GRAFT REJECTION AND GRAFT-VS-HOST DISEASE: ANALYZING THE RISKS AND ITS MANAGEMENT
From a historical perspective, successful tissue and organ transplantation took a very long time to establish. The early outlook for such practices was extremely poor, with a post-surgical survival of just a few days. Thanks to medical advancements, we now have a better understanding of how the immune system works and how it contributes towards surgical success or failure. Immune reactions remain the prime known cause for most post-surgical complications, including infection, graft rejection, and potentially fatal graft-vs-host disease.
The following article aims to review what is currently known about graft rejection and graft-vs-host disease, summarizing their similarities, differences, risk factors, treatment options, and outcomes.
What is Grafting?
Tissue grafting is a common surgical technique used for a wide variety of procedures, from organ transplants to reconstructive surgery. The procedure entails taking an organ or tissue from a healthy part of the body or a healthier donor and inserting it in a damaged or under-functioning area of the recipient’s body. Grafting has improved many surgical outcomes and extended the lifespan of many patients worldwide, with some living for over a decade.
The success of this technique depends upon the recipient’s immune system, the health of the donor tissue, and the interaction between the two. If the host’s immune system perceives the donated organ as a threat or that the organ carries immunologic materials capable of harming the recipient’s body, it can lead to either graft rejection or potentially fatal graft-vs-host disease.
Graft Rejection vs. Graft-Vs-Host Disease
Graft rejection and graft-vs-host disease (GVHD) are conditions with similar immunologic causes that have dramatically different presentations and outcomes.
Graft Rejection and Immune Tolerance. The immune system is constantly surveying tissues for signs of abnormality and threats, which occur in the form of antigens (cell-specific proteins) and patterns of inflammatory signals or cell damage. All tissues are labeled with several host-specific antigens known as self-antigens, which the host’s immune system registers as ‘self.’ The self-antigens found on the donor tissue do not resemble those of the recipient and almost always trigger an immune response after grafting (a lack of immune tolerance to the foreign tissue). If precautionary measures are not deployed, the host’s immune system often proceeds to destroy the transplanted tissue and remove it from the body. This is known as graft rejection and can occur with any tissue graft or organ transplant.
Graft-Vs-Host Disease and Immune Suppression. In GVHD, similar yet opposing mechanisms conspire to create the disease. Immune cells from the donor’s tissues react to self-antigens in the recipient’s tissues, inciting the tissue graft to attack the recipient’s body. It is a less common complication than graft rejection overall, yet occurs at a higher frequency in immune-suppressed patients and with grafted tissue that contains an abundance of immune cells from the donor. While stem cell transplantation is the most usual cause for concern, blood transfusions, and liver transplants can also give rise to GVHD.
Anticancer Benefit. There are benefits associated with acute GVHD, such as graft-vs-tumor effects, where foreign immune cells are able to destroy the recipient’s tumors better than their own immune cells. This is one of the main reasons why blood transfusions and stem cell transplants are known to be extremely successful in the treatment of lymphoma and leukemia.
Types and Prevalence. Both graft rejection and GVHD may be acute or may become a chronic lifelong illness.
- Acute. The onset of either condition may be immediate or delayed by a few days to 3 months. Acute GVHD occurs in 50% or more of patients receiving stem cell transplants. The condition is usually mild, often contained to the skin, and resolves after treatment. Acute graft rejection is considered to be a normal feature of all transplants. Both conditions are treated with immune-suppressing medications, which typically are a lifelong feature for organ transplant recipients.
- Chronic. Chronic graft rejection resembles a severe autoimmune disease of the transplanted organ, which often develops vascular lesions. Due to a lack of treatment, it tends to precipitate organ failure after several years. Chronic GVHD is indicative of multi-organ involvement, where foreign immune cells are allowed to run rogue systemically and invade any tissues they encounter along the way. The incidence rates vary between patients and transplant procedures for both conditions.
Symptoms. For either graft condition, symptoms vary from mild to severe. All severe graft diseases are potentially fatal. Other common symptoms that overlap between the two are as follows:
- Jaundice and hyperbilirubinemia
- Shortness of breath and other respiratory issues
- Abdominal discomfort, pain, and swelling due to a swollen spleen and liver
In graft rejection, symptoms are often localized to the area and are organ or tissue-specific. The patient often experiences pain, and test results reveal under-functioning of the area, which may be acute and resolve spontaneously or become chronic. Besides the above symptoms, chronic graft rejection may also show signs of urinary abnormalities (e.g., dark urine or proteinuria), anemia, anorexia or weight gain, and pulmonary edema.
In GVHD, characteristic symptoms in addition to those listed above include:
- Rash all over or on a part of the body
- Pain or burning sensations
- Blood in the stool
Complications. Chronic infections can arise from graft-related conditions due to donor tissue contamination and immune dysfunction. Bacterial infections are often treated with antibiotics, yet viral infections may be fatal in patients with chronic graft diseases.
Prognosis. Moderate to severe GVHD can be life-threatening, whether acute or chronic, with a low 5-year survival rate of 25%. Acute graft rejection tends to be treatable and has the best prognosis, with patients living over 5-10 years, depending on the type of transplant received. Chronic organ rejection results in complete organ failure within 5 years. Patients usually require a second transplant and intensive care.
Common Risk Factors
The most common risk factors are discussed briefly below. Please note that every patient is different, and these risk factors will vary for each case.
The Gut Microbiome has become an emerging focus of research with respect to graft rejection and GVHD, capable of influencing the risk of either. The cross-talk between the gut microbiome and the cells of the immune system has long been implicated in autoimmunity, immune reactivity, and immune tolerance. Gut dysbiosis, increased permeability, and other similar problems may increase the immune reactivity of both the host and donor tissues towards foreign antigens, while enhanced bacterial diversity may reduce the risk, lower immune hyper-reactivity, and help control infections.
Systemic Inflammatory Triggers and Comorbidities. Innate immune responses may also contribute to promoting tissue graft complications. Various types of chronic low-grade inflammation are able to trigger immune cells and increase their reactivity toward donor or recipient tissues. Most patients experience symptom improvement as a result of replacing the damaged organ or tissue with a healthier specimen, removing the cause of low-grade inflammation. Patients with systemic inflammatory conditions such as cardiovascular diseases, autoimmunity, severe chronic allergy, or infections are at a greater risk of contracting GVHD or experiencing graft rejection.
Split Organ Transplantation. Split liver transplantation may increase the risk of graft rejection and failure, as does partial intestinal and heart valve replacement. Repeat surgery is common among these patients. However there needs to be more research on this.
Multi-Organ Procedures. Some multi-organ transplants may have immunologic advantages that decrease the risk of graft rejection or GVHD, while others can increase the risk. Studies have shown that for diabetic patients without kidney disease, transplanting the kidneys along with the pancreas reduced the risk of graft rejection as opposed to receiving the pancreas alone. There is also evidence to suggest that simultaneous transplantation can help extend life expectancy and reduce the risk of future diabetic kidney complications. More research is required to ascertain what other organ transplant combinations may affect the risk of immune complications and other outcomes.
Living or Dead Donors. Deceased donorship is most commonly deployed for kidney, pancreatic, and intestinal transplantations. For other types of transplants, such as liver, heart, or lung, only living donors are used. In kidney transplantation, living donorship approximates roughly 30% of transplants and is associated with vastly superior survival outcomes after 5 years. However, it's important to note that not all patients are eligible for living donor kidney transplantation, and the outcomes can vary depending on individual cases
Donor Compatibility. While it is not possible to match self antigens between people, the immune system is known to react to several other factors that can be appropriately matched between donor and recipient to improve successful outcomes. These include:
- Blood Type. Blood types are characterized by the collection of antigens on the surface of red blood cells and their unique properties. In any transplantation, the risk of recipient graft disease is affected by the blood type of the donor, as differences can increase immune reactivity. Recipients are able to receive their own blood type as well as type O (the universal donor). Those with type AB can receive any other blood type without affecting the risk. Blood types should be profiled in leukemia patients prior to surgery, as malignancy may change the expression of red blood cell antigens.
- HLA Type. HLA, or Human Leukocyte Antigen, refers to another group of immune-reactive antigens that may trigger graft disease or failure if ill-matched. There are 6 main HLAs that can affect the outcome, with a match of 3 or more considered a good match. While it improves success, HLA matching is not always necessary. Various types of mismatch are currently being researched for their ability to minimize the risk of GVHD.
- Age. Older age or a greater age mismatch between recipient and donor can increase the risk of transplant rejection or GVHD.
- Gender. While research is limited, preliminary evidence suggests that gender may be an important consideration for donor matching. In one large-scale study assessing over 100,000 stem cell transplant patients, it was proven that female recipients exhibited the lowest risk of GVHD when benefiting from male donor tissue, while male recipients reported a higher risk when receiving female donor tissue. The risk was intermediate for same-gender transplantations, falling somewhere between the two.
Graft Disease and Rejection Prevention
There are no true treatment protocols for patients who develop GVHD or who suffer from graft rejection. As GVHD and chronic graft rejection are life-threatening conditions with a high mortality rate, prevention strategies are vital for patients undergoing organ or stem cell transplantation.
Immune Suppression. Patients are often placed on immunosuppressant therapy for life after receiving a transplant. This drastically improves survival outcomes, extending from several months to several years, with some patients even able to live longer than a decade. The dosage needs to be properly tailored to suit the patient’s needs as high-dose toxicity may promote graft rejection, yet too low a dose may result in GVHD.
Complementary Treatments. Patients also ought to be aware that immunosuppressive treatments have their own side effects and complications. These are often treated in a way that complements graft disease prevention, as described below:
- Chemoradiotherapy. Some agents can increase the risk of developing skin cancer, lymphoma, and cervical cancer, which can defeat the purpose of treatment for many requiring transplantation. Radiotherapy was the first successful strategy deployed in the 50s to quiet down the immune response towards foreign implanted tissue and also happens to be effective for treating cancer. Modern prevention methods deploy chemotherapeutics that can improve graft acceptance, minimize cancer risk, and enhance outcomes.
- Antibiotics. Immune-suppressing medications often increase the risk of infectious illness, and simultaneous administration of antibiotics is common. Chronic viral infections might be a major complication of organ transplantation for which current treatment options are limited.
Other Medications. Anti-inflammatory medications and those that support inflammation resolution appear to help minimize the risk of developing GVHD and graft rejection. These include NSAIDs and statins, which have the added benefit of lowering the risk for excessive coagulation post-surgery. Some evidence suggests that these are more effective than corticosteroids that aim to suppress immune functions for similar results. Those receiving kidney transplants may need to be more selective about their choice of NSAIDs, as over 10% of patients may be prone to kidney injury when using them.
Complementary Approaches for Graft Disease Management
Outcomes can be greatly improved for patients who attempt to lead a healthy lifestyle before and after transplantation occurs. An emphasis on inflammation control, cardiovascular health, and the gut microbiome ought to be of prime importance, as discussed below.
Emphasizing Gut Health and Recolonization. After transplantation, it is common for the gut microbiome to suffer a loss of diversity. This adds to the risk of graft disease by detracting from immune tolerance, increasing gut permeability, and promoting low-grade inflammation. The preventive treatment can contribute towards this effect and undermine its intended use in the long run, despite being effective for the months following surgery. A diet that emphasizes gut health is crucial, with nutrients and soluble fiber being of high importance to reduce permeability and facilitate an optimal ecology. Additionally, probiotic use has been shown to be of benefit to transplant recipients by enhancing microbial diversity and supporting overall gut health.
Cardiovascular Support. The state of the cardiovascular system is critical for the best results post-transplantation. Blood vessel cells can secrete inflammatory cytokines that can contribute towards graft disease or failure, many of which can be elicited by excessive fat and faulty fat metabolism. Regular exercise to maintain good circulation and consuming a nutritious diet low in unhealthy fats and refined carbohydrates can greatly improve the results.
Anti-inflammatory Foods and their nutrients play a role in regulating immune functions and maintaining immune tolerance. They have also been shown to lower the need for prescriptions and the risk of graft rejection and GVHD across patients. A diet inclusive of a wide variety of plant-based foods and fats high in omega-3s and PUFAs often contains a wealth of these nutrients.
Despite great prognostic improvement, graft-related diseases remain a leading cause of mortality in transplant patients. Risk reduction strategies, prevention, and treatment tend to reduce the risk of chronic disease and greatly ameliorate the severity of acute graft rejection. Outcomes appear to be based on the patient’s health and immune function, as well as the compatibility of host tissues. In some instances, multi-organ transplants can enhance the prognosis, as can waiting for an organ or tissue from a live donor. Cardiovascular and gut support show great promise in prolonging graft-disease free survival.
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