Graft-versus-Host Disease (GVHD) is a medical complication that can arise after an allogeneic transplant, which involves transplanting cells from a donor to a recipient. GVHD occurs when the newly transplanted immune cells, known as the graft, recognize the recipient’s body, the host, as foreign. This recognition triggers an immune response where the donor cells attack the host’s tissues and organs.
The Underlying Immune Conflict
GVHD is an immunological conflict initiated by the donor’s immune cells. The primary drivers of this conflict are a type of white blood cell from the donor graft called T-cells. In the context of GVHD, they mistakenly identify the recipient’s healthy cells as threats, recognizing proteins on the surface of the host’s cells, known as antigens, as being different and launching an attack.
This process is distinct from graft rejection, where the recipient’s own immune system attacks the transplanted donor cells. In GVHD, the roles are reversed: the donor cells are the aggressors. This attack on the host’s body can cause widespread inflammation and damage to various organs. The intensity of this reaction is closely linked to the degree of genetic difference between the donor and recipient.
There is a potential upside to this immune activity. The same donor T-cells that cause GVHD can also identify and destroy any cancer cells that may have survived pre-transplant chemotherapy or radiation. This is called the graft-versus-leukemia or graft-versus-tumor (GVL) effect. The GVL effect is a tool in preventing cancer relapse, creating a balance for medical teams who aim to control GVHD without eliminating this anti-cancer action.
Acute vs. Chronic Manifestations
GVHD is categorized into two forms, acute and chronic, based on the timing and nature of symptoms. The distinction is based more on clinical signs than a strict timeline, though a general timeframe is used as a guide.
Acute GVHD typically develops soon after the transplant, often within the first 100 days. Its effects are concentrated in three main organ systems: the skin, the liver, and the gastrointestinal (GI) tract. Skin involvement is frequently the first sign, appearing as a rash that can cause itching and redness. In the GI tract, symptoms can include nausea, vomiting, loss of appetite, and significant watery or bloody diarrhea. Liver problems may not cause noticeable symptoms initially but can be detected through blood tests showing elevated liver enzymes and can lead to jaundice.
Chronic GVHD generally appears later, more than 100 days post-transplant, and can persist for many years. Its symptoms are often more widespread and can resemble autoimmune disorders. The skin is commonly affected, but the manifestations differ from the acute form, featuring dryness, tightening, and changes in pigmentation. Many individuals experience issues with their eyes and mouth, leading to significant dryness or sensitivity. Chronic GVHD can also impact the joints and connective tissues, causing stiffness and reduced mobility, or affect the lungs, leading to shortness of breath.
Diagnosis and Treatment Approaches
Diagnosing GVHD involves a combination of clinical observation and medical tests. Physicians evaluate a patient’s symptoms affecting the skin, gut, or liver. A definitive diagnosis often requires a biopsy of the affected tissue to look for cellular changes characteristic of a T-cell attack. Blood tests are also performed to monitor organ function, such as liver enzyme levels, which can indicate GVHD activity.
The primary goal of treatment is to suppress the overactive donor immune response without completely shutting down the immune system. The first-line treatment for both acute and chronic GVHD is corticosteroids, such as prednisone or methylprednisolone. These anti-inflammatory drugs are administered to calm the immune attack on the host’s tissues. For many patients, steroid treatment can effectively control the symptoms, especially when started early.
If GVHD does not respond to steroids or if the condition is severe, it is known as steroid-refractory GVHD. In these situations, doctors turn to second-line therapies. This involves using other types of immunosuppressive medications, which may include drugs like calcineurin inhibitors (cyclosporine and tacrolimus), mycophenolate mofetil, or sirolimus. The specific choice of medication depends on the patient’s condition and which organs are involved. For chronic GVHD, treatment can be a long-term process requiring a careful balance of suppressing the disease while managing the side effects of immunosuppression.
Prevention and Risk Mitigation
Significant effort is focused on preventing GVHD from developing. The most important preventive measure is careful donor selection through Human Leukocyte Antigen (HLA) typing. HLAs are proteins on the surface of most cells that the immune system uses to distinguish self from non-self. A closer HLA match between the donor and recipient reduces the chance that the donor’s T-cells will see the recipient’s body as foreign.
In addition to HLA matching, patients undergoing an allogeneic transplant receive prophylactic medications to suppress the immune system. This involves a combination of immunosuppressive drugs, such as a calcineurin inhibitor combined with methotrexate, started around the time of the transplant. These drugs work to dampen the activation of donor T-cells, making them less likely to initiate an attack.
Another strategy to reduce GVHD risk is T-cell depletion of the donor graft. This process involves removing a portion of the T-cells from the donor’s collected stem cells before they are infused into the recipient. By lowering the number of T-cells in the graft, the potential for an aggressive immune reaction is diminished. While effective at preventing GVHD, this approach must be balanced, as removing too many T-cells can weaken the beneficial graft-versus-leukemia effect and potentially increase the risk of infection or cancer relapse.