A heart transplant involves removal and replacement of a diseased or damaged heart, with a healthy heart, from a deceased donor National Library of Medicine; NLM, 2012. Unless transferred between identical twins, this type of organ transplant is known as an allogeneic graft or allograft, meaning a transplant (graft) between two genetically different individuals of the same species (Doan, Melvold, Viselli, & Waltenbaugh, 2013). Heart transplant procedures are the third most common transplants performed in the United States (NLM, 2012) and are considered a last resort treatment and the best option for individuals with end-stage heart failure (U.S. Organ Procurement and Transplantation Network [U.S. OPTN] & Scientific Registry of Transplant Recipients [SRTR], 2011). The classification of end-stage heart disease implies that all other medical and surgical options have been exhausted (Kasper & Achuff, 2002). According to the United States OPTN (2012), there are currently more than 3,300 people on the waiting list to receive a heart transplant. In 2009, 1,853 heart transplants and 26 heart-lung transplants were completed and between 2005 and 2009 the median time on the waiting list to receive a heart was 135 days (U.S. OPTN & SRTR, 2011).
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Although survival rates following heart transplants have improved over the last two decades (OPTN & SRTR, 2011), failure of a donor heart following transplant is still a significant concern (American College of Cardiology Foundation, 2011). The short- and long-term causes of heart transplant failure may relate to the causes of the original organ failure, primary graft dysfunction, infection, rejection of the donor heart, or other complications related to medication or treatment (National Heart Lung and Blood Institute, 2012). According to the 28th Report of the International Society for Heart and Lung Transplantation (ISHLT), the first year following transplant presents the highest risk for mortality of the transplant recipient, especially because of rejection of the donated organ (Stehlik et al., 2011). Rejection occurs when the immune system of the organ recipient (the host) responds to the invader (the foreign organ) by attempting to destroy it (Abbas & Lichtman, 2006). Rejection may result in death of the heart or recipient, or may be controlled and reversed with the use of immunosuppression medications (Lemmer, Richenbacher, & Vlahakes, 2003). Between approximately 50 and 80% of individuals who receive a cardiac transplant experience one or more episodes of rejection (Eisen, 2012) and within ten years, rejection leads to graft failure in half of all heart transplant recipients (Parsham, 2009). As rejection is a relevant and important consideration in the heart transplant literature, this paper will focus on the physiological mechanisms of action of cardiac transplant rejection.
After years of experimental research, the first human heart transplant took place in 1967 by Dr. Christian Barnard in South Africa (Phibbs, 2007). This was considered one of the most significant developments in the history of medicine (Phibbs, 2007). However, outcomes in the initial years following this transplant were poor, resulting from complications related to infection and rejection of the transplanted organ and enthusiasm for this procedure quickly declined (Reitz, 2002). However, with continued biomedical advances in the late 1970s, and with the help of immunosuppression medications, cardiac transplantation became a successful treatment with option for end-stage heart failure in the 1980s (Reitz, 2002).
The Immune System
The immune system is a complex defense system that protects the body from threats, infections, and foreign pathogens (Szeto & Rosengard, 2002), and is vital to human survival (Parham, 2009). This system of cells, tissues, and molecules distinguishes organisms that are part of the body, or "self," from "non-self" entities, or antigens, and attacks the foreign threats (Mak & Saunders, 2006). The immune system is made up of three layers of defense (Doan et al., 2013). The first layer, which forms a physical barrier for pathogens, consists of primarily the skin and mucous membranes (Sompayrac, 2012). When the first line of defense is breached, the intruder meets the body's innate immune system, an inborn defense that is responsible for the initial action of the white blood cells to attack an invader and recruit the rest of the immune system to join in the fight (Sompayrac, 2012). The adaptive immune system, or third line of defense, can adapt to guard against any invader, especially viruses (Sompayrac, 2012). This system works in two ways: through humoral immunity, whereby antibodies from B lymphocytes eliminate extracellular microbes in the body, and through cell-mediated immunity, in which T lymphocytes trigger macrophages expunge microbes ingested by phagocytes (Abbas & Lichtman, 2006). This system responds in ways specific to the unique invader or antigen, and modifies the response to the same invader, when experienced on more than one occasion (Doan et al., 2013). Both the innate and adaptive immune systems function together, fulfilling separate roles, while complementing and depending on the other (Mak & Saunders, 2006).
The Physiological Mechanisms of Cardiac Allograft Rejection
Role of the Major Histocompatibility Complex
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The genetic similarities and disparities between the host and the donor are the most crucial factors in whether an organ transplant is successful or results in rejection (Doan et al., 2013). The Major Histocompatibility Complex (MHC), a characteristic of adaptive immunity (Mak & Saunders, 2006) located on chromosome 6 in human cells, is a section of the genome containing polymorphic genes (Szeto & Rosengard, 2002). These genes encode glycoproteins called MHC molecules, which bind to peptide antigens and move to the surface of the cell (Parsham, 2009). The MHC molecule stretches out the peptide antigen along its surface, forming an antigen-presenting cell (ATC), presenting the antigen for recognition by T cell receptors (Parsham, 2009). The antigens are recognized by T cells as being foreign and the body's immune response is triggered (Doan et al., 2013). MHC molecules are of two types: MHC class I molecules, that transport the peptides to the cell surface, informing killer T cells of problems within the cell, and MHC class II molecules, which are displayed by APCs so that helper T cells can be alerted of extracellular problems (Sompayrac, 2012).
For humans, the MHC is called the human leukocyte antigen (HLA) system (Malhotra, Malu, & Kapur, 2011). HLAs are unique to every person, except identical twins. The immune system recognizes familiar HLA combinations as self and differing HLAs on cells as foreign (Malhotra et al., 2011). When a foreign organ is implanted into a host, the immune system interprets this organ as non-self, through the HLAs (Szeto & Rosengaurd, 2002). In addition, foreign HLAs are also remembered and recognized in the future, triggering immediate immune reactions (Malhotra et al., 2011).
Cardiac allograft rejection takes three different forms: hyperacute, acute, and chronic, based on differing underlying responses of the immune system related to genetic differences between the donor and the recipient (Abbas & Lichtman, 2006). Rejection is diagnosed via transplant biopsies that indicate pathology related to the mechanisms causing the damage to the heart (Bolton & Bradley, 2011). Each type of rejection manifests clinically in a unique way, depending on the form and extent of the rejection (Bolton & Bradley, 2011).
Hyperacute rejection. Hyperacute rejection (HAR), a rare type of rejection (Berry & Billingham, 2002), develops within minutes of transplantation of the heart into the host and results in thrombosis of vessels in the heart and ischemic necrosis, death of cells in the organ caused by the lack of blood flow (Abbas & Lichtman, 2006). HAR is a form of antibody-mediated rejection (AMR), resulting when the host has existing antibodies that recognize and react against donor-specific antibodies (DSA) located in the endothelial cells of the heart's blood vessels (Mak & Saunders, 2006). The DSAs target the HLA molecules and ABO blood group antigens (Parsham, 2009). Transplant recipients may have already made anti-HLA antibodies, meaning they have been sensitized and developed immunity against certain HLA allotypes, after pregnancy, previous blood transfusions, or transplants (Parsham, 2009), as a result of contact with these foreign HLA molecules (Mak & Saunders, 2006).
When a host receives a transplant, if they have previous antibodies made against the donor ABO or HLA, these antibodies bind to the vascular endothelium of the heart, triggering complement and clotting reactions (Parsham, 2009). The complement system is a group of proteins that circulate in the bloodstream and defend against microbes, with antigens, at an infected site (nobelprize.org, 2012). Once the system is activated, C3b, a complement protein, coats the microbe so that it can easily bind to phagocytes, causing it to be engulfed. This also serves to stimulate responses by B lymphocyte cells (Abbas & Lichtman, 2006). Further, some complement proteins break down and their products induce chemotaxis, attracting neutrophils and monocytes to the area to destroy the invader and to produce inflammation of the area. Activation of the complement system concludes with the creation of a polymeric protein complex that destroys the membrane of the foreign cell or causes a change in the concentration of solvents through the membrane of the cell, or results in apoptotic death of the cell (Abbas & Lichtman, 2006). This complement activation and consequent inflammation causes occlusion of blood vessels resulting from clots and leaks (Parsham, 2009) and prevents heart vascularization (Malhotra et al., 2011). This leads to diffuse hemorrhage into the heart (Abbas & Lichtman, 2006) and death of the grafted organ (Doan et al., 2013). There are no reliable treatments for reversing HAR; however, this type of rejection is often avoided through the use of a cross-match test before transplantation, to assess the compatibility of organ donors and recipients. A cross-match test is conducted by using blood serum from the host to look for anti-HLA antibodies that may trigger a reaction against the white blood cells of the donor (Parsham, 2009). This is used to detect a match between a recipient and donor for whom HAR is unlikely to occur.
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Acute rejection. Acute rejection typically occurs days to months after the transplant and is the primary cause of early graft failure of the organ (Abbas & Lichtman, 2006). In acute rejection, the transplanted organ works for a short time before signs of rejection occur; once acute rejection starts, it proceeds rapidly to deterioration of the organ, unless medications intervene (Doan et al., 2013). Acute rejection takes two forms which are distinguished by their underlying mechanisms: acute cellular rejection (ACR) or acute humoral rejection (AHR; Mak & Saunders, 2006).
Acute cellular rejection. ACR is primarily caused by the reaction of T cells to the HLA differences between the donor organ and the host (Parsham, 2009). Through the direct pathway of allorecognition, when T cells in the host recognize foreign allogeneic MHC molecules on donor APCs, T cells become active and produce cytokines which stimulate the proliferation of antigen-specific T cells (Abbas & Lichtman, 2006). This process is called clonal expansion, as the number of antigen-specific lymphocytes drastically increases (Abbas & Lichtman, 2006). The T cell response of the immune system to the graft produces effector CD4+ and CD8+ T cells that move to the transplanted heart to attack and destroy it (Abbas & Lichtman, 2006). Effector CD8+ T cells, cytolytic T lymphocytess (CTLs), recognize and destroy the body's non-self cells, the cells of the graft (Abbas & Lichtman, 2006). Cytokines are produced by the CD4+ cells, such as tumor necrosis factor (TNF), which trigger B cells and other lymphocytes to attack cells in the heart, resulting in inflammation and vascular damage (Abbas & Lichtman, 2006).
Acute humoral rejection. AHR, also known as acute vascular rejection or AMR (Berry & Billingham, 2002), often occurs later than ACR, weeks or months after the transplantation (Mak & Saunders, 2006). AHR is similar to HAR in that they both involve antibody-mediated responses, but also has distinctive features (Mak & Saunders, 2006). AHR occurs when antibodies specific for donor HLA molecules are circulating in the blood before the transplant (Colvin & Smith, 2005), or are produced after the transplant, de novo, by effector cells, following recognition of donor antigen by the host CD4+ T cells (Mak & Saunders, 2006). These antibodies react to foreign donor antigens on the endothelium of the heart, triggering the activation of the complement system and recruiting lymphocytes, macrophages, and neutrophils to attack (Colvin & Smith, 2005). The anti-donor antibodies also work independently from the complement system through antibody-dependent cell-mediated cytotoxicity, which may result in apoptotic death of cells in the graft (Colvin & Smith, 2005). AHR typically manifests as a buildup of neutrophil in capillaries of the heart, inflammation of the vascular system, fibrosis and lesions of the endothelium, and necrosis of blood vessel walls in the heart, leading to eventual decline in functioning of the organ and organ death (Mak & Saunders, 2006).
Chronic rejection. Chronic graft rejection (CGR) occurs over months and years after transplant and is a slow-developing loss of graft functioning (Abbas & Lichtman, 2006). As treatment options for acute rejection have improved over time, CGR is now the primary cause of graft failure after transplant (Abbas & Lichtman, 2006). Within 10 years of transplantation, CGR leads to graft failure in half of all heart transplant recipients (Parsham, 2009). CGR occurs after repeated attacks on the graft by the immune system and the occurrence of CGR is higher after multiple episodes of acute rejection. Further, CGR is thought to involve the indirect pathway of allorecognition, as well as both antibody-mediated and cell-mediated responses (Mak & Saunders, 2006). According to the indirect pathway, HLA molecules from cells of the graft are processed by the host's self APCs. Peptide fragments from the donor HLA molecules are then displayed to the T cells by the host's self HLA molecules (Abbas & Lichtman, 2006). CD4+ T cells are stimulated, causing an immune response and triggering production of anti-HLA antibodies that are further causal of immune system attacks and rejection (Parsham, 2009). The CD4+ T cells also produce cytokines, growth factors such as TNF, and a B cell response, to attack cells in the graft. The cytokines and growth factors cause proliferation of cells in the endothelium of the graft (Abbas & Lichtman, 2006) and of the smooth muscle cells (Mak & Saunders, 2006), which lead to arteriosclerosis, or narrowing of blood vessels in the graft, which results in ischemia (Parsham, 2009). This is a condition called chronic graft vasculopathy (Mak & Saunders, 2006). It is also thought that CGR may have other causes or contributions that are unrelated to alloantigens, such as infections (e.g., cytomegalovirus), delayed functioning of the organ after transplant, and abnormal lipid metabolism (Mak & Saunders, 2006).
Critical to the continued success of organ transplantation is the defense against and management of rejection through the use of immunosuppressive medications (Taylor, Watson, & Bradley, 2005). Prevention and treatment of rejection typically involve combinations of steroids (e.g., predisone), anti-proliferative agents (e.g., azathioprine), calcineurin inhibitors (CNI; e.g., cyclosporine) and mammalian target of rapamycin (MTOR) inhibitors (e.g., sirolimus), and treatments are not used uniformly, as individual needs differ from person to person (Bolton & Bradley, 2011). These drugs are used over two treatment phases. In the induction phase, before the transplant and immediately after, high doses of drugs are used; lower doses are needed during the maintenance phase (Malhotra et al., 2011). Corticosteroids are the principal treatment for acute rejection and are used orally and intravenously (Taylor et al., 2005). Steroids are known for their anti-inflammatory and immunosuppressive effects and work by reducing the production of cytokines and chemokines (Bolton & Bradley, 2011). Anti-proliferative agents suppress the proliferation of lymphocytes, decreasing the immune system's ability to reject the foreign organ, and are primarily used in adjunct to steroids and CNIs (Bolton & Bradley, 2011). CNIs are considered some of the primary agents used to treat organ recipients (Bolton & Bradley, 2011). They work by preventing the production of cytokines and thereby suppressing the activation and proliferation of T cells (Taylor et al., 2005). MTOR inhibitors also have immunsuppressive effects related to the inhibition of T cell activity and also work by suppressing fibroblast growth factors and wound healing (Taylor et al., 2005). Because of the potential negative effect of toxic immunosuppressant drugs on function of the immune system, another treatment is the use of polyclonal and monoclonal antibodies, directed to work against T cells to impede CMR and AMR (Malhotra et al., 2011) both during induction phases (before the surgery) and to treat rejection (Bolton & Bradley, 2011).
Rejection following a heart transplant results from a complex process of the immune system responding to the organ as a pathogen. Although hyperacute, acute, and chronic rejection involve similar actions of the immune system they also differ, based on different underlying physiological mechanisms of action. As a result, treatment of cardiac rejection is individualized, based on the factors unique to the transplant recipient and the type of rejection being targeted.