What Causes Graft-Versus-Host Disease? 6 Factors That Raise the Risk

An allogeneic stem cell transplant can be a lifesaving procedure for people with lymphoma, leukemia, and other blood cancers. However, the benefit of a potential cure also comes with risks, including graft-versus-host disease (GVHD). In GVHD, donated immune cells attack healthy cells in the transplant recipient’s body.

This article explores the factors that can raise the risk of GVHD, helping you understand what to watch for.

How Does Graft-Versus-Host Disease Develop?

GVHD is a possible complication of an allogeneic stem cell transplant, also called an allogeneic bone marrow transplant. This procedure replaces a recipient’s damaged or destroyed bone marrow with healthy blood-forming cells from a donor, usually after a conditioning regimen.

GVHD happens when the transplanted immune cells (the graft) mistake healthy cells in the transplant recipient’s body (the host) for foreign invaders. This complication can develop when donated T cells (a type of white blood cell, also called T lymphocytes) identify the host’s cells as harmful invaders.

Normally, T cells help fight infections and cancer. However, donated T cells may recognize the recipient’s healthy cells as foreign and begin to attack.

Your cancer care team will try to prevent GVHD by selecting the best donor match and prescribing immunosuppressive medications before your transplant. However, GVHD is a complex condition influenced by many factors. We’ll discuss some of the risk factors below.

Human leukocyte antigens (HLAs) are proteins on most cells. These proteins help the immune system tell the difference between the body’s own cells and foreign cells.

When donor and recipient HLA markers are very different, the donor’s immune cells are more likely to see the transplanted cells as a threat, increasing the risk of GVHD. A closer HLA match helps lower this risk.

Tissue-typing tests determine whether a donor is a good match. HLA matching is often based on either eight or 10 markers, and closer matches generally lower the risk of GVHD. A fully matched donor has the same HLA markers as the recipient, while a haploidentical donor (a partially matched donor) shares about half of the recipient’s HLA markers.

Even with a partial match, a transplant may succeed without causing GVHD. Certain treatments, such as posttransplant cyclophosphamide, can help reduce the risk of GVHD. Among people with haploidentical donors, from 14 percent to 41 percent develop acute GVHD, whereas chronic GVHD occurs in 0 percent to 31 percent of cases.

Acute GVHD usually appears within the first 100 days and mainly affects the skin, liver, and digestive system. Chronic GVHD, which can develop later, often involves more organs and can last for months or years.

Getting a transplant from an unrelated donor can increase the risk of GVHD, even with a very close HLA match.

HLA proteins are inherited from both parents, so a fully matched sibling is often a preferred donor. Biological parents and children are typically half-matched, while full biological siblings have a 1 in 4 chance of being a full match.

If no matching relatives are available, volunteer donor registries can help find an unrelated donor. However, even a well-matched unrelated donor carries a higher GVHD risk compared with a matched sibling donor.

Bone marrow transplants were once limited to younger people because of the risks linked to the intensive chemotherapy required before the transplant. However, advances in research have made this treatment an option for some older adults when the benefits outweigh the risks. One key consideration for older recipients is an increased risk of developing GVHD.

Studies also show that a donor’s age affects the risk of GVHD. A 2020 study of more than 600 people found that recipients with donors between ages 30 and 49 were about 50 percent more likely to develop acute GVHD than those with donors younger than 29.

A male recipient of a transplant from a female donor may have a higher risk of both acute and chronic GVHD, according to a study in the journal Biology of Blood and Marrow Transplantation. The exact reason isn’t fully understood, but researchers think the increased risk may be linked to differences in sex chromosomes (X and Y). The risk is even higher if the female donor has been pregnant, possibly due to immune system changes that occur during pregnancy.

The type of conditioning regimen you receive before a transplant can also affect your risk of GVHD. A conditioning regimen, which helps destroy diseased blood cells and weaken the immune system, usually includes chemotherapy and sometimes total body irradiation.

High-dose chemotherapy can cause tissue damage, triggering an immune response. This increases the number of immune cells in circulation, giving the donor’s immune cells — the graft — more chances to recognize and attack the host.

Researchers have also linked total body irradiation, another method used in some conditioning regimens, to a higher GVHD risk. If you’re preparing for a transplant, talk to your cancer care team about how your conditioning regimen may affect your risk of GVHD.

In an allogeneic stem cell transplant, donor transplant cells can come from different sources, including:

Donated cells from peripheral blood carry a higher risk of chronic GVHD compared to bone marrow donations, while umbilical cord blood has the lowest risk.

Lowering the Risk of Graft-Versus-Host Disease

Your healthcare team will try to prevent GVHD by minimizing your risk factors and prescribing immunosuppressive medications. You may start taking these medications before or after the transplant procedure, depending on your treatment plan.

There is no single best drug regimen for preventing GVHD. Your healthcare team will suggest a treatment plan based on your individual needs and overall health.

Examples of immunosuppressive medications to prevent GVHD include:

Another strategy to reduce the risk of GVHD is T-cell depletion, which removes some T cells from the donor sample before transplantation. Your oncology (cancer) care team can give you more information about whether T-cell depletion may help lower your GVHD risk.

If GVHD does occur, several treatment options can help manage symptoms and improve your quality of life. You can also consider joining a clinical trial looking for new GVHD treatments.