Target Injury

Candidate Mechanisms of Specific Donor Cell Injury in Rejection

The hallmark of acute T-cell mediated rejection is injury to the endothelial and parenchymal cells, initially reversible, but eventually becoming irreversible and proceeding to infarction. Inflammation is probably necessary but not sufficient for rejection injury. The parenchymal injury is usually conceptualized as apoptosis of individual parenchymal cells triggered by cytotoxic T cells. Many cytokines such as TNF-a are expressed in rejecting or inflamed grafts,178 but no single cytokine has been shown to mediate rejection injury. Understanding of what constitutes rejection injury should begin with the pathology, not with immuno-logic theory.

The Pathology of Acute Rejection

International collaborations have classified the histologic lesions which correlate with rejection.196,197 Classifications are all based on the concept that donor cell injury, not the inflammatory infiltrate or interstitial edema, defines rejection. Thus tubulitis in kidney transplants, myocyte necrosis in heart transplants, injury to the biliary epithelium of liver transplants, and injury to the epithelium of small airways in lung transplants, constitute rejection. In general, areas of high MHC class I and II expression, either basal or inducible, are important targets of acute rejection.

Tubulitis in renal transplants refers to invasion by lymphocytes which cross the basement membrane and attack the basolateral membrane of the epithelial cells, where MHC products are expressed (Fig. 1.6). Bile ductule invasion, damage to small airway epithelium, and myocyte necrosis probably involve analogous mechanisms. The lymphocytes are believed to be T cells expressing cytotoxic molecules, but more details on the cells in these lesions are needed.

The endothelium of small arteries and arterioles in all types of grafts is damaged in the lesion known as intimal arteritis or endothelialitis. (Such lesions are often missed in biopsies: for example, endomyocardial biopsies of rejecting heart transplants are relatively poor at sampling arteries.) Lymphocytes adhere to the endothelium, infiltrate beneath it and lift up the endothelial cells. The result is increased resistance, perhaps due to loss of endothelial regulation of vasomotion, increased coagulation, and eventual loss of perfusion and downstream ischemia.

Tubulitis in a renal transplant


Fig. 1.6. Acute tubulitis. Lymphocytes infiltrate through the basement membrane and recognize alloantigens expressed on the MHC of graft epithelial cells and mediate cell death via apoptosis or cell lysis.


Fig. 1.6. Acute tubulitis. Lymphocytes infiltrate through the basement membrane and recognize alloantigens expressed on the MHC of graft epithelial cells and mediate cell death via apoptosis or cell lysis.

The candidate mediators of specific cell injury include cytokines, Fas and granule contents (serine esterases and perforins), both concentrated on the target cell by receptor directed exocytosis, and in some cases cytotoxic alloantibody. Serine esterases are expressed in the infiltrate of rejecting grafts.198 At least some of the injured graft cells probably die by apoptosis. Numerous cytokines are found in the infiltrate of rejecting grafts or in the serum, but the roles of these mediators are not established. Some may cause injury, but some may reflect the response to injured tissue. Both CD4 and CD8 T cells are present in rejection and neither has an exclusive role.199

There are nonspecific as well as alloantigen-specific lymphocytes in the cellular infiltrate. Macrophages are abundant within rejecting grafts and may play a role in the immune injury. Macrophages make a wealth of cytokines, growth factors, eicosanoids, enzymes, procoagulant activities, NO, etc, and may contribute to the parenchymal and endothelial cell injury and dysfunction in vascularized grafts. But the majority of early injury is probably due to specific T cells.

The Role of Antibody in Acute Rejection

Alloantibody can play a major role in acute transplant rejection, especially in the increasing population of recipients sensitized to MHC antigens. EC are important targets for alloantibody. The sequence of events in antibody-mediated rejection seems to involve endothelial dysfunction and injury, via complement and neutrophils, followed by vasospasm, ischemic injury, fibrin and/or platelet deposition, and infarction or hemorrhage.

Hyperacute rejection is predominantly a problem in renal transplantation, mediated by preformed antibodies against HLA class I molecules or by antibodies such as ABO blood group antigens.15 A population of antibodies against poorly defined endothelial antigens of arteries ("anti-endothelial antibodies") also mediates hyperacute and accelerated rejection.200 Anti-class II antibodies rarely mediate hyperacute rejection. A positive B-cell crossmatch is frequently due to antibodies which are not class II specific. For example, antibodies against B cells are often autoantibodies. Low levels of anti-class I can also produce a positive B-cell crossmatch with a negative T cell crossmatch because B cells are relatively rich in class I. Thus a positive B-cell crossmatch may have several explanations.

Successful immunosuppressive strategies usually suppress primary alloantibody as well as T cell responses, probably by suspending help from CD4 T cells, but do little to preformed antibody and may have difficulty suppressing secondary antibody responses.

Anti-class I-mediated rejection of kidney transplants can be recognized clinically.201,202 Typically a transplant into a presensitized patient with a negative crossmatch functions initially, then suddenly loses function after 1-7 days. The kidney may rapidly develop acute tubular necrosis secondary to severe decrease of perfusion. The pathology shows evidence of endothelial injury in the microcirculation, rather than tubulitis or endothelialitis. Neutrophils may be present. The demonstration of antibody against donor class I can aid the diagnosis. OKT3 can sometimes suppress this rejection by abrogating T-cell help. Anti-class I-mediated acute rejection of the heart may also occur.

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