Causes and Risk Factors of Graft-Versus-Host Disease

Graft-versus-host disease (GvHD) is a complication of a stem cell or bone marrow transplant caused by a genetic mismatch between the cells of the donor and the recipient. Although there is no way to predict who will develop GvHD, certain risk factors can increase the likelihood of this common complication.

While most risk factors are non-modifiable (you can't change them), identifying them can help your doctor decide if a stem cell or bone marrow transplant is the most appropriate option.

This article will discuss the underlying cause of graft-versus-host disease, risk factors, and treatment choices that can affect the risk.

Genetics

At its heart, GvHD is caused by a mismatch between the genes of the transplant donor and the transplant recipient. The genes, collectively referred to as major histocompatibility complex (MHC), are responsible for encoding proteins on the surface of cells called human leukocyte antigen (HLA).

These antigens are inherited as a matched set from your genetic parents—one set from one parent and one set from your other parent—and serve as cellular "ID tags," helping the immune system differentiate your cells from foreign cells (like viruses and cancer).

If an antigen is regarded as foreign, the immune system will activate white blood cells called leukocytes to fight the invader. In people with GvHD, the donor tissues ultimately "misread" HLA and launch a hostile assault against normal cells and tissues.

Inheritance Patterns

To better help avoid GvHD, doctors will perform extensive tests, called HLA typing, to see if the donor and recipient are a "match." Siblings are generally considered the best donors because they get their genes from the same parents. With that said, the set of HLA that one child inherits may not be the same as what the other child inherits.

To be an "identical match," the donor and recipient will need to have inherited the same set of antigens—namely HLA-A, HLA-B, and HLA-DR—from each of their parents.

Because each parent also has two sets of HLA-A, HLA-B, and HLA-DR (which they inherited from their parents), a sibling ultimately has a one-in-four chance of being an "identical match."

GvHD Incidence

Even if siblings are an identical match, there is no guarantee that GvHD won't occur. In some cases, tissues from a matched donor can still trigger a hostile immune response.

Although there are tests that can help predict this—called crossmatch testing—there will always remain a risk of GvHD with any allogeneic transplant (meaning a transplant in which the donor and recipient are different people).

In some cases, this can lead to acute GvHD (in which symptoms develop within the first 100 days) and, in others, chronic GvHD (occurring after 100 days).

The risk of GvHD increases if an HLA-matched second- or third-degree relative (such as a cousin) is recruited as a donor, or if the matched donor is unrelated. And, in some cases, the doctor may have no option but to use an HLA-mismatched donor if the benefits outweigh the risks.

Even autologous transplants, in which the donor and recipient are the same person, can sometimes trigger GvHD, albeit less commonly and typically less seriously.

Common Risk Factors

While genetics play a central role in predicting the risk of GvHD, they are not the only risk factor. And even though these risk factors are non-modifiable, their identification can aid with donor selection and, in some cases, determine which type of transplant is most appropriate.

Acute GvHD

By definition, acute GvHD occurs within the first 100 days of a transplant and most commonly affects the skin, liver, and gastrointestinal tract. Most cases develop within the first few weeks.

Some of the risk factors associated with acute GvHD include:

• Older age of the donor or recipient
• Having an HLA-mismatched donor, either related or unrelated
• Having a female donor for a male recipient
• Undergoing a peripheral blood stem cell transplant (PBSCT)
• Having undergone total body irradiation (TBI) to prevent transplant rejection
• Testing positive for cytomegalovirus or Epstein-Barr virus

Other risk factors may contribute, including having a comorbid (co-occurring) disease, having had your spleen removed, and undergoing a post-transplant transfusion.

Chronic GvHD

Chronic GvHD is characterized by symptoms that develop more than 100 days after a transplant. Although it typically starts with a rash and scleroderma-like symptoms, chronic GvHD can involve a wider range of organ systems, including the liver, lungs, eyes, muscles, joints, nerves, genitals, gastrointestinal tract, urinary tract, and endocrine system.

Some of the risk factors for chronic GvHD are the same as for acute GvHD, while others are different. These include:

• Older age of the donor or recipient
• Having an HLA-mismatched donor, either related or unrelated
  
• Having an HLA-matched unrelated donor
• Having a female donor for a male recipient
• Having experienced acute GvHD
• Using growth factors (GF) like Neupogen (filgrastim) to boost stem cell production
  

Lifestyle Risk Factors

While smoking, diet, and other lifestyle choices commonly influence health outcomes, none of these have any direct impact on whether you experience GvHD or not. With that said, there is evidence that your performance status—meaning your level of ability to perform daily tasks—can influence the risk of GvHD.

Performance status is most commonly measured using the Karnofsky Performance Status Scale (KPS), which describes a person's functional status based on a scale of 0% (for death) to 100% (no limitation of activity).

A 2019 study from the University of Michigan Medical School found a direct association between a transplant recipient's performance status and the incidence of chronic GvHD of the lungs, muscles, joints, and liver. The higher the KPS score, the lower the risk of these specific conditions.

Other studies have found that a KPS score of 80% or greater is associated with improved overall survival and a reduced risk of GvHD relapse.

This suggests that keeping active and staying healthy may lower the risk of developing GvHD over the long term (or, at the very least, having less severe GvHD symptoms).

Treatment Considerations

When deciding upon a treatment plan, the doctor will evaluate the benefits and risks of each treatment option on a case-by-case basis. This not only includes choosing between a bone marrow or stem cell transplant but other treatments designed specifically to reduce the risk of GvHD.

Transplant Selection

The choice of allogeneic transplant plays a central role in GvHD prevention. Depending on the type of disease being treated—whether malignant (cancerous) or nonmalignant (noncancerous)—the choice of transplant can vary from one individual to the next.

In people with a malignant disease, a peripheral blood stem cell transplant is considered a high priority as it contains five to 10 times more donor cells than a bone marrow transplant. While this may increase the risk of acute GvHD, the benefits generally outweigh the risks.

By contrast, in people with a nonmalignant disease—such as sickle cell disease or thalassemia—a bone marrow transplant may be preferred as it is associated with a lower risk of acute and chronic GvHD.

T-Cell Depletion

Other treatment choices play a role in the prevention of GvHD. Chief among these is a procedure called T-cell depletion in which white blood cells called T-cell lymphocytes are extracted from the donor graft.

These cells are responsible for instigating the immune response. Removing T-cells makes the graft less likely to act against the recipient's own cells and tissues.

There are two main methods used for T-cell depletion (TCD):

• Ex vivo TCD is performed using immunomagnetic separation, a technique in which magnetic antibodies are attached to targeted cells so that they can be removed from a graft.
• In vivo TCD is performed using either anti-T-cell antibodies, called anti-thymocyte globulin (ATG), or the targeted drug Lemtrada (alemtuzumab).

Both techniques have their benefits and risks. For example, while ex vivo TCD generally offers the best results in GvHD prevention, it may not improve survival in people with certain cancers, such as acute myeloid leukemia (AML).

Similarly, while in vivo TCD is regarded as the standard of GvHD prevention following a peripheral blood stem cell transplant, such transplants typically require post-transplant immunosuppressants like cyclosporine and methotrexate, which can be toxic. Conditions treated with ex vivo TCD may not.

By weighing the benefits and risks of the various treatment options, your doctor can select the treatments that are not only the most effective but less likely to cause GvHD.

Summary

The underlying cause of graft-versus-host disease is a mismatch in the genes between the donor and the recipient. There are a few other factors that may increase the risk. A peripheral blood stem cell transplant has a higher risk of GvHD than a bone marrow transplant. T-cell depletion may be used to reduce the risk.

A Word From Verywell

Graft-versus-host disease is a concern to anyone who has undergone a stem cell or bone marrow transplant. This is especially true since there is usually no way to know who will be affected and little that you can do to avoid it actively.

Even so, it is important to remember that GvHD has some positive benefits. The same immune response causing GvHD is also targeting and destroying any surviving cancer cells. This is called the "graft-versus-tumor effect." Moreover, people who develop GvHD often have lower cancer relapse rates than those who don't.

Most importantly, keep yourself healthy if you are due to undergo (or have undergone) a transplant of any sort. This includes eating well, exercising appropriately, ensuring you get plenty of rest, getting the recommended vaccines, and avoiding infection wherever possible.