Immunologic Aspects of Organ Transplantation

Susan Smith MN, PhD


Organ Transplant 

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.

Figure 26.

Direct and indirect antigen presentation.

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.

Figure 27.

T cell activation.

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.

Figure 28.

Graft damage from the allogeneic response - CTLs, endothelial cells.

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.