Breaking News
June 23, 2018 - Infant omega-3 supplementation tied to decreased waist size
June 23, 2018 - Massive analysis of genomes reveals insights into genetic overlap among psychiatric diseases
June 23, 2018 - New therapeutic approach may delay neurodegeneration in rare genetic disease
June 23, 2018 - Broken shuttle protein may hinder learning in patients with brain disorders
June 23, 2018 - Study finds increase in daily cannabis use among American adults
June 23, 2018 - Researchers create electronic skin that brings back real sense of touch to prosthetic limbs
June 23, 2018 - FIRS: Guidance Offered for Protecting Youth From E-Cigarettes
June 23, 2018 - Scientists unravel molecular mechanisms of Parkinson’s disease
June 23, 2018 - When the Heart Stops, Drugs Often to Blame
June 23, 2018 - Scientists show that a key Parkinson’s biomarker can be identified in the retina
June 23, 2018 - Study finds factors underlying current rise in radicalization among European youth
June 23, 2018 - New study finds higher heart disease risk in bisexual men
June 23, 2018 - Coconut oil diet increases vitality, lifespan of fruit flies with peroxisomal disorder
June 23, 2018 - Jumping genes or transposons and their role in the genetic code
June 23, 2018 - The Current issue of “The view from here” is concerned with Therapeutics
June 23, 2018 - Abnormal lipid metabolism in fat cells predicts future weight gain and diabetes in women
June 23, 2018 - Alcohol problems linked to sex without condom use among black gay men
June 23, 2018 - DNA patterns in circulating blood cells can help identify spastic cerebral palsy
June 23, 2018 - Unsubstantiated health claims widespread within weight loss industry
June 23, 2018 - FDA grants marketing authorization for use of two catheter-based devices in hemodialysis patients
June 23, 2018 - An ingrown toenail not the same as a bypass
June 23, 2018 - Study suggests proteinuria lowering as important target in managing pediatric CKD
June 23, 2018 - Schizophrenia patients account for over 1 in 10 suicide deaths, study shows
June 23, 2018 - Overdose risk increases five-fold with concurrent opioid and benzodiazepine use
June 23, 2018 - FDA Alert: Kratom (mitragyna speciosa) powder products by Gaia Ethnobotanical: Recall
June 23, 2018 - Study highlights inadequate effort of health care insurers to combat opioid epidemic
June 23, 2018 - CDC chief asks for, and gets, cut to his record $375K pay
June 22, 2018 - Novel cellular pathway may clarify how arterial inflammation develops into atherosclerosis
June 22, 2018 - Pioneering exercise program improves physical, mental health of elderly people living in care homes
June 22, 2018 - Rutgers Cancer Institute educates childhood cancer survivors about late effects of treatment
June 22, 2018 - Study tests accuracy of device designed to detect heart dysfunction in childhood cancer survivors
June 22, 2018 - Study links annual haze with increased hospitalizations for respiratory problems
June 22, 2018 - Robotic surgery appears to be as effective as open surgery in treating bladder cancer
June 22, 2018 - Many Drugs Made Available Via FDA Expanded Access Programs
June 22, 2018 - Normal eye dominance is not necessary for restoring visual acuity in amblyopia
June 22, 2018 - Parent-Child Interaction Therapy can reduce depression rates in children
June 22, 2018 - Study provides insights into how components of different cells in the brain are altered
June 22, 2018 - Research does not confirm antidiabetic action of natural fatty acid derivatives
June 22, 2018 - Oxidative stress can be used against tumors to treat cancer
June 22, 2018 - Simple, cost-effective test may help improve early diagnosis of mild cognitive impairment
June 22, 2018 - New guide published to help battle fatal disease caused by kissing bugs
June 22, 2018 - Stigma Adds to Burden of Type 1 Diabetes
June 22, 2018 - In retinoblastoma survivors, oculo-visual issues tied to QoL
June 22, 2018 - Most adults with allergies do not use prescribed epinephrine even in emergency situations
June 22, 2018 - Study provides clues to how cancer cells develop resistance to chemotherapies
June 22, 2018 - New consensus paper serves as basis for uniform medical management of DSD
June 22, 2018 - Researchers work to identify areas of the brain that help us wake up
June 22, 2018 - Alcohol hangovers more significant and costly than people realize, shows research
June 22, 2018 - Targeting cells involved in blood vessel formation could hinder brain tumor growth
June 22, 2018 - Young cancer survivors need more support as they feel dissatisfied with their sexuality
June 22, 2018 - Unusual cell-to-cell communication in glioblastoma promotes aggressiveness and therapy resistance
June 22, 2018 - Turning A Phage – Drug Discovery Today
June 22, 2018 - World-first study links birth interventions and long-term childhood illness
June 22, 2018 - Improving the quality of biomedical research samples
June 22, 2018 - Researchers identify cerebral palsy using AI and DNA sequencing
June 22, 2018 - Administering nitric oxide gas after heart surgery may decrease risk of kidney problems
June 22, 2018 - Measuring levels of ethyl sulphate in hair can help assess alcohol consumption
June 22, 2018 - Researchers develop robot bloodhound that can rapidly detect odors on the ground
June 22, 2018 - AAA doses first patients in two clinical studies with PSMA-R2 for prostate cancer
June 22, 2018 - LSTM led consortium receives grant to investigate how human behavior impacts AMR
June 22, 2018 - Researchers discover drug compound that inhibits movement of cancer cells
June 22, 2018 - Normalization of ‘plus-size’ body shapes may prevent recognition of health risks of obesity
June 22, 2018 - UC San Diego launches new bacteriophage therapy center
June 22, 2018 - New review outlines current state of sex-sensitive issues linked to heart failure drugs
June 22, 2018 - Pelvic pain a major issue for women nearing mid-life, research reveals
June 22, 2018 - Researchers develop reliable DNA barcodes for biomedical research
June 22, 2018 - New risk-prediction model may help identify diabetic patients at high risk of pancreatic cancer
June 22, 2018 - Study reveals how mTORC1-driven changes in crowding could influence major diseases
June 22, 2018 - Researchers uncover new therapeutic opportunity in the treatment of malignant melanoma
June 22, 2018 - UC Riverside researcher receives grants to advance cancer, ALS research
June 22, 2018 - Radiation therapy alone may be enough to treat older, sicker patients with anal cancers
June 22, 2018 - Technical report describes how to make accurate particle size measurements on carbon black samples
June 22, 2018 - Nocdurna (desmopressin acetate) Approved by FDA as First Sublingual Tablet to Treat Nocturia due to Nocturnal Polyuria
June 22, 2018 - Neuroscientists locate neurons in the brain that respond when a visual target is found
June 22, 2018 - First human Keystone virus infection reported
June 22, 2018 - New study reveals how ‘good’ bacteria help in regulating our metabolism
June 22, 2018 - Osteopathic manual therapy affecting the diaphragm improves chronic low back pain
June 22, 2018 - Researchers create revolutionary model to study pulmonary diseases
June 22, 2018 - Diagnosing Heart Disease Using AI
June 22, 2018 - Increasing biodefense risks posed by synthetic biology
Study uncovers mechanism causing chronic GVHD after bone marrow transplant

Study uncovers mechanism causing chronic GVHD after bone marrow transplant

image_pdfDownload PDFimage_print

Allogeneic bone marrow transplant (BMT) is an essential treatment to cure patients with blood cancers such as leukemia. In patients who have undergone chemotherapy and radiation, a small number of cancer cells can remain in the bloodstream and allow the malignancy to recur.

Replacing host bone marrow is the best strategy for preventing relapse but recipients cannot always find an ideal, biologically matched donor. The less well-matched the donor, the higher the risk for developing graft-versus-host disease (GVHD). In GVHD, donor cells trigger an immune response that attacks normal tissues, leading to a chain reaction of cellular and molecular responses that increase morbidity and mortality in these patients. A long-standing question has been how to improve the success of BMT by reducing GVHD incidence while, at the same time, preserving the anti-tumor response of donor cells.

New research by a team of investigators at the Medical University of South Carolina (MUSC) directed by Xue-Zhong Yu, M.D., professor of Microbiology and Immunology, in collaboration with researchers at the University of Minnesota, demonstrates that one particular family of microRNAs (miRs), called miR-17-92, is responsible for the T-cell and B-cell pathogenicity that causes GVHD. The findings were reported in an article prepublished online on March 12, 2018 by Blood.

GVHD can be divided into acute (aGVDH) or chronic forms (cGVHD). “They are very different diseases,” explains Yongxia Wu, Ph.D., a postdoctoral fellow and lead author on the article. “Our ability to prevent or treat aGVHD has considerably improved, but the incidence of cGVHD continues to increase. Chronic GVHD has a different pathophysiology and different target organs than aGVHD. It’s been a big challenge to try to find a target for cGVHD therapies, because of the more complex immune reaction in cGVHD and the fact that its cellular and molecular mechanisms are not as well understood.”

Chronic GVHD is characterized by autoimmune-like, fibrotic changes in multiple organs such as the skin (causing scleroderma) and the lungs (causing bronchiolitis obliterans), and fibrosis of the salivary glands, liver, and gut. With 30 to 70 percent of patients who receive allogeneic BMT developing cGVHD, the lack of effective therapies is a major unmet clinical need.

The MUSC team previously found that, in aGVHD, miR-17-92 played a critical role in regulating CD4 T-cell proliferation and Th1 and Treg differentiation. Based on this work, they decided to investigate whether miR-17-92 regulates T- and B-cell differentiation and function in the development of cGVHD.

“We decided to extend our aGVHD study to cGVHD. But there’s no single, well-defined murine model that can reflect all of the clinical manifestations seen in cGVHD patients,” explains Wu. “Different patients experience different symptoms because cGVHD can be manifested in many organs — some patients have skin symptoms, some have lung symptoms — it varies. So, we decided to study four different cGVHD models to best understand how miR-17-92 contributes overall, across many clinical presentations.”

The team undertook a series of experiments to define the role of miR-17-92 in regulating T- and B-cell pathogenicity using murine models of allogeneic BMT, including models of scleroderma that had transitioned from aGVHD to cGVHD, classic cGVHD scleroderma, lung inflammation and a lupus-like condition. The team also conducted two clinical translation studies to test whether pharmacologically blocking miR-17-92 might have clinical relevance in the lupus-like condition and the scleroderma cGVHD model.

Their results demonstrated shared mechanisms by which miR-17-92 mediates cGVHD progression — namely by regulating T helper-cell differentiation, B-cell activation, germinal center responses, and autoantibody production. The clinical translation studies also found that miR-17 blockade alleviated proteinuria (in the lupus-like condition) and scleroderma symptoms.

“The mechanism for how miR-17-92 regulates T- and B-cells was very consistent. In other words, we did not find any big differences among the models,” says Wu. “So, we not only found a new mechanism for cGVHD development by demonstrating that this miR-17-92 is heavily involved in the T- and B-cell responses that lead to cGVHD, but we also found that blocking miR-17 substantially reduced cGVHD symptoms in mice. That’s exciting because it provides strong evidence that this miR may be a good target for controlling cGVHD after allogeneic BMT.”

Although miR-17-92 has been well studied, its role in cGVHD development has never before been defined. Because cGVHD has a similar pathophysiology to some autoimmune diseases, it is likely that these findings will be useful for developing new treatments and preventive therapies in other conditions.

“We are very excited to publish this work because we are hoping that a clinical research group will be inspired to take our study findings further in patients,” says Wu.

In the meantime, the MUSC team, led by Yu, will continue their work and try to extend the current findings by investigating how other miRs may be involved in regulating T- and B-cell function during allogeneic BMT.​​

Tagged with:

About author

Related Articles