Abstract
Organ transplantation is an important life-saving procedure for those people, who have some problems in their organs. However, the problem of organ transplant rejection is an important issue in this case. In this problem, patient’s immune system starts rejecting the organ as a foreign body. This problem of rejection of the organ can be acute or become chronic. Several diagnostic procedures have also been developed to reduce the problem of rejection of an organ. Scientists have done a lot of research in this regard. Acute rejection needs immediate care. In order to reduce the problem, specialists will check the area of the transplanted organ. They may type or match the antigens on the cells of the organ of donor and the recipient. Similarity between the antigens of the donor and the recipient can result in reduction of the chances of organ rejection by the body. Usually, immunosuppressant drugs are prescribed. Antibodies have also been used in the problem of rejection of organs by the body in case of antibody mediated rejection. It has been reported more chances of HLA mismatches, patient nonadherence to treatment, incidences of acute rejection, previous organ transplantation, improper immune suppression, pregnancy, and blood transfusion, can cause sensitization resulting in more chances of antibody-mediated rejection. Despite all advancements, scientists still have to done a lot of research to increase the efficiency of this procedure. In this paper, several points of organ transplant rejection have been discussed including future prospects about the problem.
Organ transplantation can be considered as the life-saving procedure (Klipa, Mahmud, & Ahsan, 2010) as it can revive the functions of the damaged organ in the body of the affected person. It has been estimated that in 2012, 115,000 solid organ transplants were performed globally (Monguió-Tortajada, Lauzurica-Valdemoros, & Borràs, 2014). In the previous few years, the number of children having solid-organ transplant has been increased significantly (Lipshultz et al., 2014). However, a serious complication of Organ transplant rejection, also known Graft rejection, arises in this case. It is a process in which the organ is transplanted from one person to the other, but the other person’s immune system attacks the transplanted part of the body. In other words, we can say that the immune system of the receiver rejects the transplanted organ. Some of the most important signs and symptoms of organ transplant rejection are that the function of the organ may start decreasing, thereby affecting the patient; feelings of discomfort or uneasiness that can disturb the quality-of-life of the patient; in rare cases, there is a pain or swelling in some areas or most parts of the organ; rare cases are also represented by fever, and flu-like symptoms may also develop such as body aches, chills, cough, nausea, and shortness of breath.
However, it has to be considered that symptoms are dependent on the transplanted organ or tissue in the recipient as, for example, patients who have the problem of rejection of transplanted kidney may have reduced urine, and patients who have the problem of rejection of the transplanted heart may show the problems of heart failure.
Usually, the immune system protects the body from foreign substances that can be harmful for our body as, for example, poisons, germs, and some cancer cells. These foreign substances can have proteins known as antigens on their surfaces. Soon after the entry of these antigens into the body, the immunity of the body identifies them as something from outside of the body and attacks them.
After getting an organ from some other person during transplant surgery, recipient’s body recognizes that organ as a foreign substance. This is due to the fact that the immune system of the person detects antigens on cells of the transplanted organ, which are not matching to the body’s own antigens (Klipa et al., 2010). Mismatched organs can stimulate the blood transfusion reaction and can result in transplant rejection. This graft-host interaction causes an allo-immune response having three phases: 1) Induction phase is the phase of antigen identification, activation of T-cells and B-cells, and differentiation and expansion; 2) Effector phase is the phase when direct allograft injury occurs. Allograft is the tissue or organ transplanted from a donor of the same species but different genetic makeup; and 3) Resolution phase is the phase when the immune response to the allograft is removed. Unluckily, residual memory to donor antigens can develop. These anti-donor memory cells become a major problem in organ transplantation (Klipa et al., 2010). Researchers have found that thymus has also an important role in the rapid and stable induction of tolerance (Yamada et al., 1997).
Organ transplant rejection is of three types, which are; 1) Hyperacute rejection that occurs after few minutes of transplantation of organ. Hyperacute rejection occurs as a result of complete unmatching of the transplanted organ. In this case, the tissues have to be removed immediately, otherwise the patient would die. An example of this type of rejection is the rejection seen by the recipient when he or she receives the wrong type of blood as, for example, the person may face hyperacute rejection, when he receives type A blood despite his blood is type B. 2) Acute rejection is the type of rejection that can occur after the first week to 3 months of transplantation of the organ. It has been found that nearly all recipients show some level of acute rejection of organ transplant. 3) Chronic rejection is the type of rejection that can take place after many months and even after many years. In this case, constant level of slow immune response of the recipient’s body against the new organ can destroy or damage the transplanted tissue or organ, thereby affecting the health of the patient.
The physicians will check the area of the transplanted organ. In case of organ rejection, the area over and around the organ may become tender, particularly in case of the kidney transplant. There are some signs that can show that the organ is not working properly. These signs may include elevated blood pressure particularly in case of pancreas transplant; reduced release of urine particularly in case of kidney transplant; reduced breath, thereby affecting the ability to work or exercise particularly in case of heart transplant, and yellow color of the skin and bleeding without any difficulty particularly in case of liver transplant.
Biopsy can help in confirming that the transplanted organ has been rejected or not. It is the examination of pieces of tissues from the living body to determine the existence of a disease. Routine biopsy is usually performed to check the rejection in the start, even before the start of symptoms. However, in case of organ rejection, chest X-ray, abdominal CT scan, kidney arteriography, heart echocardiography, kidney ultrasound, and other lab tests to check the function of the liver or kidney, either alone or in combination, can be used before biopsy.
Before the transplantation of the organ, ABO blood typing and human leukocyte antigen (HLA) (tissue antigen) typing can help in confirming a close match. In fact, kidney transplantation has become a huge success after the discovery of HLA in 1960s. Researchers have reported that even primary consideration in the transplantation of tissues and organs is given to ABO blood group compatibility, but huge national databases show that graft survival enhances with better HLA antigen matching, and this matching could have an important role in long-term graft survival. In the present times, biotechnology has increased the accuracy and reproducibility of tissue typing, detection of anti-HLA antibodies, and cross-matching (Lipshultz et al., 2014). Recent advancements of solid-phase assays (SPA), which shows more sensitivity and specificity, has helped in increased identification of antibody-mediated rejection (Lipshultz et al., 2014).
The Banff standards for identification of antibody-mediated rejection are (Lipshultz et al., 2014): 1) Revolving antibodies to the donor major histocompatibility complex (MHC) antigens; 2) Relative placement of the complement split product C4d in peritubular capillaries showing the activity of antibody (with more than 50% of peritubular capillaries); 3) Structural properties of acute injury of tissue, and 4) Medical evidence of organ or graft dysfunction.
Regarding properties related to the acute injury of tissue, researchers have noted acute tubular injury, intimal arteritis, intramural or transmural inflammation, monocytes or neutrophils in the peritubular capillaries and/or glomeruli, and fibrinoid death of the arteries. Antibody mediated rejection has been found in 1-6 percent of renal biopsies in unsensitized patients, whereas it has been found in 60-70 percent of patients with chances of acute organ rejection. On the other hand, chronic antibody-mediated rejection shows damage to the tubular and glomerular basement membrane. Moreover, capillary injury can be considered as the starting event in the process (Lipshultz et al., 2014).
In order to remove or reduce this problem of organ transplant rejection; doctors type, or match the antigens on the cells of the organ of donor and the recipient. Similarity between the antigens of the donor and the recipient can result in reduction of the chances of organ rejection by the body.
Tissue typing confirms that the organ or other donated tissue is similar to the tissues of the person, who is receiving the organ. Usually, the typing or matching is not 100% perfect, even in the case of identical twins; tissue antigens are not completely similar, but doctors can give medicines to decrease the response of the immune system of the receiver. The purpose is to stop the immune system from attacking or affecting the newly transplanted organ, in case the organ is not closely matched. If these medications are not used, the body almost always attacks the foreign tissue by producing an immune response. However, rare cases are always there as, for example, in the case of cornea transplants there are no organ rejections as the cornea has no blood supply. Moreover, transplantation from one identical twin to another rarely faces organ rejection phenomenon.
Primary purpose of the treatment of organ transplant rejection is to confirm that the transplanted organ or tissue is working properly. Improved surgical techniques and advances in biological and pharmaceutical products have increased the survival chances of transplanted patients. It has been reported that the maximum survival for a kidney transplanted patient is about 46 years, and 39 years for the patient with liver transplantation (Monguió-Tortajada et al., 2014).
Treatment usually involves the suppression of the immune system that can result in reduced rejection of transplanted organs. First of all, the immunosuppressive drug therapy was used in canine renal homotransplants and showed noteworthy prolongation of survival. On a further note, research on the combinations of drugs and its refinements in drug therapy has resulted in increased levels of success (Murray, Merrill, Harrison, Wilson, & Dammin, 1963). A brief course of corticosteroids in high doses can be used, and repeated. Usually, medicines such as azathioprine and cyclosporine A are also added to suppress the immune system.
Most of the immunosuppressive drugs work by targeting T-cell immune responses. Activation of T-cell needs the delivery of distinctive signals through many different pathways such as the RAS-mitogen-activated protein (MAP) kinase pathway, the calcium-calcineurin pathway, and the nuclear factor-κB pathway. These pathways activate the expression of several new molecules such as interleukin-2 (IL-2) and IL-15, cluster designation (CD) 154 and CD25, and other cytokines (Klipa et al., 2010). IL-2 triggers the mTOR pathway to stimulate proliferation.
Bortezomib, which is an inhibitor of proteosome, is also useful in organ rejection. It is efficient against antibody-generating plasma cells, and has been used successfully with rituximab and plasmapheresis to cure the problem of heart transplant rejection in children. Plasmapheresis eliminates some of the antibodies, Rituximab stops CD20-positive cells, and plasma cells are devoid of this marker. That’s why; bortezomib is helpful in stopping anti-HLA antibody levels as it needs stimulated plasma cells, which are found in acute antibody mediated resistance. However, this medicine is unable to sufficiently attack memory B-cells (Lipshultz et al., 2014).
Main purpose of all immunosuppressive therapies is to finish the immune response against the grafted organ, to stop organ rejection, and enhance long-term acceptance of the grafted organ by reducing the side-effects. Dosage of the medicine changes with the condition as, for example, in case of high level of rejection, dosage of the medicines can be increased. In case of reduced levels of rejection, dosages can be decreased.
In the present times, scientists and doctors are successfully using polyclonal as well as monoclonal antibodies to prevent and cure solid organ rejection. These agents are especially helpful in the patients, who have compromised function of the kidney. They can help in significant reduction of the chances of acute rejection of organs. Although, they can increase the chances of neoplastic complications and opportunistic infections, they can effectively be used under effective patient management (Klipa et al., 2010).
One of the monoclonal antibodies is Eculizumab. It is involved in the target and inhibition of the terminal portion of the complement cascade, which is related to the immune system of the body, and destroys and removes foreign particles. Stimulation of the terminal portion of the complement system is important in the production of acute antibody-mediated rejection. It has been successfully used as a salvage therapy in patients, who are not giving response to other therapeutic strategies for antibody mediated rejection. Researchers have reported reduced rates of acute as well as chronic antibody mediated rejection after treating with eculizumab. It is found to reduce tissue injury, as well as graft disturbance and dysfunction. However, further studies are required in this regard (Lipshultz et al., 2014).
Several alternative therapies have also been proposed in order to replace the classical treatment for the rejection of the transplanted organ. These alternative therapies are primarily based in pre-infusions of various regulatory cells such as MSCs, DCs, and Tregs. However, they don’t have full efficiency, and can have many problems related to applicability and availability. Extracellular vesicles, particularly exosomes, are cell-free alternative approaches in developing transplant tolerance and survival (Monguió-Tortajada et al., 2014).
Usually, immunosuppressive therapy has three phases (Klipa et al., 2010); 1) Induction Phase is that phase in which there is an elevated immunosuppressive load during the initial stages of transplant. This includes an induction-antibody therapy in combination with calcineurin inhibitor medicines such as cyclosporine A or tacrolimus. Both of these are considered as fundamental medicines for immunosuppressive therapy. Along with calcineurin inhibitors, corticosteroids and antiproliferative agents such as azathioprine or mycophenolate mofetil can also be used in combination. 2) Maintenance Phase in that phase in which calcineurin inhibitors, if tolerated, are used alone. Sometimes, mycophenolate mofetil, a mammalian-target-of-rapamycin (mTOR) inhibitor, sirolimus or azathioprine, can also be used along with calcineurin inhibitors, if there is some issue with the type of allograft and other such side effects of immunosuppressive agents. 3) Anti-rejection phase is that phase in which the organ or tissue may face dysfunction as a result of immunological damage by the recipient’s body. Identification and strong treatment, without any delay, are important to enhance the function of the organ, and the survival of the organ and patient.
Some transplantation surgeries are more successful as compared to others. On the start of rejection, medicines can stop or reduce the rejection phenomenon, but these medicines can become the requirement for the rest of the life. However, despite the suppression of immune system through medicines, organ transplants can face the failure due to rejection.
Usually, single incidences of acute rejection can easily be treated, and can rarely result in organ failure. However, chronic type of rejection is the main cause of organ transplant failure. In this case, gradually the organ loses its ability to function properly and symptoms of the rejection start appearing. This type of rejection can efficiently be treated with medicines. Some people may also face another surgery of transplantation due to the failure of first transplantation.
Some of the possible complications faced by the patient, who has gone through organ transplant rejection, are: It can result in the development of certain cancers, especially in people who take potent immunosuppressive drugs for a long time; It can result in infections due to suppression of the immune system of the patient as result of taking immunosuppressive drugs; It can result in decreased or complete loss of function of the transplanted organ or tissue that can affect the normal working of the patient, and some of the immunosuppressive medicines can have serious side effects that can affect the body of the patient.
Investigations have shown that more chances of HLA mismatches, patient nonadherence to treatment, incidences of acute rejection, previous organ transplantation, improper immune suppression, pregnancy, and blood transfusion, can cause sensitization resulting in more chances of antibody-mediated rejection. It has been reported that presently, about 17% of patients, who are on the end-stage kidney disease and are on the waiting line for transplantation of kidney, have already gone through previous transplants. Nearly, 50% of all childhood kidney transplant recipients could receive a second transplant of kidney by the age of 25 years (Lipshultz et al., 2014). However, the real incidence as well as prevalence of antibody mediated rejection in children needs further studies.
Organ transplantation is considered as the sole solution for the organ failure, whereas rejection is still an unresolved problem for the science (Monguió-Tortajada et al., 2014). Moreover, the problem to know the patients who could be gradually deprived from the immunosuppression treatment is still there. Investigations on this problem can help in designing the research directed towards the tolerance induction (Lee et al., 2014). Scientists have also to work on the side effects of the immunosuppressive drugs, malignancies, infections, post-transplant lymphoproliferative disorders, nephrotoxicity, and in some cases recurrence of the primary disease (Lipshultz et al., 2014) for better life of patients, who could have the surgery for organ transplant.
References
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