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Transplant rejectionClassification and external resources

Micrograph showing lung transplant rejection. Lung biopsy. H&E stain.

ICD-10 T 86 MedlinePlus 000815MeSH D006084

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.[1]

Contents

1 Pretransplant rejection prevention 2 Immunologic mechanisms of rejection

o 2.1 Immunization o 2.2 Immune memory o 2.3 Cellular immunity o 2.4 Humoral immunity

2.4.1 Antibody 2.4.2 Opsonization 2.4.3 Complement cascade

3 Medical categories of rejection o 3.1 Hyperacute rejection o 3.2 Acute rejection o 3.3 Chronic rejection

4 Rejection detection 5 Rejection treatment

o 5.1 Immunosuppressive therapy o 5.2 Antibody-based treatments o 5.3 Blood transfer o 5.4 Marrow transplant

6 References 7 External links

Pretransplant rejection prevention

Main article: Histocompatibility

The first successful organ transplant, performed in 1954 by Joseph Murray, involved identical twins, and so no rejection was observed. Otherwise, the number of mismatched gene variants, namely alleles, encoding cell surface molecules called major histocompatibility complex (MHC), classes I and II, correlate with the rapidity and severity of transplant rejection. In humans MHC is also called human leukocyte antigen (HLA).

Though cytotoxic-crossmatch assay can predict rejection mediated by cellular immunity, genetic-expression tests specific to the organ type to be transplanted, for instance AlloMap Molecular Expression Testing, have a high negative predictive value. Transplanting only ABO-compatible grafts, matching blood groups between donor and recipient, helps prevent rejection mediated by humoral immunity.

Immunologic mechanisms of rejection

Rejection is an adaptive immune response via cellular immunity (mediated by killer T cells inducing apoptosis of target cells) as well as humoral immunity (mediated by activated B cells secreting antibody molecules), though the action is joined by components of innate immune response (phagocytes and soluble immune proteins). Different types of transplanted tissues tend to favor different balances of rejection mechanisms.

Immunization

An animal's exposure to the antigens of a different member of the same or similar species is allostimulation, and the tissue is allogenic. Transplanted organs are often acquired from a cadaver (usually a host who had succumbed to trauma), whose tissues had already sustained ischemia or inflammation.

Dendritic cells (DCs), which are the primary antigen-presenting cells (APCs), of the donor tissue migrate to the recipient's peripheral lymphoid tissue (lymphoid follicles and lymph nodes), and present the donor's self peptides to the recipient's lymphocytes (immune cells residing in lymphoid tissues). Lymphocytes include two classes that enact adaptive immunity, also called

specific immunity. Lymphocytes of specific immunity T cells—including the subclasses helper T cells and killer T cells—and B cells.

The recipient's helper T cells coordinate specific immunity directed at the donor's self peptides or at the donor's Major histocompatibility complex molecules, or at both.

Immune memory

When memory helper T cells' CD4 receptors dock to MHC class II molecules, expressed on the surfaces of select cells, the memory helper T cells' T cell receptors (TCRs) can recognize their target antigen being presented within the MHC class II. The memory helper T cell produces clones that, as effector cells, secrete immune signaling molecules (cytokines) in approximately the cytokine balance that had prevailed at the memory helper T cell's priming to memorize the antigen. As the priming event in this instance occurred amid inflammation, the immune memory is proinflammatory.

Cellular immunity

As a cell is indicated by the prefix cyto, a cytotoxic influence destroys the cell. Alloreactive killer T cells, also called cytotoxic T lymphocytes (CTLs), have CD8 receptors that dock to the transplanted tissue's MHC class I molecules,which display the donor's self peptides. (In the living donor, such presentation of self antigens helped maintain self tolerance.) Thereupon, the T cell receptors (TCRs) of the killer T cells recognize their matching epitope, and trigger the target cell's programmed cell death by apoptosis.

Humoral immunity

Developed through an earlier primary exposure that primed specific immunity to the nonself antigen, a transplant recipient can have specific antibody crossreacting with the donor tissue upon the transplant event, a secondary exposure. This is typical after earlier mismatching among A/B/O blood types during blood transfusion. At this secondary exposure, these crossreactive antibody molecules interact with aspects of innate immunity—soluble immune proteins called complement and innate immune cells called phagocytes—which inflames and destroys the transplanted tissue.

Antibody

Secreted by an activated B cell, then called plasma cell, an antibody molecule is a soluble immunoglobulin (Ig) whose basic unit is shaped like the letter Y: the two arms are the Fab regions, while the single stalk is the Fc region. Each of the two tips of Fab region is the paratope, which binds a matching molecular sequence and its 3D shape (conformation), altogether called epitope, within the target antigen.

Opsonization

The IgG's Fc region also enables opsonization by a phagocyte, a process by which the Fc receptor on the phagocyte—such as neutrophils in blood and macrophages in tissues—binds the antibody molecule's FC stalk, and the phagocyte exhibits enhanced uptake of the antigen, attached to the antibody molecule's Fab region.

Complement cascade

When the paratope of Ig class gamma (IgG) binds its matching epitope, IgG's Fc region conformationally shifts and can host a complement protein, initiating the complement cascade that terminates by punching a hole in a cell membrane. With many holes so punched, fluid rushes into the cell and ruptures it.

Cell debris can be recognized as damage associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), on membranes of phagocytes, which thereupon secrete proinflammatory cytokines, recruiting more phagocytes to traffic to the area by sensing the concentration gradient of the secreted cytokines (chemotaxis).

Tissue MechanismBlood Antibodies (isohaemagglutinins)Kidney Antibodies, cell-mediated immunity (CMI)Heart Antibodies, CMISkin CMI

Bonemarrow CMICornea Usually accepted unless vascularised: CMI

Medical categories of rejection

Hyperacute rejection

Initiated by preexisting humoral immunity, hyperacute rejection manifests within minutes after transplant, and if tissue is left implanted brings systemic inflammatory response syndrome. Of high risk in kidney transplants is rapid clumping, namely agglutination, of red blood cells (RBCs or erythrocytes), as an antibody molecule binds multiple target cells at once.

Acute rejection

Developing with formation of cellular immunity, acute rejection occurs to some degree in all transplants, except between identical twins, unless immunosuppression is achieved (usually through drugs). Acute rejection begins as early as one week after transplant, the risk highest in the first three months, though it can occur months to years later. Highly vascular tissues such as kidney or liver often host the earliest signs—particularly at endothelial cells lining blood vessels—though it eventually occurs in roughly 10 to 30% of liver transplants, and 50 to 60% of kidney transplants. A single episode of acute rejection can be recognized and promptly treated, usually preventing organ failure, but recurrent episodes lead to chronic rejection.

Chronic rejection

Micrograph showing a glomerulus with changes characteristic of a transplant glomerulopathy. Transplant glomerulopathy is considered a form of chronic antibody-mediated rejection. PAS stain.

The term chronic rejection initially described long-term loss of function in transplanted organs via fibrosis of the transplanted tissue's blood vessels. This is now chronic allograft vasculopathy, however, leaving chronic rejection referring to rejection due to more patent aspects of immunity.

Chronic rejection explains long-term morbidity in most lung-transplant recipients,[2][3] the median survival roughly 4.7 years, about half the span versus other major organ transplants.[4] In histopathology the condition is bronchiolitis obliterans, which clinically presents as progressive airflow obstruction, often involving dyspnea and coughing, and the patient eventually succumbs to pulmonary insufficiency or secondary acute infection.

Airflow obstruction not ascribable to other cause is labeled bronchiolitis obliterans syndrome (BOS), confirmed by a persistent drop—three or more weeks—in forced expiratory volume (FEV1) by at least 20%.[5] BOS is seen in over 50% of lung-transplant recipients by 5 years, and in over 80% by ten years. First noted is infiltration by lymphocytes, followed by epithelial cell injury, then inflammatory lesions and recruitment of fibroblasts and myofibroblasts, which proliferate and secrete proteins forming scar tissue.[6] Generally thought unpredictable, BOS progression varies widely: lung function may suddenly fall but stabilize for years, or rapidly progress to death within a few months. Risk factors include prior acute rejection episodes, gastroesophageal reflux disease, acute infections, particular age groups, HLA mis-matching, lymphocytic bronchiolitis, and graft dysfunction (e.g., airway ischemia).[7]

Rejection detection

Diagnosis of acute rejection relies on clinical data—patient signs and symptoms—but also calls on laboratory data such as tissue biopsy. The laboratory pathologist generally seeks three main histological signs: (1) infiltrating T cells, perhaps accompanied by infiltrating eosinophils, plasma cells, and neutrophils, particularly in telltale ratios, (2) structural compromise of tissue anatomy, varying by tissue type transplanted, and (3) injury to blood vessels. Tissue biopsy is restricted, however, by sampling limitations and risks/complications of the invasive procedure. Cellular magnetic resonance imaging (MRI) of immune cells radiolabeled in vivo might offer noninvasive testing.[8]

Rejection treatment

Hyperacute rejection manifests severely and within minutes, and so treatment is immediate: removal of the tissue. Chronic rejection is generally considered irreversible and poorly amenable to treatment—only retransplant generally indicated if feasible—though inhaled cyclosporine is being investigated to delay or prevent chronic rejection of lung transplants. Acute rejection is treated with one or multiple of a few strategies.

Immunosuppressive therapy

A short course of high-dose corticosteroids can be applied, and repeated. Triple therapy adds a calcineurin inhibitor and an anti-proliferative agent. Where calcineurin inhibitors or steroids are contraindicated, mTOR inhibitors are used.

Immunosuppressive drugs:

Corticosteroids o Prednisolone o Hydrocortisone

Calcineurin inhibitors o Ciclosporin o Tacrolimus

Anti-proliferatives o Azathioprine o Mycophenolic acid

mTOR inhibitors o Sirolimus o Everolimus

Antibody-based treatments

Antibody specific to select immune components can be added to immunosuppressive therapy. The monoclonal anti-T cell antibody OKT3, once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe cytokine release syndrome and late post-transplant lymphoproliferative disorder. (OKT3 is available in the United Kingdom for named-patient use only.)

Antibody drugs:

Monoclonal anti-IL-2Rα receptor antibodies o Basiliximab o Daclizumab

Polyclonal anti-T-cell antibodies o Anti-thymocyte globulin (ATG)o Anti-lymphocyte globulin (ALG)

Monoclonal anti-CD20 antibodies o Rituximab

Blood transfer

Cases refractory to immunosuppressive or antibody therapy are sometimes given blood transfusions—removing antibody molecules specific to the transplanted tissue.

Marrow transplant

Bone marrow transplant can replace the transplant recipient's immune system with the donor's, and the recipient accepts the new organ without rejection. The marrow's hematopoietic stem cells—the reservoir of stem cells replenishing exhausted blood cells including white blood cells forming the immune system—must be of the individual who donated the organ or of an identical twin or a clone. There is a risk of graft versus host disease (GVHD), however, whereby mature lymphocytes entering with marrow recognize the new host tissues as foreign and destroy them.

Organ Transplantation: Concepts, Issues, Practice, and Outcomes

Immunologic Aspects of Organ TransplantationSusan Smith MN, PhD

Disclosures Jun 17, 2002  

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Rejection: The Allogeneic Immune Response

Transplantation of organs or tissues between genetically nonidentical individuals of the same species (and different species) is plagued by rejection and its associated problems. "Foreignness" is equated with the presence on transplanted tissue membrane of antigens that the host does not have and therefore recognizes as foreign or nonself. If all other factors are optimal (eg, donor management, the functional state of the donor organ, the surgical procedure, and intraoperative management of the recipient), the major reason for transplant failure is rejection.

The transplanted organ represents a continuous source of HLA alloantigens capable of inducing a rejection response at any time posttransplantation. Because it cannot be eliminated, the allograft continuously activates the immune system, resulting in lifelong overproduction of cytokines, constant cytotoxic activity, and sustained alteration in the graft vasculature. Therefore, lifelong immunosuppression is required to ensure allograft survival.

Transplanted organs express donor MHC molecules, resulting in 2 pathways of antigen recognition (allorecognition) by T cells: direct and indirect. Allorecognition refers to T cell recognition of genetically encoded polymorphisms between members of the same species. [13] The primary targets of the immune response to allogeneic tissues are MHC molecules on donor cells.

Direct and indirect pathways of T-cell allorecognition are mediated by different APCs, and their cellular mechanisms are different (Figure 26). The direct pathway requires that recipient T cells recognize intact donor MHC molecules complexed with peptide and expressed on donor cells. Allorecognition via the indirect pathway requires that recipient APCs process the donor-MHC antigen before presenting it to recipient T cells. Both pathways are important in mechanisms of allograft rejection. It is thought that the direct pathway is responsible for acute rejection and that the indirect pathway is responsible for chronic rejection.

Table 6.

 

Table 6. Immunogenecity of Different Tissues

Complete activation of T cells requires 2 distinct, but synergistic, signals (Figure 27). [14] The first signal is provided by a specific antigen and is delivered via the T-cell receptor. The second signal (costimulatory signal) is not antigen-specific. Instead, many T-cell molecules may serve as receptors for costimulation. The most well characterized costimulatory molecule is CD28, which has 2 ligands (B7-1 [CD80] and B7-2 [CD86]) that are expressed primarily on APCs. Another molecule, CTLA-4, is similar to CD28 and is also expressed on T cells. Although CTLA-4 binds B7-1 and B7-2, it transmits an inhibitory signal that serves to terminate the immune response.

(Enlarge Image)

Figure 26.

Direct and indirect antigen presentation.

Rejection is an immunologic response involving the recognition of HLA antigens on donor endothelial tissue cells by recipient lymphocytes or antibodies and subsequent destruction of the antigen-bearing graft. Transplantation of a vascular organ induces MHC sensitization by direct stimulation of circulating host immune cells (ie, macrophages, reticular [RE] cells) that encounter donor MHC antigens on allograft cell surfaces. The MHC epitopes are recognized, the antigen is processed by the RE cells and presented to the lymphoid system by APCs.

Both donor and host factors contribute to the immune response of rejection. The major donor factor is the expression of MHC antigens on the donor tissue and the presence of APCs within the transplanted graft. The major host factor is prior sensitization against ABO and HLA antigens expressed on the graft. In addition, microbial or other non-MHC antigens may stimulate antibodies that cross-react with MHC antigens. Rejection is generally classified as 1 of 3 types: hyperacute, acute, or chronic, according to temporal and histopathologic characteristics of the allograft.

Hyperacute Graft Rejection

Hyperacute rejection occurs immediately, within minutes to hours of vascularization of the transplanted graft, and is caused by a humoral immune response. Hyperacute rejection is an antibody-mediated cytotoxic response to the fixation of antibodies to specific class I antigens on vascular endothelium, followed by entrapment of formed blood elements and clotting factors in the microvasculature of the graft, resulting in complement activation, massive intravascular coagulation, lack of tissue perfusion, and graft necrosis. Hyperacute rejection results in immediate thrombotic occlusion and loss of the allograft.

Antibodies responsible for hyperacute rejection include antibodies to ABO blood group antigens and those produced against vascular endothelial antigens and histocompatibility antigens. For example, if an ABO blood group O recipient receives a kidney from an ABO blood group A

donor, once blood circulates through the transplanted kidney, antibody to the A antigen will combine with antigens on the endothelial cells of the kidney and activate the complement system. The activated complement system causes chemotaxis for phagocytes and induces fibrin deposition. Recruited phagocytes degranulate and release hydrolytic enzymes that cause tissue destruction and rapid rejection of the kidney. Hyperacute rejection most commonly occurs while the patient is still in the operating room; the kidney frequently turns black before the surgical team's eyes.

Antibody-to-transplant antigens can develop in recipients who have received multiple blood transfusions or prior transplants or who have had multiple pregnancies. Transfusion exposes the potential transplant recipient to foreign HLA proteins, which naturally stimulate the production of anti-HLA antibodies. Ensuring ABO blood group compatibility and avoiding positive lymphocyte cross-matches are universally accepted methods for prevention of hyperacute rejection.

Initially, hyperacute rejection was thought to occur only in transplanted kidneys. However, all solid organs are susceptible. Liver grafts in particular, however, are more tolerant of ABO and HLA incompatibility than are renal and heart grafts. [15] Retrospective histocompatibility antigen typing and lymphocyte cross-matching have not shown these factors to be relevant to liver graft survival. Although the reason that hyperacute rejection does not occur in liver grafts is not fully understood, it is speculated that the enormous cell mass of the liver is capable of absorbing circulating antibody. [16] Another reason may be differences in microvascular structures (capillaries vs sinusoids). [17] The major complication associated with ABO-incompatible liver transplantation is hemolysis. [18] A form of graft-vs-host reaction is caused by B lymphocytes in lymphoid tissue transplanted with the graft. Donor B lymphocytes produce antibodies to ABO antigens on recipient RBCs, resulting in lysis or hemolysis.

Accelerated Acute Graft Rejection

A variation of hyperacute rejection, accelerated acute rejection, is a cellular immune response. Accelerated acute rejection can occur when the recipient has been exposed previously to low levels of donor tissue antigens and makes a rapid memory response when the donor organ is transplanted. Accelerated acute rejection manifests within a few days to a few weeks following transplantation, and leads to allograft loss.

Acute Graft Rejection

Acute rejection occurs within a week to approximately 4 months after transplantation; the risk is greatest during the first 6 months and few episodes occur after the first year posttransplantation. The vast majority of acute rejection episodes do not lead to graft loss because they are diagnosed and treated promptly and aggressively.

Acute rejection is a cellular immune response involving mononuclear, cytotoxic and Th cells, monokines, and lymphokines (Figure 28). Acute rejection occurs when antigen is trapped within recipient macrophages and cannot be cleared by the RE system. Quiescent, nonactivated Th cells encounter specific class II antigens displayed on the donor organ, become activated, and

synthesize receptors for lymphokines that are simultaneously released from monocytes. Activated monocytes release the lymphokine IL-1, which causes clonal expansion of activated Th cells. Monocytes also release the lymphokine IL-2, which activates and causes the clonal expansion of CTLs. Clinical signs of rejection are nonspecific and vary depending on the organ transplanted. A biopsy is required to make a definitive diagnosis of acute rejection.

(Enlarge Image)

Figure 27.

T cell activation.

Acute rejection has short-term and long-term implications. The short-term implications seem obvious -- increased need for immunosuppressive therapy with consequent morbidity and increased cost of care for monitoring and treating acute rejection episodes. Only recently has acute rejection been appreciated for its adverse impact on long-term outcomes. In fact, the acute rejection history is the most significant immunologic predictor of chronic renal allograft dysfunction. [19] The frequency, histologic type, and timing of acute rejection are important with respect to the effect on long-term graft function. Multiple and late-occurring episodes are particularly predictive.

Of the 4 types of rejection, acute rejection has the greatest clinical significance for nurses, because it can be prevented and treated through pharmacologic interventions administered and monitored by nurses. A significant amount of time spent caring for an organ transplant recipient involves clinical assessment of the patient for rejection responses and administration of immunosuppressive agents to treat rejection. Diagnosis of acute rejection depends on the specific organ transplanted, but is generally based on clinical and laboratory evidence of graft injury or dysfunction and biopsy findings. Patient responses to acute rejection vary, depending on the organ being rejected.

Chronic Graft Rejection

Chronic rejection probably begins at the time of transplantation, but may take months or years to manifest clinically. While the clinical and biochemical signs are organ-specific, the result of chronic rejection is the same for all solid organ allografts. Slowly deteriorating graft function caused by fibrosis of the graft parenchyma and widespread arteriopathy are the hallmarks of chronic rejection that lead to loss of function and eventual graft loss. A comprehensive review of the pathophysiology of chronic allograft rejection has been previously published in Medscape Transplantation. [20]

The cause of chronic rejection is unclear. However, there is evidence that both immune and nonimmune events are responsible. T cells and B cells contribute to the damage characteristic of

chronic rejection. Overproduction of cytokines, including TGF-beta and platelet-derived growth factor, contribute to fibrosis. Continuous production of alloantibody by B cells under the influence of T cells contributes to the arteriopathy. Formerly thought to be the product of donor factors including reduced nephron mass, prolonged cold ischemia time, advanced donor kidney age, and donor hypertension, recent evidence suggests that recipient immune reactivity against the allograft also contributes to the development of DGF.

Chronic rejection is a prolonged process of declining allograft function. Thus, it is not surprising that transplant recipients who develop chronic rejection often experience many of the same health problems associated with primary organ failure. In addition, they develop the complications and cumulative adverse effects associated with years of daily administration of immunosuppressive agents. Susceptibility to infection, development of skin cancer, cardiovascular disease, osteoporosis, and mood changes are common in patients who receive substantial doses of corticosteroids.

Treatment for Chronic Rejection

Although retransplantation is the only cure for chronic rejection, prevention is the strategy of choice. This requires understanding and controlling the risk factors for chronic rejection. For kidney, lung, and liver allografts, there is evidence that patients who experience acute rejection episodes are at higher risk for developing chronic rejection. Hypertension, high atherogenic serum lipid levels, and diabetes mellitus also increase the risk of chronic rejection among kidney and heart allograft recipients. The use of pravastatin, an HMG CoA reductase inhibitor with relatively low lipophilicity, has been associated with enhanced heart allograft survival and a reduced incidence of acute rejection among recipients of kidney allografts. Thus, the cardiovascular benefits of pravastatin are compounded by the immunologic benefits in a transplant setting.

Overview

Transplantation is the act of transferring cells, tissues, or organs from one site to another. The malfunction of an organ system can be corrected with transplantation of an organ (eg, kidney, liver, heart, lung, or pancreas) from a donor. However, the immune system remains the most formidable barrier to transplantation as a routine medical treatment. The immune system has developed elaborate and effective mechanisms to combat foreign agents. These mechanisms are also involved in the rejection of transplanted organs, which are recognized as foreign by the recipient's immune system.

Understanding these mechanisms is important, as it aids in understanding the clinical features of rejection and, hence, in making an early diagnosis and delivering appropriate treatment. Knowledge of these mechanisms is also critical in developing strategies to minimize rejection and in developing new drugs and treatments that blunt the effects of the immune system on transplanted organs, thereby ensuring longer survival of these organs.

While African Americans have historically had inferior outcomes after renal transplantation, a recent analysis suggests that this holds true for younger recipients but not for older recipients.[1]

For more information on various transplantation procedures, see Transplantation journal and the Medscape resource centers for Heart & Lung Transplant, Kidney & Pancreas Transplant, and Liver & Intestine Transplant.

History

In 1944, Medawar showed that skin allograft rejection is a host versus graft response. Mitchison later demonstrated the cell-mediated features of this response. The first successful identical twin transplant of a human kidney was performed by Joseph E. Murray in 1954 in Boston, followed by the first successful liver transplant by Dr. Thomas E. Starzl in 1967, the first heart transplantation by Christian Barnard in 1967, and the first successful bone marrow transplant by E. Donnall Thomas in 1968. Schwartz and Dameshek, in 1959, showed that 6-mercaptopurine was immunosuppressive in rats, ushering in the era of immunosuppressive drug treatment. Since then, many new and progressively more selective immunosuppressive agents have been developed. These therapies have enabled the transplantation of and improved the survival of transplanted organs.

Types of Grafts

The degree of immune response to a graft depends partly on the degree of genetic disparity between the grafted organ and the host. Xenografts, which are grafts between members of different species, have the most disparity and elicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the body to another (eg, skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are grafts between genetically identical individuals (eg, monozygotic twins), also undergo no rejection.

Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation. The degree to which allografts undergo rejection depends partly on the degree of similarity or histocompatibility between the donor and the recipient.

The degree and type of response also vary with the type of the transplant. Some sites, such as the eye and the brain, are immunologically privileged (ie, they have minimal or no immune system cells and can tolerate even mismatched grafts). Skin grafts are not initially vascularized and so do not manifest rejection until the blood supply develops. The heart, kidneys, and liver are highly vascular organs and lead to a vigorous cell mediated response in the host.

Immunobiology of Rejection

Genetic background

The antigens responsible for rejection of genetically disparate tissues are called histocompatibility antigens; they are products of histocompatibility genes. Histocompatibility antigens are encoded on more than 40 loci, but the loci responsible for the most vigorous allograft rejection reactions are located on the major histocompatibility complex (MHC).

In humans, the MHC is called the human leukocyte antigen (HLA) system and is located on the short arm of chromosome 6, near the complement genes. Other antigens cause only weaker reactions, but combinations of several minor antigens can elicit strong rejection responses. The MHC genes are codominantly expressed, which means that each individual expresses these genes from both the alleles on the cell surface. Furthermore, they are inherited as haplotypes or 2 half sets (one from each parent). This makes a person half identical to each of his or her parents with respect to the MHC complex. This also leads to a 25% chance that an individual might have a sibling who is HLA identical.

The MHC molecules are divided into 2 classes. The class I molecules are normally expressed on all nucleated cells, whereas the class II molecules are expressed only on the professional antigen-presenting cells (APCs), such as dendritic cells, activated macrophages, and B cells. The physiological function of the MHC molecules is to present antigenic peptides to T cells, since the T lymphocytes only recognize antigen when presented in a complex with an MHC molecule. The class I molecules are responsible for presenting antigenic peptides from within the cell (eg, antigens from the intracellular viruses, tumor antigens, self-antigens) to CD8 T cells. The class II molecules present extracellular antigens such as extracellular bacteria to CD4 T cells.

Mechanisms of rejection

The immune response to a transplanted organ consists of both cellular (lymphocyte mediated) and humoral (antibody mediated) mechanisms. Although other cell types are also involved, the T cells are central in the rejection of grafts. The rejection reaction consists of the sensitization stage and the effector stage.

Sensitization stage

In this stage, the CD4 and CD8 T cells, via their T-cell receptors, recognize the alloantigens expressed on the cells of the foreign graft. Two signals are needed for recognition of an antigen; the first is provided by the interaction of the T cell receptor with the antigen presented by MHC molecules, the second by a costimulatory receptor/ligand interaction on the T cell/APC surface. Of the numerous costimulatory pathways, the interaction of CD28 on the T cell surface with its APC surface ligands, B7-1 or B7-2 (commonly known as CD80 or CD86, respectively), has been studied the most.[2] In addition, cytotoxic T lymphocyte–associated antigen-4 (CTLA4) also binds to these ligands and provides an inhibitory signal. Other costimulatory molecules include the CD40 and its ligand CD40L (CD154).

Typically, helices of the MHC molecules form the peptide-binding groove and are occupied by peptides derived from normal cellular proteins. Thymic or central tolerance mechanisms (clonal deletion) and peripheral tolerance mechanisms (eg, anergy) ensure that these self-peptide MHC complexes are not recognized by the T cells, thereby preventing autoimmune responses.

At least 2 distinct, but not necessarily mutually exclusive, pathways of allorecognition exist, the direct and indirect pathways. Each leads to the generation of different sets of allospecific T cell clones.

Direct pathway

In the direct pathway, host T cells recognize intact allo-MHC molecules on the surface of the donor or stimulator cell. Mechanistically, host T cells see allo-MHC molecule + allo-peptide as being equivalent in shape to self-MHC + foreign peptide and, hence, recognize the donor tissue as foreign. This pathway is presumably the dominant pathway involved in the early alloimmune response.

The transplanted organ carries a variable number of passenger APCs in the form of interstitial dendritic cells. Such APCs have a high density of allo-MHC molecules, and are capable of directly stimulating the recipient's T cells. The relative number of T cells that proliferate on contact with allogeneic or donor cells is extraordinarily high as compared with the number of clones that target antigen presented by self-APC. Thus, this pathway is important in acute allorejection.

Indirect pathway

In the indirect pathway, T cells recognize processed alloantigen presented as peptides by self-APCs. Secondary responses such as those that occur in chronic or late acute rejection are associated with T cell proliferative responses to a more variable repertoire, including peptides that were previously immunologically silent. Such a change in the pattern of T cell responses has been termed epitope switching or spreading.

A link between self-MHC + allopeptide-primed T cells and the development of acute vascular type rejection has been demonstrated to be mediated in part by accelerated alloantibody production. In addition, chronic allograft vasculopathy may be mediated by T cells primed by the indirect pathway.

Molecular mechanisms of T cell activation

During T cell activation, membrane-bound inositol phospholipid is hydrolyzed into diacylglycerol (DAG) and IP3. This increases the cytoplasmic calcium. The elevation in calcium promotes the formation of calcium-calmodulin complexes that activate a number of kinases as well as protein phosphatase IIB or calcineurin. Calcineurin dephosphorylates cytoplasmic nuclear factor of activated T cells (NFAT), permitting its translocation to the nucleus, where it binds to the IL-2 promoter sequence and then stimulates transcription of IL-2 mRNA. Numerous other intracellular events, including protein kinase C (PKC) activation by DAG and activation of nuclear factor kappa B (NFkB) also occur at the molecular level.

Effector stage

Alloantigen-dependent and independent factors contribute to the effector mechanisms. Initially, nonimmunologic "injury responses" (ischemia) induce a nonspecific inflammatory response. Because of this, antigen presentation to T cells is increased as the expression of adhesion molecules, class II MHC, chemokines, and cytokines is upregulated. It also promotes the shedding of intact, soluble MHC molecules that may activate the indirect allorecognition

pathway. After activation, CD4-positive T cells initiate macrophage-mediated delayed type hypersensitivity (DTH) responses and provide help to B cells for antibody production.

Various T cells and T cell-derived cytokines such as IL-2 and IFN-γ are upregulated early after transplantation. Later, ß-chemokines like RANTES (regulated upon activation, normal T cell expressed and secreted), IP-10, and MCP-1 are expressed, and this promotes intense macrophage infiltration of the allograft. IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and growth factors, also play a role in this process. The growth factors, including TGF-ß and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis, and, in the case of the kidney, glomerulosclerosis.

Endothelial cells activated by T cell–derived cytokines and macrophages express class II MHC, adhesion molecules, and costimulatory molecules. These can present antigen and thereby recruit more T cells, amplifying the rejection process. CD8-positive T cells mediate cell-mediated cytotoxicity reactions either by delivering a "lethal hit" or, alternatively, by inducing apoptosis.

Apoptosis

The final common pathway for the cytolytic processes is triggering of apoptosis in the target cell.[3] After activation of the CTLs, they form cytotoxic granules that contain perforin and granzymes.[3] At the time of target cell identification and engagement, these granules fuse with the effector cell membrane and extrude the content into the immunological synapse. By a yet unknown mechanism, the granzymes are inserted into the target cell cytoplasm where granzyme B can trigger apoptosis through several different mechanisms, including direct cleavage of procaspase-3 and indirect activation of procaspase-9. This has been shown to play the dominant role in apoptosis induction in allograft rejection.

Alternatively, CD8-positive CTLs can also use the Fas-dependent pathway to induce cytolysis and apoptosis. The Fas pathway is also important in limiting T cell proliferation in response to antigenic stimulation; this is known as fratricide between activated CTLs. Cell-mediated cytotoxicity has been shown to play an important role in acute, although not chronic, allograft rejection.

Role of natural killer cells

The natural killer (NK) cells are important in transplantation because of their ability to distinguish allogenic cells from self and their potent cytolytic effector mechanisms.[4] These cells can mount a maximal effector response without any prior immune sensitization. Unlike T and B cells, NK cells are activated by the absence of MHC molecules on the surface of target cells (“missing self” hypothesis). The recognition is mediated by various NK inhibitory receptors triggered by specific alleles of MHC class I antigens on cell surfaces.

In addition, they also possess stimulatory receptors, which are triggered by antigens on nonself cells. These effector responses include both cytokine release and direct toxicity mediated through perforin, granzymes, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL).

Through this “double negative” mode of activation, they are thought to play a role in the rejection of both bone marrow and transplantable lymphomas in animal models.

NK cells also provide help to CD28-positive host T cells, thereby promoting allograft rejection.[5]

Their importance in the field of bone marrow transplants has been recognized for years. In humans, their graft-versus-host alloresponse has been used for its potent graft-versus-leukemia effect and has contributed to an increase in the rate of sustained remission in patient with acute myelogenous leukemia.

NK cells are now being recognized as active participants in the acute and chronic rejection of solid tissue grafts.[4] Recent studies have indicated that NK cells are present and activated following infiltration into solid organ allografts.[4] They may regulate cardiac allograft outcomes. Studies have also shown that humans with killer cell immunoglobulin-like receptors that are inhibited by donor MHC have a decreased risk of liver transplant rejection. In cases of renal transplantation, these cells are not suppressed by the current immunosuppressive regimens.

Role of innate immunity

Although T cells have a critical role in acute rejection, the up-regulation of proinflammatory mediators in the allograft is now recognized to occur before the T cell response; this early inflammation following engraftment is due to the innate response to tissue injury independent of the adaptive immune system. Several recent studies have examined the role of Toll-like receptor (TLR) agonists and TLR signals in allorecognition and rejection.

These innate mechanisms alone do not appear sufficient to lead to graft rejection itself. However, they are important for optimal adaptive immune responses to the graft and may play a major role in resistance to tolerance induction. The development of methods to blunt innate immune responses, which has potential implications for a wide variety of diseases, is likely to have a significant impact on transplantation, as well.

Clinical Stages of Rejection

Hyperacute rejection

In hyperacute rejection, the transplanted tissue is rejected within minutes to hours because vascularization is rapidly destroyed. Hyperacute rejection is humorally mediated and occurs because the recipient has preexisting antibodies against the graft, which can be induced by prior blood transfusions, multiple pregnancies, prior transplantation, or xenografts against which humans already have antibodies. The antigen-antibody complexes activate the complement system, causing massive thrombosis in the capillaries, which prevents the vascularization of the graft. The kidney is most susceptible to hyperacute rejection; the liver is relatively resistant, possibly because of its dual blood supply, but more likely because of incompletely understood immunologic properties.

Acute rejection

Acute rejection manifests commonly in the first 6 months after transplantation.

Acute cellular rejection

Acute cellular rejection is mediated by lymphocytes that have been activated against donor antigens, primarily in the lymphoid tissues of the recipient. The donor dendritic cells (also called passenger leukocytes) enter the circulation and function as antigen-presenting cells (APCs).

Humoral rejection

Humoral rejection is form of allograft injury and subsequent dysfunction, primarily mediated by antibody and complement. It can occur immediately posttransplantation (hyperacute) or during the first week. The antibodies are either preformed antibodies or represent antidonor antibodies that develop after transplantation. Proteinuria is associated with donor-specific antibody detection and is likely to be an important factor that determines rapid glomerular filtration rate decline and earlier graft failure in patients developing de novo HLA antibodies.[6]

The presence of even low levels of donor-specific antibodies that may not be detected by complement-dependent cytotoxic and flow cytometry crossmatches have been shown to be associated with inferior renal allograft outcomes.[7] These patients may require augmented immunosuppression.

The classic pathway inactive product C4d has been shown to be deposited in the peritubular capillaries (PTC), and immune detection of this product in renal allograft biopsies is used in diagnosis of antibody-mediated rejection. However, one study has demonstrated that there is a substantial fluctuation in the C4d Banoff scores in the first year posttransplant, and this may reflect the dynamic and indolent nature of the humoral process.[8] Thus, C4d by itself may not be a sufficiently sensitive indicator, and microvascular inflammation with detection of donor-specific antibodies may be more useful in diagnosing humoral rejection.

Chronic rejection

Chronic rejection develops months to years after acute rejection episodes have subsided. Chronic rejections are both antibody- and cell-mediated. The use of immunosuppressive drugs and tissue-typing methods has increased the survival of allografts in the first year, but chronic rejection is not prevented in most cases.

Chronic rejection appears as fibrosis and scarring in all transplanted organs, but the specific histopathological picture depends on the organ transplanted. In heart transplants, chronic rejection manifests as accelerated coronary artery atherosclerosis. In transplanted lungs, it manifests as bronchiolitis obliterans. In liver transplants, chronic rejection is characterized by the vanishing bile duct syndrome. In kidney recipients, chronic rejection (called chronic allograft nephropathy) manifests as fibrosis and glomerulopathy. The following factors increase the risk of chronic rejection:

Previous episode of acute rejection

Inadequate immunosuppression Initial delayed graft function Donor-related factors (eg, old age, hypertension) Reperfusion injury to organ Long cold ischemia time Recipient-related factors (eg, diabetes, hypertension, hyperlipidemia) Posttransplant infection (eg, cytomegalovirus [CMV])

Transplant Tolerance and Minimizing Rejection

Rejection cannot be completely prevented; however, a degree of immune tolerance to the transplant does develop. Several concepts have been postulated to explain the development of partial tolerance. They include clonal deletion and the development of anergy in donor specific lymphocytes, development of suppressor lymphocytes, or factors that down-regulate the immune response against the graft. Other hypotheses include the persistence of donor-derived dendritic cells in the recipient that promote an immunologically mediated chimeric state between the recipient and the transplanted organ.

Tissue typing or crossmatching is performed prior to transplantation to assess donor-recipient compatibility for human leukocyte antigen (HLA) and ABO blood group. These tests include the following:

The ABO blood group compatibility is tested first because incompatibility between the blood groups leads to rapid rejection.

In the lymphocytotoxicity assay, patient sera are tested for reactivity with donor lymphocytes. A positive crossmatch is a contraindication to transplantation because of the risk of hyperacute rejection. This is used mainly in kidney transplantation.

Panel-reactive antibody (PRA) screens the serum of a patient for lymphocytic antibodies against a random cell panel. Patients with prior transfusions, transplants, or pregnancies may have a high degree of sensitization and are less likely to have a negative crossmatch with a donor. A reduced risk of sensitization at the time of second transplant has been observed when using more potent immunosuppression with rabbit antithymocyte globulin, tacrolimus, and mycophenolate mofetil/sodium for nonsensitized primary kidney or kidney/pancreas transplant patients.[9]

Mixed lymphocyte reaction (MLR) can be used to assess the degree of major histocompatibility complex (MHC) class I and class II compatibility. However, it is not a rapid test and can be used only in cases involving living related donors. It is rarely used at present.

Immunosuppression

Initially, radiation and chemicals were used as nonselective immunosuppressive agents. In the late 1950s and 1960s, the agents 6-mercaptopurine and azathioprine were used in conjunction with steroids. Newer immunosuppressive agents have since been developed; they are more

effective, more selective, and less toxic and have made possible the advances in the field of transplantation.

Recent adverse experience with medications including rofecoxib, erythropoietin, and rosiglitazone, even after their approval, has resulted in increased safety measures, which address perceived deficits in the system for drug approval and postmarketing safety. Legislation has enabled the US Food and Drug Administration (FDA) to legally enforce introduced risk evaluation and mitigation strategies and postmarketing requirements.[10]

Immunosuppressive drugs are used in 2 phases: the initial induction phase, which requires much higher doses of these drugs, and the later maintenance phase. Immunosuppressive agents in current use include the following:

Immunophilin-binding agents

The available immunophilin-binding agents are cyclosporine and tacrolimus. These agents are calcineurin inhibitors; they primarily suppress the activation of T lymphocytes by inhibiting the production of cytokines, specifically IL-2. They are associated with numerous toxicities that are often dose-dependent. Nephrotoxicity occurs with both the drugs. Hirsutism, gingival hypertrophy, hypertension, and hyperlipidemia develop more often with cyclosporine than tacrolimus. (Click here to complete a Medscape CME activity on hirsutism.) Potential drug interactions are also important to recognize.

Tacrolimus is a macrolide lactone antibiotic produced by the soil fungus Streptomyces tsukubaensis. It binds to a different intracellular protein (FKBP-12) than cyclosporine but has the same mechanism of action. Neurotoxicity, alopecia, and posttransplant diabetes mellitus develop more frequently with tacrolimus than with cyclosporine.

Conversion from brand name to generic tacrolimus is routinely feasible, but it requires close monitoring of tacrolimus levels.[11]

Mammalian target of rapamycin (mTOR) inhibitors

Sirolimus is a macrocyclic antibiotic produced by fermentation of Streptomyces hygroscopicus. It binds to FKBP-12 and presumably modulates the activity of the mTOR inhibitor, which inhibits IL-2–mediated signal transduction and results in T- and B-cell cycle arrest in the G1-S phase. Sirolimus is associated with numerous adverse effects, such as leukopenia, thrombocytopenia, anemia, hypercholesterolemia, and hypertriglyceridemia. It has also been associated with mucositis, delayed wound healing, lymphocele formation, pneumonitis, and prolonged delayed graft function.

Antiproliferative agents

Azathioprine and mycophenolate mofetil (MMF) are the agents commonly used in this category. Other antiproliferative agents, such as cyclophosphamide and, more recently, leflunomide, have also been used.

Antiproliferative agents inhibit DNA replication and suppress B- and T-cell proliferation. MMF is an organic synthetic derivative of the natural fermentation product mycophenolic acid (MPA) that causes noncompetitive reversible inhibition of inosine monophosphate dehydrogenase. This interferes with purine synthesis. Adverse effects of MMF are nausea, diarrhea, leukopenia, and thrombocytopenia. Invasive CMV infection has been sometimes associated with MMF. The introduction of MMF has been shown to be associated with improvement or stabilization of renal function, even several years after transplantation.[12]

Antibodies

Two antibodies that are IL-2 receptor antagonists (basiliximab and daclizumab) are FDA-approved for kidney transplantation induction. Antilymphocyte globulin, such as the monoclonal antibody muromonab-CD3, and the polyclonal antibodies, antithymocyte globulins derived from either equine or rabbit sources, are approved for the treatment of rejection. They also have been used as induction agents at some transplantation centers.

Antibodies interact with lymphocyte surface antigens, depleting circulating thymus-derived lymphocytes and interfering with cell-mediated and humoral immune responses. Lymphocyte depletion also occurs either by complement-dependent lysis in the intravascular space or by opsonization and subsequent phagocytosis by macrophages. Adverse effects such as fever, chills, thrombocytopenia, leukopenia, and headache typically occur with the first few doses.

Corticosteroids

Steroids have been the cornerstone of immunosuppression and are still used. However, the newer regimens are trying to minimize the use of steroids and thereby avoid the adverse effects that are associated with them. Steroids are still important in treating episodes of acute rejection.

Future Therapies

Many new agents are designed to interfere with secondary signaling, and this may aid in induction of tolerance.

Efalizumab is a humanized monoclonal antibody that targets the T-cell lymphocyte function-associated antigen-1 (LFA-1) receptor through the CD11a side chain. Efalizumab (Raptiva), a drug indicated for psoriasis, is being withdrawn from the US market and will no longer be available after June 8, 2009, because of potential risk for progressive multifocal leukoencephalopathy (PML). PML is a rapidly progressive infection of the central nervous system caused by the JC virus that leads to death or severe disability. Demyelination associated with PML is a result from the JC virus infection. JC virus belongs to the genus Polyomavirus of the Papovaviridae. PML should be considered in any patient presenting with new-onset neurologic manifestations who have taken efalizumab. For more information, see the Food and Drug Administration MedWatch Safety Alert.[13]

Monoclonal antibodies to B7-1 (CD80) and B7-2 (CD86) have been developed to block T-cell CD28 activation and proliferation responses. In a recent trial, one of these antibodies, belatacept,

did not appear to be inferior to cyclosporine as a means of preventing acute rejection after renal transplantation.

Studies involving the humanized anti-C5 antibody, eculizumab, have demonstrated the effects of a new antibody therapy on the prevention of antibody-mediated rejection in highly sensitized patients who undergo transplantation.[14]

Cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) can simultaneously inhibit B7-1 and B7-2 interaction with CD28 and has been used successfully in animal models, demonstrating a beneficial effect on chronic allograft rejection.

Other antibodies targeting CD28 are also in development.

Monoclonal anti-CD45-RB, leflunomide, FK778, FTY720, alemtuzumab (anti-CD52 antibody), and rituximab are some of the other agents in different phases of evaluation.

Natural killer (NK) cell inactivation or depletion also harbors the promise that it may improve the long-term outcome of transplanted organs.

The use of any immunosuppressive drug requires a balance between the risk of loss of transplanted organ and the toxicity of the agent. The goal is to balance an appropriate level of immunosuppression with the long-term risks, which include development of infections, cancer, and metabolic complications.

If you're living with a transplant, "rejection" is a word that can send shivers up your spine. But organ rejection is often not as bad as it sounds. As scary as the word may be, it doesn't mean necessarily that you're going to lose the organ. It often means your medication needs to be adjusted. Once you've established a new medication regimen that works, you can usually go back to business as usual.

But that doesn't mean you can ignore the problem. Be on the lookout for the signs of rejection. Symptoms vary depending on the kind of organ transplant you've had. General signs include:

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Transplant rejectionEmail this page to a friend Share on facebook Share on twitter Bookmark & Share Printer-friendly version

Transplant rejection is a process in which a transplant recipient's immune system attacks the transplanted organ or tissue. See also: Graft-versus-host disease

Causes

Your body's immune system usually protects you from substances that may be harmful, such as germs, poisons, and cancer cells.

These harmful substances have proteins called antigens on their surfaces. As soon as these antigens enter the body, the immune system recognizes them as foreign and attacks them.

In the same way, an organ that is not matched can trigger a blood transfusion reaction or transplant rejection. To help prevent this reaction, doctors "type" both the organ donor and the person who is receiving the organ. The more similar the antigens are between the donor and recipient, the less likely that the organ will be rejected.

Tissue typing ensures that the organ or tissue is as similar as possible to the tissues of the recipient, but the match is usually not perfect. No two people (except identical twins) have identical tissue antigens.

Doctors use a variety of drugs to suppress the immune system and prevent it from attacking the newly transplanted organ when the organ is not closely matched. If these drugs are not used, the body will almost always launch an immune response and destroy the foreign tissue.

There are some exceptions, however. Cornea transplants are rarely rejected because the cornea has no blood supply. Immune cells and antibodies are not able to reach the cornea to cause rejection. In addition, transplants from one identical twin to another are almost never rejected.

There are three types of rejection:

Hyperacute rejection occurs a few minutes after the transplant, if the antigens are completely unmatched. The tissue must be removed right away so the recipient does not die. This type of rejection is seen when a recipient is given the wrong type of blood.

Acute rejection may occur any time from the first week after the transplant to 3 months afterward. Everyone has some amount of acute rejection.

Chronic rejection takes place over many years. The body's constant immune response against the new organ slowly damages the transplanted tissues or organ.

Symptoms

The organ's function may start to decrease General discomfort, uneasiness, or ill feeling Pain or swelling in the area of the organ (rare) Fever (rare) Flu-like symptoms, including chills, body aches, nausea, cough, and shortness of breath

The symptoms depend on the transplanted organ or tissue. For example, patients who reject a kidney may have less urine, and patients who reject a heart may have symptoms of heart failure.

Exams and Tests

The doctor will examine the area over and around the transplanted organ, which may feel tender to you (especially with a kidney transplant).

There are often signs that the organ isn't working properly, such as:

High blood sugar (pancreas transplant) Less urine released (kidney transplant) Shortness of breath and less ability to exercise (heart transplant) Yellow skin color and easy bleeding (liver transplant)

A biopsy of the transplanted organ can confirm that it is being rejected. A routine biopsy is often performed to detect rejection early, before symptoms develop.

When organ rejection is suspected, one or more of the following tests may be done before the organ biopsy:

Abdominal CT scan Chest x-ray Heart echocardiography Kidney arteriography Kidney ultrasound Lab tests of kidney or liver function

Treatment

The goal of treatment is to make sure the transplanted organ or tissue works properly, and to suppress your immune system response. Suppressing the immune response can prevent transplant rejection.

Many different drugs can be used to suppress the immune response. The medication dose depends on your condition. The dose may be very high while the tissue is being rejected. Then the dose may be lowered to prevent rejection from happening again.

Outlook (Prognosis)

Some organ and tissue transplants are more successful than others. If rejection begins, drugs that suppress the immune system may stop the rejection. Most people need to take these drugs for the rest of their life.

Even though potent drugs are used to suppress the immune system, organ transplants can still fail because of rejection.

Single episodes of acute rejection are easy to treat and rarely lead to organ failure.

Chronic rejection is the leading cause of organ transplant failure. The organ slowly loses its function and symptoms start to appear. This type of rejection cannot be effectively treated with medicines. Some people may need another transplant.

Possible Complications

Certain cancers (in some people who take strong immune suppressing drugs for a long time)

Infections (because the person's immune system is suppressed) Loss of function in the transplanted organ/tissue Side effects of medications, which may be severe

When to Contact a Medical Professional

Call your health care provider if the transplanted organ or tissue does not seem to be working properly or if other symptoms occur. Also, call your health care provider if medication side effects develop.

Prevention

ABO blood typing and HLA (tissue antigen) typing before a transplant helps to ensure a close match. You will usually need to take medicine to suppress your immune system for the rest of your life to prevent the tissue from being rejected.

Being careful about taking your post-transplant medications, and being closely watched by your doctor may help prevent rejection.