Researchers identify new target to reduce risk of GVHD

February 5, 2018, H. Lee Moffitt Cancer Center & Research Institute

Stem cell transplants can cure patients with high-risk leukemia or lymphoma. Graft-versus-host disease (GVHD) is a potentially life-threatening side effect that occurs when the donor's immune cells attack the recipient's normal tissues. Moffitt Cancer Center researchers are trying to identify new drug targets to reduce the risk of GVHD. Their new study, published last week in the Proceedings of the National Academy of Sciences, shows a drug that targets the protein JAK2 may reduce the risk of GVHD.

The goal of stem cell transplants is to replenish the bone marrow and eliminate residual cancer using the donor's . However, in some cases the donor's mount an immune response against the recipient's normal tissues. It is estimated that GVHD affects up to half of all stem cell recipients. The symptoms of GVHD can vary from mild to severe and include skin inflammation and rash, liver inflammation, jaundice, gastrointestinal problems, pain, and fatigue. Despite modern immune suppressive medications, death is possible when severe GVHD occurs.

The goal of GVHD treatment is to block the donor immune cells from targeting the body's normal cells, while at the same time maintaining the ability of the donor cells to target cancer cells for destruction. GVHD is commonly treated with drugs that suppress the immune system, such as glucocorticoids, but the scientific community is trying to find better alternatives with less side effects.

"An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation," said Brian C. Betts, M.D, lead study author and associate member of the Blood and Marrow Transplant and Cellular Immunotherapy Department at Moffitt.

The protein JAK2 is believed to be involved in the development of GVHD. In collaboration with researchers from the Medical University of South Carolina, the Moffitt research team wanted to confirm the link and assess if blocking JAK2 could reduce the occurrence of GVHD. They performed experiments with mice that were genetically engineered to be missing the JAK2 gene. They discovered that JAK2 regulates several of the immune cell mechanisms that lead to GVHD. They also showed that donor cells missing the JAK2 gene induced GVHD less than normal donor cells, and the were still able to target tumor cells for destruction.

These observations suggest drugs that target JAK2 may prevent GVHD and still allow the to target cancer cells. The researchers confirmed this by transplanting normal stem cells into recipient mice and treating the mice with the drug pacritinib that inhibits JAK2. They discovered that pacritinib reduced the number of immune responsible for GVHD and the number of mice that died from GVHD. Importantly, pacritinib did not inhibit the ability of the from targeting for destruction. The Moffitt research team also discovered that pacritinib could protect mice from tissue graft rejection, suggesting this approach could be used to prevent kidney or liver transplant rejection.

These results suggest that pacritinib may be a potential drug option to prevent GVHD in stem cell recipients. Betts and his Moffitt colleague, Joseph Pidala, M.D., Ph.D., are investigating a phase 1/2 acute GVHD prevention trial combining pacritinib with standard immune suppression after stem cell transplant.

Explore further: Researchers develop novel treatment to prevent graft-versus-host-disease

More information: Brian C. Betts et al, Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1712452115

Related Stories

Researchers develop novel treatment to prevent graft-versus-host-disease

January 11, 2017
Graft-versus-host-disease (GVHD) is the leading cause of non-relapse associated death in patients who receive stem cell transplants. In a new study published as the cover story in Science Translational Medicine, Moffitt Cancer ...

Researchers develop new strategy to limit side effects of stem cell transplants

August 15, 2016
Scientists in Germany have developed a new approach that may prevent leukemia and lymphoma patients from developing graft-versus-host disease (GvHD) after therapeutic bone marrow transplants. The researchers describe the ...

Depletion of naive T cells from stem cell grafts limits chronic graft-versus host disease

June 8, 2015
Stem cell transplantation is used to treat hematologic malignancies, such as leukemia. Patients that receive donor cells are at risk of developing graft-versus host disease (GVHD). This potentially fatal complication results ...

B and T cell-targeting drug ameliorates chronic graft-versus-host disease in mice

October 1, 2014
Hematopoietic stem cells (HSCs) can differentiate into all types of blood cells, including red blood cells and immune cells. While HSC transplantation can be life saving for patients with aggressive forms of blood cancer ...

Immunotherapy drug nearly eliminates severe acute graft-versus-host disease

December 9, 2017
Results from a phase 2 clinical trial, presented by Seattle Children's Research Institute at the 59th American Society of Hematology (ASH) Annual Meeting, show that the drug Abatacept (Orencia) nearly eliminated life-threatening ...

Immune cell subset is associated with development of gastrointestinal GVHD after HSCT

May 5, 2016
Gastrointestinal graft vs. host disease (GI-GVHD) is a life threatening complication that can occur after allogeneic hematopoietic cell transplantation, a procedure that is commonly used to treat patients with leukemia. There ...

Recommended for you

Gut hormone and brown fat interact to tell the brain it's time to stop eating

November 15, 2018
Researchers from Germany and Finland have shown that so-called "brown fat" interacts with the gut hormone secretin in mice to relay nutritional signals about fullness to the brain during a meal. The study, appearing November ...

Brain, muscle cells found lurking in kidney organoids grown in lab

November 15, 2018
Scientists hoping to develop better treatments for kidney disease have turned their attention to growing clusters of kidney cells in the lab. One day, so-called organoids—grown from human stem cells—may help repair damaged ...

How the Tasmanian devil inspired researchers to create 'safe cell' therapies

November 15, 2018
A contagious facial cancer that has ravaged Tasmanian devils in southern Australia isn't the first place one would look to find the key to advancing cell therapies in humans.

Precision neuroengineering enables reproduction of complex brain-like functions in vitro

November 14, 2018
One of the most important and surprising traits of the brain is its ability to dynamically reconfigure the connections to process and respond properly to stimuli. Researchers from Tohoku University (Sendai, Japan) and the ...

Gene mutation found to cause macrocephaly and intellectual deficits

November 13, 2018
The absence of one copy of a single gene in the brain causes a rare, as-yet-unnamed neurological disorder, according to new research that builds on decades of work by a University at Buffalo biochemist and his colleagues.

Can scientists change mucus to make it easier to clear, limiting harm to lungs?

November 12, 2018
For healthy people, mucus is our friend. It traps potential pathogens so our airways can dispatch nasty bugs before they cause harm to our lungs. But for people with conditions such as cystic fibrosis (CF) and chronic obstructive ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.