Histocompatibility Antigens

When an organ is transplanted into a genetically dissimilar animal, the recipient will mount an immune response against many different antigens in and on the cells of the allograft. These are called histocompatibility antigens. Three types of histocompatibility antigens are of major importance in stimulating graft rejection. These are the MHC class I molecules, the MHC class II molecules, and the major blood group molecules. All are expressed on the surface of the graft cells, but their distribution varies. MHC class I antigens are found on almost all nucleated cells. The major blood group antigens are found both on red cells and nucleated cells. MHC class II antigens, in contrast, have a restricted distribution that varies among mammals (Chapter 11). For example, in rats and mice, MHC class II molecules are expressed only on the professional antigen-presenting cells (APCs): macrophages, dendritic cells, and B cells. In other species, such as humans and pigs, MHC class II molecules are also expressed on the endothelium of renal arteries and glomeruli, the sites where host cells first make contact with the graft. These MHC class II molecules are recognized as foreign and trigger the rejection process. It is interesting to note that, as a result of these differences, it is much easier to prolong renal allograft survival in laboratory rodents than in humans or pigs.

As would be expected, grafts that differ minimally from the recipient will generally survive longer than grafts that are highly incompatible. When blood group A-O-compatible pigs are given renal allografts, median survival is about 12 days for MHC-unmatched grafts, 25 days for grafts compatible for MHC class I alone, 32 days for grafts compatible for MHC class II alone, and 80 days for grafts compatible for both class I and class II (Figure 32-2). When dogs are given MHC-unmatched renal allografts, the grafts survive for about 10 days. Completely matched allografts in dogs survive for about 40 days. A more impressive result is obtained with canine liver grafts, which survive for about 8 days in unmatched animals and for 200 to 300 days in DLA-matched recipients.

The failure of MHC and blood group–compatible grafts to survive indefinitely is a result of the cumulative effects of many other minor antigenic differences. For example, skin grafts from male donors placed on histocompatible females are usually rejected, although the reverse is not the case. This is because male cells carry an antigen coded for by genes on the Y chromosome called the H-Y antigen.

During the acute rejection process, the grafted tissue gradually becomes infiltrated with cytotoxic T cells, which cause progressive damage to the endothelial cells lining small blood vessels (Figure 32-3). The T cells roll along the endothelial surface and bind using leukocyte function-associated antigen-1 (LFA-1). T cell–mediated damage releases chemokines that attract more T cells into the graft. Cellular destruction, stoppage of blood flow, hemorrhage, and death of the grafted organ follow thrombosis of these vessels. The blood vessels of second organ grafts become blocked even more rapidly as a result of the action of antibodies and complement on the vascular endothelium. This secondary reaction is specific for any graft from the original donor or from a donor syngeneic with the first. It is not restricted to any particular site or to any specific organ since MHC and blood group molecules are present on most nucleated cells.

In practice it is usually not difficult to ensure that the donor and recipient have identical major blood group antigens. MHC compatibility is much harder to achieve because MHC polymorphism ensures that individuals differ widely in their MHC haplotype. In general, the more closely donor and recipient are related, the less will be their MHC difference. For this reason it is preferable that grafts be obtained from a recipient’s parents or siblings. If this is not possible, a donor must be selected at random and the inevitable rejection responses suppressed by drugs such as cyclosporine or tacrolimus (Chapter 39).

Pathogenesis of Allograft Rejection

The allograft rejection process is directed against the dominant antigens on the cells of the graft. The MHC molecules tend to trigger a T cell–mediated rejection response, whereas the blood group antigens tend to trigger antibody formation. The rejection process may be divided into two stages. First, the host’s lymphocytes encounter the antigens of the graft and trigger a response. Second, cytotoxic T cells and antibodies from the host enter the graft and destroy graft cells (Figure 32-4).

Adaptive Mechanisms

Donor antigens are presented to the T cells of the recipient by APCs. The graft recipients may be sensitized by a direct pathway in which recipient T cells circulating through the graft encounter antigens presented by donor APCs. These donor APCs may also carry antigens to draining lymph nodes and the spleen. Alternatively, recipients may be sensitized when their own APCs circulate through the graft and encounter and process donor antigens (the indirect pathway). The direct pathway operates early in the rejection process but is replaced by the indirect pathway once donor APCs have been destroyed. In humans, the direct pathway is responsible for the vigorous immune response that occurs in acute rejection, whereas the indirect pathway is more important in chronic rejection. Although macrophages and dendritic cells are important APCs, donor B cells and tubular epithelial and endothelial cells can also process antigen, and they can migrate to lymphoid organs where they activate recipient T cells.

In laboratory rodents, MHC class II molecules are expressed on professional APCs. In these species the intensity of graft rejection is related to the number of donor B cells, macrophages, and dendritic cells transplanted within the graft. Removal of these cells by careful flushing of the graft before surgery or by pretreatment of the donor with cytotoxic drugs greatly reduces the intensity of the rejection process. In other mammals in which MHC class II molecules are also expressed on vascular endothelial cells, these “passenger” cells are of less significance.

The APCs that process donor MHC molecules migrate to the draining lymph node and activate other T cells. The paracortical regions of lymph nodes draining a graft therefore contain dividing lymphocytes. The number of these cells is greatest about 6 days after grafting and declines rapidly once the graft has been rejected. In addition to these signs of an active T cell–mediated immune response, germinal center formation occurs in the cortex, and plasma cells accumulate in the medulla, indicating that antibody formation is also occurring. In a conventional immune response, only one cell in 10⁵ to 10⁶ T cells can respond to a specific antigen. In graft rejection, however, there may be 1% to 10% of responding T cells since these cells have low activation thresholds for foreign MHC molecules.

The activated Th1 cells produce interleukin-2 (IL-2) and interferon-γ (IFN-γ) and so activate cytotoxic T cells and NK cells. The NK cells produce more IFN-γ and tumor necrosis factor-α (TNF-α) that activates macrophages and additional NK cells. The cytotoxic CD8+ T cells recognize the foreign peptides bound to recipient MHC class I molecules and kill any target cell they encounter. Donor MHC class II molecules trigger an immune response in two ways. First, because they are foreign proteins, they are processed as endogenous antigens. Second, they may directly bind to recipient T cell receptors (TCRs) and trigger cytotoxicity.

IL-2 and IFN-γ not only promote cytotoxic T cell activity but also enhance the expression of MHC molecules on the cells of the graft. During allograft rejection, therefore, MHC expression is increased, and the graft becomes an even more attractive target for cytotoxic T cells.

Although cytotoxic T cells are of major importance in acute allograft rejection, B cells, eosinophils, and macrophages also play a significant role in hyperacute and chronic rejection (Figure 32-5). Hyperacute rejection occurs when the recipient has preexisting antibodies to graft MHC or blood groups. These bind to graft vascular endothelial cells, activate complement by the classical pathway, and cause endothelial cell lysis. The damaged endothelial cells trigger platelet deposition as well as multiple chemokines and cytokines, especially IL-1β, CXCL8, and CCL2. These attract leukocytes as well, and the damage results in thrombosis and infarction. Anti-MHC antibodies also play a major role in secondary rejection, in which they activate the classical complement pathway and mediate antibody-dependent cytotoxic cell activity.

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