Organ Rejection and Immunosuppression
Transplant Immunology and the Prevention of Graft Failure
Introduction
For patients facing issues involving their organs or tissues, such as organ failure, an organ transplant is a lifesaving and effective medical choice for treatment. Organ transplants provide patients with functioning organs that can be life saving. One risk associated with transplants is the possibility of rejection, which happens when the immune system of the organ recipient identifies a newly transplanted organ as a foreign invader and attacks it. To prevent organ rejection, immunosuppression is medically induced to weaken the immune system's response. In this article, we will examine the immune system’s response to transplantation and how doctors counteract this response with medication, as well as the challenges and outcomes that arise during the transplant process.
Types of Transplants
There are several types of transplants:
An autograft is the transplantation of cells, tissues, or organs within sites in the same individual.
An allograft is the transplantation of tissues or organs from a donor who is not genetically identical to the individual receiving the transplant. Allografts are the most common types of transplants.
A xenograft is transplantation of tissues or organs between two different species. One common example of a xenograft transplantation is the transplantation of a pig valve to a human heart.
ABO-incompatible transplantation occurs when the donor and recipient have incompatible blood types. Although this increases the risk of rejection, ABO-incompatible transplants can be performed successfully in certain circumstances. For example, infants have less-developed immune responses to blood group antigens, which can make these transplants more feasible.
The final type is stem cell transplants. Stem cells are cells that can develop into a range of different types of cells in the body, and can be used to replace damaged or destroyed cells. Stem cells can be either an autograft or an allograft.
The Immune Reaction
The immune system is responsible for fighting foreign organisms and infections that enter the body, and plays a large role in keeping us safe and healthy.
The immune system works by distinguishing “self” from “non-self”. The body’s cells have self-markers called major histocompatibility complex (MHC), and the immune system does not react to these genetic markers when it realizes they are a part of the body. On the other hand, the immune system reacts when it detects a foreign substance, “non-self”, called an antigen. To fight off “non-self”, the body produces antibodies, which bind to and neutralize foreign invaders. This is why, when an organ is transplanted, especially if it is an allograft transplant where the donor is not genetically identical to the recipient, the immune system fights against this “foreign” object.
In a healthy state, the body usually does not and should not target its own cells. If it does target itself, this leads to autoimmune disease, where the immune system attacks healthy cells in one’s own body. This can also result in organ damage, causing chronic inflammation and scarring that can impair the function of or permanently destroy crucial organs.
When a foreign organ is transplanted, it can result in the activation of the immune system. The donor’s organ usually has its own unique set of identification proteins known as HLA proteins, and thus is recognized as foreign by the recipient's immune system. HLA proteins are the human-specific name for MHC proteins, which are generalizable to all organisms. When the recipient's immune system recognizes foreign proteins on the transplanted organ, it can activate T cells and produce antibodies against donor antigens. These immune responses can damage the transplanted tissue and potentially lead to organ rejection.
In order to allow the body to accept the organ, doctors have to suppress the immune system and override its primary function. So, how do we overcome this and successfully transplant an organ? For that, we have to analyze the types of rejection a graft can face.
Hyperacute Rejection: This is a rare but severe form of rejection that can occur within minutes to hours after transplantation. It is usually caused by pre-existing antibodies in the recipient’s blood that recognize antigens on the donor organ, such as incompatible ABO blood group antigens or donor-specific HLA antigens. These antibodies can rapidly activate the immune system and damage the blood vessels supplying the transplanted organ, causing the graft to lose function. Due to the severity of this rejection, the transplanted organ may need to be removed.
Acute rejection: Can occur days to months after transplantation, and even later, particularly when immunosuppression is inadequate. This is led by T-cell and antibody- mediated rejection. Early diagnosis of acute rejection is critical in order to prevent the loss of donor cells and stop rejection.
Chronic Rejection: Generally develops over months to years and is associated with progressive graft dysfunction, often involving vascular injury and fibrosis.
Medication
To suppress the activation of the immune system so that the body has the chance to accept the transplant, doctors use medication. These anti-rejection medicines work in three phases:
Induction Medicines: These are given intravenously before and after the transplant, and help get the body ready to accept the transplanted organ or tissue. Induction medicines stop the immune system’s white blood cells (T-cells) from immediately attacking the organ during the critical transplant period.
Maintenance Medicines: These medications are often needed for as long as a patient has a transplant in order to keep the organ functional. Their functions include stopping chemical signals that activate T-cells, preventing rapid cell growth, blocking the replication of immune cells, and lowering overall body inflammation. These are used long-term to continue suppression of the immune system, and are often started not long after surgery.
Rejection Treatments: This medication is used if the body starts to reject the transplanted organ. Similar to maintenance medicines, rejection treatments also block chemical signals that turn on T-cells, but also lower overall inflammation and decrease the intensity of active immune cells.
By working together to stop the processes and cells in the body that comprise the immune system, these medications enable transplant to occur and the organ to function successfully. Some common medications include:
Tacrolimus which reduces T-cell activation.
Mycophenolate which inhibits lymphocyte growth.
Prednisone which is a steroid that suppresses inflammation and immune responses.
There are risks to being on these immunosuppressant medications. Although suppressing the immune system increases the chance of transplant function, it also leaves the immune system weaker and more susceptible to infection. In addition, a responsibility of the immune system is to find and destroy abnormal cells before they turn into cancerous cells. A weakened immune system has a reduced ability to do this, leading to a greater risk for cancer.
The Transplant Process
The transplant process is long and is oftentimes reserved for people who need a transplant for survival.
First, a doctor must refer the patient to a transplant center or program. Then the patient receives education about the transplant recovery, and maintenance process. After going through the process of finding a transplant center, getting evaluated for a transplant, and receiving qualification status, the patient will be added to the Organ Procurement and Transplantation Network waiting list.
In the United States, organ allocation is coordinated through the Organ Procurement and Transplantation Network (OPTN). The matching process considers factors such as blood type, organ size, medical urgency, geographic distance, and expected transplant outcomes. Specific allocation criteria vary depending on the organ being transplanted. For example, a heart or a lung can only be preserved anywhere from 4 to 6 hours; thus, UNOS has to consider medical urgency, distance from donor hospital, and pediatric status. UNOS prioritizes the people who are in the most urgent need of the transplant and have the best chance of survival after the transplant, making them the top of their rank-order list of candidates to be offered each organ.
Once a transplant has been received, one has to consider a large variety of factors. One of them is infection. Since the immune system is in its most vulnerable state after transplantation, the risk of infection increases to a large percentage. Minor infections are common, such as a cold, but they become serious if one has other chronic conditions. Some concerning infections include Encephalitis (brain infection), Hepatitis, and Herpes, which make managing organ transplantation difficult for doctors and transplant teams. Another factor is patient safety. After getting a transplant, one has to keep their body healthy and functioning. The hospital will most likely do its job in preventing one from contamination; however, they also have to put in effort to keep the transplant functioning. One has to take their transplant medication daily or as their doctor advises. One also has to follow water and food safety guidelines, as this lowers their chance of infection from bacteria or parasites in such substances. Finally, one has to keep themself healthy and fit, but avoid activities that have a higher chance of physical injury.
An Ethical Dilemma
Receiving a transplant is a difficult process, and there are many ethical aspects that need to be considered. There are laws and codes that each country has for its donors and hosts. The three principles that are constant throughout these are utility, justice, and respect for a person. A central ethical principle of deceased organ donation is the dead donor rule, which requires that organ procurement must not cause the donor's death. Death must be determined according to applicable medical and legal standards before organs are recovered. Certain procedures intended to preserve organ viability may take place before death, subject to appropriate consent and ethical safeguards.
Conclusion
In 2025, 49,064 organ transplants were conducted in the United States. This number is steadily rising every year. Unfortunately, over 100,000 Americans still wait for an organ each year. The hope for the future is that transplant technology improves so that more civilians are able to receive successful organ transplants that can help them live happy, healthy lives.
Written by Sai Sahana Diwakar
Edited by Rachel Levantovsky, MD
References
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