have gunshot wounds, been stabbed in the neck, and assaulted with a head injury. The casualty fills up as time passes and the number of patients waiting for referrals now grew by three, while the other four are still waiting in casualty. The three may be all orthopaedic patients. The doctor will ask the nurse about the patients and is told EMS said “no ambulances available”. “Maybe you have the energy to paste this update on the EMS WhatsApp group. Maybe you try to phone someone yourself to escalate this issue. Maybe someone is able to contact the provincial office and request a private ambulance to assist. But by morning, there are still six patients waiting… then one dies. The oncoming team will now have to re-discuss these patients with the new team at the referral centre. The same thing happens day after day… patients miss appointments, have to be re-discussed, get a new date due to the perseverance of the doctors, then maybe miss another date due to EMS not being available… It is extremely exhausting for all concerned,” the doctor says.
According to two paramedics (who also spoke on condition of anonymity), they struggle with inadequate equipment in EMS vehicles. This, coupled with poor road infrastructure, often puts them under enormous pressure, they say. “Cellphone network also disappears during loadshedding and this makes it impossible for patients to reach our services,” says one of the paramedics. “When we eventually arrive at the accident scene or at a sick patient, we are often met with insults from frustrated patients who said they’ve been trying to get hold of an ambulance for hours. Often, they forget about the challenges we face in trying to get to them on time,” he said.
Three-phased plan – yet to be financed
Meth in her parliamentary response last year said, “The[se] frequent transfers of patients put a heavy burden on the emergency medical services as there are no ambulances to do inter-facility transfers and therefore the emergency ambulances are used to transfer patients from hospitals to other hospitals over long distances with no ambulances left for emergency response at community level.” She said this is why there are often poor ambulance response times or no response at all.
In an attempt to address this, the provincial health department is working on a three-phased EMS plan targeting 28 hospitals across districts – among them All Saints.
This plan, however, will need funding to get off the ground.
Explaining the department’s three-phased plan, provincial health spokesperson Yonela Dekeda last week said the department plans to recruit additional personnel as funding becomes available and so did not provide timeframes. She says phase one is aimed at providing a dedicated inter-hospital transfer ambulance on a day-shift basis at the 28 priority hospitals. They aim to appoint 120 new staff members for this.
In phase two, the department wants to appoint an additional 120 personnel to make the day service a twenty-four-hour service and phase three is to extend this to other hospitals and provide them with the personnel needed.
But, says Dekeda, the department will need R27 million and they expect funding only to be made available in the 2023/24 financial year.
Working to address EMS challenges
Meanwhile, she says, the department has been working to address the many challenges facing EMS in the province and there are some improvements. “These include the response rate to priority 1 calls (life-threatening calls). Over the past three quarters – ending December 2022 – the department has been meeting its targets for priority 1 calls by responding within 30 minutes (urban areas) and 60 minutes (rural areas).” She didn’t however specify what percentage of calls met these targets.
According to her, the department has taken a developmental approach to achieve compliance with the national EMS regulations. She says over the next three years there will be continued investments in infrastructure, equipment, staffing, and vehicles to promote compliance with the ideal promulgated in the regulations.
“We have purchased an additional 50 ECG monitors at a cost of R19 million to supplement the equipment in our ambulances as required by the regulations. About R15 million has been allocated to improving the infrastructure at selected EMS stations around the province and an additional allocation is expected in the next financial year to support the strategy,” she says.
In the current financial year, she says, the Engcobo Local Service Area where All Saints Hospital is located was allocated two intermediate life support practitioners.
Dekeda says the department’s priority remains emergency patient care, so the majority of the current resources are still allocated to this.
“We are using our staff interchangeably between planned patient transport and the emergency transport service. One will understand that the planned patient transport works on weekdays (Monday to Friday) while emergency ambulance services are a 7-day operation, 24 hours a day. We are committed to increasing the number of staff on the emergency transport and then developing a separate staff complement for the planned patient transport service.”
Dekeda also says recruiting more staff is coupled with interventions to have the district hospitals offer the appropriate package of services, which will reduce the number of trips transferring patients. She says by employing dedicated teams to manage transfers of patients at the 28 priority hospitals as part of the three-phased plan, the hope is to improve the overall responsiveness of the ambulance fleet.
“We will continue with this recruitment in the next financial year and also focus on the operational staff to assist with the transfers of critical patients. All Saints is one of the district hospitals that will benefit,” she stresses.
“A total mess”
But some Eastern Cape residents remain sceptical.
Responding to the new plans, activist and community leader from Xhora Mouth, Phumzile Msaro says they are tired of empty promises. “This EMS problem is going to be with us for a long time as long as there are still unreliable people at the top. Every day we are faced with challenges as rural dwellers. Just yesterday (09 February), I called an ambulance for an elderly villager from Xhora Mouth who had fits. The assistants at the call centre lied and said the ambulance was on its way but we waited all day, only for the ambulance to arrive at 7 pm after a number of frantic calls throughout the day. The elderly person only managed to arrive and get assistance at Madwaleni Hospital at 9 pm. We keep hearing about all these so-called plans but nothing gets implemented on the ground. It’s a total mess,” he says.
Cowley echoes these sentiments. She says due to ambulance shortages and the severe shortage of EMS personnel, especially advanced life support paramedics, ambulance turnaround times are very slow, particularly in rural areas. “People can wait up to a day for an ambulance and sometimes that is too late. They have many plans but cannot seem to implement them as there is no political will to do so. It’s just a talk shop. In all my extensive oversight visits, the constant and main complaint is the lack of or slow ambulance service.”
Acute low back pain is a common cause of disability, and while opioid drugs are effective at controlling pain, excessive use creates a great potential for substance abuse. An analysis in the Journal of Orthopaedic Research examined which non-opioid drugs are best for relieving this pain.
The analysis, which included all randomised controlled trials published to date (18 studies with 3478 patients), showed that muscle relaxants and non-steroidal anti-inflammatory drugs (NSAIDs) could effectively and rapidly reduce symptoms.
The combination of NSAIDs and paracetamol was associated with a greater improvement than NSAIDs alone.
“This is a first step towards the optimisation of the management of acute low back pain. However, specific patient characteristics such as having allergies and comorbidities must always be taken into consideration,” said lead author Alice Baroncini, MD, PhD, of RWTH University Hospital in Germany. “Further research will need to focus on the identification of the type of drugs that not only offer the best and quickest pain relief, but also show the lowest rate of symptom recurrence.”
A study published in PLoS ONE has confirmed the role of the corpus callosum in language lateralisation, ie the distribution of language processing functions between the brain’s hemispheres. To get to this finding, the researchers applied advanced neuroimaging methods to study subjects performing an innovative language task for their study.
Functional asymmetry between the two cerebral hemispheres in performing higher-level cognitive functions is a major characteristic of the human brain. For example, the left hemisphere plays a leading role in language processing in most people. However, between 10% and 15% of people also use the right hemisphere to varying degrees for the same task.
Traditionally, language lateralisation to the right hemisphere was explained by handedness, as it is mainly found in left-handed and ambidextrous (using both hands equally well) individuals. But recent research has demonstrated a genetic difference in the way language is processed by left-handed and ambidextrous people. In addition to this, some right-handed people also involve their right hemisphere in language functions.
These findings prompted the scientists to consider alternative explanations, especially by looking at brain anatomy to find out why language functions can shift to the right hemisphere. Researchers at the HSE Centre for Language and Brain hypothesised that language lateralisation may have something to do with the anatomy of the corpus callosum, the largest commissural tract in the human brain connecting the two cerebral hemispheres.
Tractography of the corpus callosumDo Tromp et al. / brainimaging.waisman.wisc.edu
The researchers asked 50 study participants to perform a sentence completion task. The subjects were instructed to read aloud a visually presented Russian sentence and to complete it with an appropriate final word (eg ‘Teper’ ministr podpisyvaet vazhnoe…‘ – ‘Now the minister is signing an important …’). At the same time, the participants’ brain activity was recorded using functional magnetic resonance imaging (fMRI). Additionally, the volume of the corpus callosum was measured in each subject.
A comparison between the fMRI data and the corpus callosum measurements revealed that the larger the latter’s volume, the less lateralisation of the language function to the right hemisphere was observed.
When processing language, the brain tends to use the left hemisphere’s resources efficiently and the corpus callosum suppresses any additional involvement of the right hemisphere. The larger a person’s corpus callosum, the less involved their right hemisphere is in language processing (and vice versa). This finding is consistent with the inhibitory model suggesting that the corpus callosum inhibits the action of one hemisphere while the other is engaged in cognitive tasks.
The study’s innovative design and use of advanced neuroimaging have made this conclusion possible. Brain lateralisation in language processing is usually hard to measure accurately, as typical speech tasks used in earlier studies (eg image naming, selecting words that begin with a certain letter or listening to speech) tend to cause activation only in some parts of the brain responsible for language functions but not in others. Instead, we developed a unique speech task for fMRI: sentence completion, which reliably activates all language areas of the brain.
The researchers reconstructed the volume and properties of the corpus callosum from MRI data using an advanced tractography technique: constrained spherical deconvolution (CSD). This is more suitable than traditional diffusion tensor imaging for modelling crossing fibres in the smallest unit of volume, the voxel (3D pixel), and is therefore more reliable.
A new poll done in the US suggests that some parents may not be properly measuring or responding to elevated temperatures in children, and are unnecessarily using antipyretics to bring down their temperatures.
While most parents recognise that a low-grade fever helps a child’s body fight off infection, one in three would give fever-reducing medication for spiked temperatures below 38°C (which isn’t recommended) according to the C.S. Mott Children’s Hospital National Poll on Children’s Health at University of Michigan Health.
Half of parents would also use medicine if the fever was between 38 and 38.9°C, and a quarter of parents would likely give another dose to prevent the fever from returning.
“Often parents worry about their child having a fever and want to do all they can to reduce their temperature. However, they may not be aware that in general the main reason to treat a fever is just to keep their child comfortable,” said Mott Poll co-director and Mott pediatrician Susan Woolford, M.D.
“Some parents may immediately rush to give their kids medicine but it’s often better to let the fever runs its course. Lowering a child’s temperature doesn’t typically help cure their illness any faster. In fact, a low-grade fever helps fight off the infection. There’s also the risk of giving too much medication when it’s not needed, which can have side effects.”
The report is based on 1,376 responses from parents of children ages 12 and under polled between August and September 2022.
Two in three parents polled say they’re very confident they know whether their child needs medication to reduce a fever. But just over half are sure they understand how temperature readings can change according to the method used.
The method used to take a child’s temperature matters and can affect the accuracy of the measurement, Woolford notes. Parents polled most commonly take their child’s temperature by forehead scan or mouth while less than a sixth use ear, underarm or rectal methods.
Remote thermometers at the forehead or inside the ear canal can be accurate if used correctly. But forehead readings may be inaccurate, Woolford says, if the scanner is held too far away or if the child’s forehead is sweaty. With ear thermometers, which aren’t recommended for newborns, earwax can also interfere with the reading.
For infants and young children, rectal temperatures are most accurate. Once children are able to hold a thermometer in their closed mouth, oral temperatures also are accurate while armpit temperatures are the least accurate method.
“Contact thermometers use electronic heat sensors to record body temperature but temperatures may fluctuate depending on how it’s measured,” Woolford said.
“Regardless of the device used, it’s important that parents review the directions to ensure the method is appropriate for the child’s age and that the device is placed correctly when measuring temperature.”
Three in four parents say they take their child’s temperature as soon as they notice a possible problem, while a little less than a fourth wait to see if the problem continues or worsens before taking the temperature.
Two-thirds of parents also prefer to try methods like a cool washcloth before using fever-reducing medication. Most parents also say they always or usually record the time of each dose and re-take their child’s temperature before giving another dose.
“A quarter of parents would give their child more medicine to prevent a fever from returning even though it doesn’t help them get better,” Woolford said. “If a child is otherwise doing well, parents may consider monitoring them and using alternative interventions to help keep them comfortable.”
However, if a newborn or infant less than three months old has a fever, they should immediately see a health professional, Woolford adds.
Researchers have found that compounds in the edible Lions’ Mane mushroom (Hericium erinaceus), already used in herbal medicine for stomach complaints, can promote nerve growth and boost memory. Their findings are published in The Journal of Neurochemistry.
The compounds are neurotrophins – a family of proteins associated with the growth, functioning and maintenance of neurons. In mammals, brain-derived neurotrophic factor (BDNF) is highly expressed in central nervous system neurons. Because BDNF pathway impairment is associated with several diseases, including schizophrenia, Alzheimer’s disease, Rett syndrome, and Huntington’s disease, experimental treatments for neurological and neurodegenerative disorders often target neutrophins.
So far, such treatments have run into problems with crossing the blood-brain barrier and off-target effects. H. erinaceus is high in neutrophins, though it has traditionally been used in herbal medicine to treat stomach complaints and cancer. It is also known for promoting peripheral nerve regeneration.
Two of the biologically active types of compounds, hericenones and erinacines, can successfully cross the the blood-brain barrier and confer neuroprotective effects.
The researchers tested crude and purified H. erinaceus extracts and found that they exhibited BDNF-like neurotrophic activity in both in vitro cultured hippocampal neurons and in mouse models of hippocampal memory. The extracts also promoted neurite outgrowth and improved memory.
They concluded that Hericene A acts through a novel signalling pathway, giving rise to improved cognitive performance. These findings however will need to be validated by future research.
Researchers have discovered that the difference between people who do and do not respond to immunotherapy may have to do with an immune cell known as CD5+ dendritic cells, because they bear the protein CD5 on their outer surfaces. Their research, published in Science, showed that survival was longer in patients with a range of cancers, including melanoma, if they had more CD5+ dendritic cells in their tumours, and that mice lacking CD5 on their dendritic cells failed to respond well to immunotherapy.
The findings suggest that a supplementary therapy designed to increase the number or activity of CD5+ dendritic cells potentially could extend the lifesaving benefits of immunotherapy to more cancer patients.
“Immunotherapy has revolutionized the field of cancer therapy, but there are a lot of patients with cancer who don’t benefit from it,” said senior author Eynav Klechevsky, PhD, an assistant professor of pathology & immunology and a researcher at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Part of the reason some people do not respond well to some forms of immunotherapy is because this population of dendritic cells is reduced dramatically. We’re developing some novel immune-based approaches to boost the activation of these CD5-expressing dendritic cells with a goal of helping more patients respond to immunotherapy.”
The immune system defends the body against cancer by activating immune cells known as T cells to recognise and kill tumour cells. In response, tumour cells manipulate the immune checkpoint system — a safeguard that prevents T cells from mistakenly attacking healthy cells — to hoodwink T cells into leaving them alone. Immune checkpoint blockade therapy works by thwarting tumour cells’ manipulations, thereby freeing T cells to recognise and destroy tumours. But even with therapy, some people’s T cells are unable to do their job effectively.
Klechevsky and colleagues — including first author Mingyu He, PhD, a staff scientist, and co-author Kate Roussak, MD, a postdoctoral researcher — suspected that people who don’t respond to immunotherapy may have a problem with their dendritic cells. Without dendritic cells, T cells are subdued and aimless.
By analysing data in The Cancer Genome Atlas, Klechevsky and colleagues discovered that patients with types of skin, lung, bone and soft tissue, breast and cervical cancers fared better if they had higher levels of CD5+ dendritic cells in their tumours.
Further work with human cells and mice showed that CD5+ dendritic cells are required for effective T cell activity against tumours. CD5+ dendritic cells from people powerfully induced T cells to activate and multiply. Mice with tumours responded only weakly to immunotherapy and failed to reject the tumors if they lacked CD5 on their dendritic cells.
The findings suggest that the amount of CD5+ dendritic cells inside tumours could be used to help doctors assess which patients are most likely to benefit from immunotherapy. They also suggest that increasing the numbers or the activity of such dendritic cells potentially could help more people benefit from immunotherapy. As part of this study, the researchers discovered that the immune protein IL-6 increases the amounts of CD5+ dendritic cells.
“We still don’t completely understand how immunotherapies work,” Klechevsky said. “This study indicates that there is more we can do to increase the efficacy of these treatments. I’m confident that if we can find ways to harness these cells or expand these cells in patients, we can help more people.”
