Graft versus host disease is a serious complication that can occur after receiving donated stem cells or bone marrow from another person, where the donor’s immune cells mistakenly attack the recipient’s body tissues and organs.
Understanding Graft Versus Host Disease
Graft versus host disease, commonly shortened to GvHD, develops when someone receives an allogeneic transplant, which means getting stem cells or bone marrow from another person rather than using their own cells. This type of transplant is often necessary for people with blood cancers like leukemia or lymphoma, or other conditions affecting the bone marrow such as aplastic anemia (a condition where the bone marrow fails to produce enough blood cells).[1]
The term “graft versus host” describes exactly what happens in this condition. The graft refers to the donated stem cells or bone marrow, while the host is the person receiving the transplant. In GvHD, the immune cells from the donor see the recipient’s body as foreign and launch an attack against it. This happens because the donated immune cells don’t recognize the recipient’s tissues as belonging to the same body.[2]
It’s important to understand that not everyone who receives an allogeneic transplant will develop GvHD. Some people never experience it, while others may have mild, moderate, or severe forms of the disease. The severity can range from manageable symptoms to life-threatening complications that require intensive medical care.[4]
Types of Graft Versus Host Disease
Healthcare providers classify GvHD into two main types based on when symptoms appear and which organs are affected. Understanding these distinctions helps doctors provide the right treatment at the right time.[1]
Acute graft versus host disease typically develops within the first 100 days after transplant, though it can sometimes appear later. This form most commonly affects the skin, digestive system, and liver. The skin symptoms often appear first, showing up as a rash that looks similar to sunburn. This rash usually starts on the neck, shoulders, ears, and on the palms of the hands and soles of the feet before potentially spreading to other parts of the body. When acute GvHD affects the digestive system, people experience nausea, vomiting, and diarrhea that can become severe enough to require hospitalization. Liver involvement causes jaundice, where the skin and whites of the eyes turn yellow.[1]
Chronic graft versus host disease can appear any time after the transplant, but most cases start within the first two years. This form can affect nearly any part of the body, including the skin, mouth, eyes, liver, lungs, digestive system, muscles, joints, and genital areas. Chronic GvHD can last anywhere from a few months to several years, with the average duration being between one and three years. Some people experience improvement over time, while others may live with symptoms for longer periods.[1]
Medical experts have refined these classifications beyond just timing. They now recognize that features of both acute and chronic GvHD can sometimes occur together, creating what’s called overlap syndrome. This can happen at any point after the transplant and requires careful evaluation by the medical team.[2]
Epidemiology
The occurrence of GvHD varies widely depending on several factors related to both the donor and the recipient. Understanding how common this condition is helps patients and families know what to expect after an allogeneic transplant.[7]
Acute GvHD affects between 10% and 80% of people who receive allogeneic stem cell transplants. This wide range exists because the risk depends heavily on how closely the donor’s tissue matches the recipient’s tissue. When the donor is a close family member with very similar tissue types, the risk is lower, typically around 35% to 45%. However, when the donor is unrelated to the recipient, the risk increases significantly to about 60% to 80%.[7]
Chronic GvHD develops in approximately 30% to 70% of people who survive beyond 100 days after their transplant. This form of the disease typically begins around four to six months after the transplant, though it can appear earlier or later. The wide range in these numbers reflects differences in transplant procedures, donor matching, and preventive measures used at different medical centers.[10]
The risk of developing GvHD is not evenly distributed across all transplant recipients. Older patients face higher risks than younger ones. The type of conditioning treatment used before transplant also matters—people who receive total body irradiation as part of their preparation have an increased chance of developing GvHD compared to those who receive only chemotherapy.[3]
Causes
The underlying cause of GvHD relates to how the immune system recognizes what belongs in the body and what doesn’t. Understanding this process helps explain why this complication occurs after allogeneic transplants but not when people receive their own cells back.[1]
Every cell in the body carries special proteins on its surface called human leukocyte antigens, or HLA. These proteins act like identification tags that the immune system uses to distinguish the body’s own cells from foreign invaders like bacteria and viruses. We inherit our HLA pattern from our parents, and except for identical twins, each person’s HLA pattern is unique.[3]
Before a transplant, doctors perform tissue typing tests to compare the HLA patterns between potential donors and the recipient. The goal is to find the closest possible match. However, even with the best matching available, there are often small differences between the donor’s HLA and the recipient’s HLA. These differences create the foundation for GvHD to develop.[3]
After the transplant, the donated stem cells travel to the bone marrow and begin producing new blood cells. Among these new blood cells are T lymphocytes, or T cells, which are specialized immune cells from the donor. These donor T cells carry the donor’s HLA pattern and are programmed to recognize cells with different HLA patterns as foreign threats. When these donor T cells encounter the recipient’s cells, which have a different HLA pattern, they may identify them as enemies and begin attacking them. This attack by donor immune cells against recipient tissues is what causes the symptoms of GvHD.[2]
The severity of GvHD often correlates with how many differences exist between the donor’s HLA and the recipient’s HLA. Greater mismatches generally lead to more severe disease, though this isn’t always predictable. The transplant process itself also contributes to GvHD risk. The high-dose chemotherapy and sometimes radiation used to prepare the body for transplant damages tissues and causes inflammation, which can make the immune attack worse.[2]
Risk Factors
Several factors can increase the likelihood of developing GvHD after an allogeneic transplant. Knowing these risk factors helps medical teams take appropriate preventive measures and helps patients understand their individual risk.[3]
The degree of HLA matching between donor and recipient stands out as one of the most important risk factors. When the donor is an unrelated person, the risk of GvHD increases substantially compared to having a related donor, even if the HLA match appears similar on testing. Even small mismatches in HLA can raise the risk significantly. Transplant centers work hard to find the best possible match, but sometimes a perfect match isn’t available, and doctors must weigh the risks of GvHD against the need for the transplant.[3]
The number of T cells in the donated stem cells or bone marrow affects GvHD risk. Higher numbers of donor T cells increase the chance of GvHD developing because there are more immune cells available to attack the recipient’s tissues. However, this presents a dilemma because T cells also help fight cancer cells and protect against infections. Completely removing T cells from the graft reduces GvHD risk but can increase the chances of cancer returning or serious infections occurring.[3]
Gender combinations between donor and recipient can influence risk. Male recipients who receive stem cells or bone marrow from female donors face increased risk, especially if the female donor has been pregnant in the past. During pregnancy, women develop antibodies against their baby’s cells, which carry the father’s genes. These antibodies can contribute to a stronger immune reaction in the transplant recipient.[3]
Previous exposure to certain viruses affects risk as well. Cytomegalovirus, or CMV, is a common virus that many people carry without symptoms. If the recipient has never been exposed to CMV but receives cells from a donor who has CMV, this mismatch can increase the risk of GvHD developing.[3]
The type of conditioning treatment used before transplant matters too. People who receive total body irradiation as part of their preparation for transplant generally have higher rates of GvHD than those who receive only chemotherapy. The radiation causes more tissue damage and inflammation, which can worsen the immune attack.[3]
Symptoms
The symptoms of GvHD vary greatly depending on which form develops and which organs are affected. Recognizing these symptoms early is crucial because prompt treatment can prevent complications and improve outcomes.[1]
Acute GvHD Symptoms
Skin involvement is usually the first sign of acute GvHD. People notice a rash that looks and feels similar to a sunburn. The skin may appear red, feel itchy, and sometimes becomes painful. This rash typically starts in specific areas—the neck, shoulders, ears, palms of the hands, and soles of the feet—before potentially spreading to cover larger areas of the body. In more severe cases, the skin can blister and peel.[1]
When acute GvHD affects the digestive system, symptoms can be quite uncomfortable and sometimes dangerous. People experience nausea that makes eating difficult, frequent vomiting, and diarrhea that can become severe. Abdominal cramping and pain often accompany these symptoms. The diarrhea can lead to dehydration and weight loss, and in serious cases, blood may appear in the stool.[1]
Liver involvement in acute GvHD causes jaundice, where the skin and the whites of the eyes take on a yellow color. This happens because the immune attack damages the liver’s ability to process bilirubin, a yellow pigment that normally gets removed from the body. Blood tests show elevated liver enzymes, indicating that liver cells are being damaged. People may also notice that their urine becomes darker in color.[4]
Chronic GvHD Symptoms
Chronic GvHD creates a different pattern of symptoms because it can affect virtually any organ system in the body. The symptoms often develop gradually and can persist for extended periods.[1]
Skin changes in chronic GvHD differ from those in acute disease. Rather than appearing as a simple rash, the skin may become tight, thick, and hard. This tightening can restrict movement, particularly when it affects areas around joints. The skin may also become very dry, develop raised discolored patches, or lose its normal texture. Hair loss can occur on both the head and body.[1]
Eye symptoms are common in chronic GvHD. People describe their eyes feeling dry, gritty, or like sand is in them. The eyes may burn, become sensitive to light, or produce excessive tears as the body tries to compensate for dryness. Vision can become blurry or unstable. These symptoms occur because the immune attack damages the glands that produce tears and the surface of the eye itself.[1]
Mouth problems frequently develop with chronic GvHD. Severe dryness makes eating, swallowing, and speaking difficult. White patches may appear inside the mouth, and painful mouth sores can form. The tongue may appear smooth and red. Gum disease can develop, and people often find that spicy or acidic foods cause significant discomfort.[1]
Lung involvement causes shortness of breath and a dry, persistent cough that doesn’t go away. People may find that activities they could previously do easily now leave them winded. This happens because the immune attack causes scarring and narrowing of the small airways in the lungs, a condition called bronchiolitis obliterans.[1]
Muscle and joint symptoms include weakness, cramping, pain, and stiffness. The joints may lose their normal range of motion, making everyday activities like reaching overhead or bending down more difficult. Some people develop tightness in their muscles that restricts movement.[1]
Digestive symptoms can continue in chronic GvHD, including persistent diarrhea, nausea, loss of appetite, and weight loss. The liver can remain affected, continuing to show abnormal enzyme levels and jaundice. Some people develop difficulty swallowing or a feeling that food gets stuck in the throat or chest.[1]
Genital symptoms occur in both men and women. Women experience vaginal dryness, itchiness, and pain during sexual intercourse. Men may have itching of the penis or scrotum and also experience pain during intercourse. These symptoms significantly affect quality of life and relationships but often go unreported due to embarrassment.[1]
General symptoms that can accompany either form of GvHD include overwhelming fatigue that doesn’t improve with rest, unexplained fevers, and an increased susceptibility to infections because the immune system is suppressed by both the disease and its treatment.[4]
Prevention
Preventing GvHD or reducing its severity starts before the transplant and continues for months or even years afterward. Multiple strategies work together to lower the risk while maintaining the beneficial effects of the transplant.[11]
The most important preventive step happens during donor selection. Transplant centers perform extensive tissue typing tests on potential donors to find the closest possible HLA match. Better matches significantly reduce the risk of GvHD. When multiple potential donors are available, doctors consider not just the HLA match but also other factors like the donor’s age, gender, and CMV status to select the donor who presents the lowest overall risk.[3]
After the transplant, all recipients of allogeneic transplants take medications designed to suppress the immune system and prevent GvHD from developing. The most common preventive treatment combines two medicines: cyclosporine and methotrexate. Cyclosporine is typically given for about six months after transplant, with blood tests performed regularly to ensure the level stays high enough to be effective. Methotrexate is given in the first few weeks after transplant. This combination has become the standard approach because it effectively reduces GvHD risk.[11]
Some transplant centers use tacrolimus instead of cyclosporine, particularly when the donor is unrelated to the recipient. Tacrolimus works similarly to cyclosporine but may provide better control of GvHD in certain situations. Other medications that may be added to preventive regimens include mycophenolate, sirolimus, and prednisone, though adding more immunosuppressive drugs must be balanced against increased infection risk.[4]
Some transplant procedures involve removing T cells from the donated stem cells or bone marrow before the transplant. This process, called T-cell depletion, significantly reduces GvHD risk. However, it also increases the chances of the cancer coming back and raises infection risk, so it’s not used in all cases. Another approach uses medication called antithymocyte globulin, or ATG, given before the transplant to reduce the number of active T cells. While ATG decreases severe GvHD risk, it doesn’t improve overall survival because of increased infections.[11]
A newer preventive approach called extracorporeal photopheresis, or ECP, involves collecting white blood cells from the blood, treating them with a light-sensitive medication and ultraviolet light, then returning them to the body. This process changes the cells in ways that reduce their ability to cause GvHD. Some centers use ECP as part of the conditioning regimen before transplant with promising results.[11]
Preventing infections is crucial for people at risk of GvHD because the immunosuppressive medications used to prevent and treat GvHD make the body more vulnerable to bacteria, viruses, and fungi. Doctors prescribe antibiotics, antiviral medications, and antifungal medications to prevent common infections. People must follow strict hygiene practices, avoid crowds, stay away from people who are sick, and sometimes wear masks in public places.[4]
Pathophysiology
Understanding what happens inside the body during GvHD helps explain why symptoms develop and why treatment takes specific approaches. The process involves complex interactions between the donated immune cells and the recipient’s tissues.[2]
The development of GvHD follows several steps that build upon each other. First, the high-dose chemotherapy and radiation given before transplant damage tissues throughout the body. This damage causes cells to release danger signals and inflammatory chemicals. The inflammation attracts immune cells to the damaged areas and makes the recipient’s cells more visible to the donor’s immune system.[2]
Next, donor T cells that arrive with the transplanted stem cells become activated when they recognize the recipient’s HLA as different from their own. These T cells multiply rapidly and travel throughout the body looking for cells with the “foreign” HLA pattern. Special cells called antigen-presenting cells help activate the donor T cells by showing them pieces of the recipient’s proteins.[2]
Once activated, donor T cells launch a direct attack on the recipient’s tissues. They do this in several ways. Some T cells directly kill target cells by releasing toxic chemicals. Others release signaling molecules called cytokines that recruit more immune cells to join the attack and amplify inflammation. These cytokines include substances like tumor necrosis factor and interferons, which cause tissue damage and many of the symptoms people experience.[2]
Different organs respond to the immune attack in characteristic ways. In the skin, the attack targets cells in the outer layers, causing the rash, blistering, and peeling seen in GvHD. In the digestive system, immune cells attack the lining of the intestines, damaging the cells that absorb nutrients and maintain the intestinal barrier. This explains the diarrhea, cramping, and weight loss. In the liver, the attack focuses on the bile ducts, small tubes that carry bile out of the liver. Damage to these ducts causes bile to back up, leading to jaundice and abnormal liver tests.[2]
Chronic GvHD involves additional processes beyond the initial immune attack. Over time, the ongoing inflammation triggers fibrosis, where normal tissue is replaced by scar tissue. This scarring causes many of the long-term problems in chronic GvHD, like skin tightening, lung scarring, and restricted joint movement. The scarring process involves cells called fibroblasts that produce excess collagen, the protein that makes up scar tissue. Once established, this fibrosis can be difficult to reverse even if the immune attack is controlled.[2]
The immune attack in chronic GvHD also damages glands throughout the body, particularly those that produce moisture. This explains why dry eyes, dry mouth, and dry skin are such common symptoms. The glands become infiltrated with immune cells and eventually stop functioning properly, similar to what happens in autoimmune diseases like Sjögren’s syndrome.[2]
Interestingly, some degree of immune reaction against the recipient’s cells can be beneficial. The same donor T cells that cause GvHD also attack any remaining cancer cells in the body, an effect called graft versus tumor or graft versus leukemia. This beneficial immune reaction is one reason why allogeneic transplants can cure cancers that would otherwise be incurable. The challenge in transplant medicine is finding the balance between allowing enough immune reaction to kill cancer cells while preventing harmful GvHD from developing. This is why doctors describe GvHD as having both disadvantages and potential benefits.[3]
