Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

U N I T 4

In the direct pathway, T cells of the transplant recipi- ent directly recognize donor MHC molecules of the surface of antigen-presenting cells in the graft. 1,2 Both the CD4 + and CD8 + cells of the transplant recipient are involved in the reaction. Recipient CD8 + T cells recog- nize donor class I MHC molecules and differentiate into mature CTLs that kill cells in the grafted tissue (see type IV hypersensitivity reactions). The CD4 + helper T-cell subset is triggered into proliferation and differentiation into T H 1 effector cells by recognition of donor class II MHC molecules. As with delayed hypersensitivity reac- tions, cytokines secreted by activated CD4 + cells cause increased vascular permeability and local accumulation and activation of macrophages, resulting in graft injury. In the indirect pathway, recipient CD4 + T cells recog- nize donor MHC molecules after they have been picked up, processed, and presented by the recipient’s own antigen-presenting cells. 1,2 Thus, the indirect pathway is similar to the physiologic processing and presentation of other foreign antigens. This form of recognition mainly activates DTH pathways of the type IV hypersensitivity reactions. This indirect pathway is also involved in the production of antibodies against graft alloantigens. If the alloantigens are proteins, they are picked up by host B cells and processed, and their peptides presented to helper T cells, which then stimulate antibody responses. 2 The basic patterns of transplant rejection have histori- cally been classified based on the time course of the response and the pathologic mechanisms involved. 1–3 Based on experience with kidney transplants, which have been done for a longer time and more often than any other organ, the patterns of response are called hyper- acute, acute, and chronic. In actual practice, however, there is often an overlap in features. The diagnosis is fur- ther complicated by the effects of immunosuppressant drugs or the possible recurrence of the original disease. Hyperacute Rejection Hyperacute rejection occurs almost immediately after transplantation. 3 In kidney transplants, it can often be seen at the time of surgery. As soon as blood flow from the recipient to the donor kidney begins, it takes on a cyanotic, mottled appearance. At other times, the reac- tion may take hours or days to develop. The hyperacute response is produced by existing recipient antibodies to graft antigens that initiate a type III, Arthus-type hypersensitivity reaction in the blood vessels of the graft. These antibodies usually have devel- oped in response to previous blood transfusions, preg- nancies in which the mother makes antibodies to fetal antigens, or infections with bacteria or viruses possess- ing antigens that mimic MHC antigens. Acute Rejection Acute rejection may occur within the first few days to weeks after transplantation, or it may occur suddenly Patterns and Mechanisms of Solid Organ Graft Rejection

SUMMARY CONCEPTS (continued)

antibody complexes and are responsible for vasculitis (as seen in systemic lupus erythematosus or acute glomerulonephritis), systemic immune complex disease (serum sickness), and local immune complex disease (Arthus reaction). ■■ Type IV cell-mediated hypersensitivity reactions include direct cell cytotoxicity, in which sensitized CD8 + T cells kill antigen-bearing target cells, and delayed-type hypersensitivity reactions, in which presensitized CD4 + T cells release cytokines that damage and kill antigen-containing cells.

Transplantation Immunopathology

Transplantation is the process of taking cells, tissues, or organs, called a graft, from one individual and placing them into another individual. Sometimes grafts are trans- planted from another site in the same individual. The indi- vidual who provided the tissue is called the donor, and the individual who receives the graft is called either the recipient or the host. Transplantation rejection is discussed here because it involves several of the previously discussed immunologic reactions. Amajor barrier to transplantation is the process of rejection, in which the recipient’s immune system recognizes the graft as foreign and attacks it. The cell surface antigens that determine whether the tis- sue of transplanted organs is recognized as foreign are the MHC or human leukocyte antigens (HLA) that were dis- cussed in Chapter 15. Transplanted tissue can be catego- rized as an autologous graft if the donor and recipient are the same person, syngeneic graft if the donor and recipient are identical twins, and allogeneic (genetic variations of the same gene within a given species) if the donor and recipi- ent—whether related or not—share similar HLA types. The molecules that are recognized as foreign on allografts are called alloantigens. Donors of solid organ transplants can be living or dead (cadaver) and related or nonrelated (heterologous). Rejection of allografts is a response to MHC molecules, which are so polymorphic that no two individuals are likely to express the same MHC molecules, unless they are identical twins. The likelihood of rejection varies indirectly with the degree of MHC or HLA related- ness between the donor and recipient. Immune Recognition of Allografts Rejection of allografts is a complex process that involves cell-mediated immunity and circulating antibodies. Although many cells may participate in the process of acute transplant rejection, only the T lymphocytes seem to be absolutely required. 1–3 The recipient’s T cells rec- ognize allogeneic antigens in the graft by two pathways: the direct and indirect recognition pathways. 2