Graft Rejection Of The Kidney Transplant

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Graft Rejection Kidney Transplant

Graft Rejection Kidney Transplant


Until recently, most studies on the mechanisms of renal allograft rejection have focused on the central role of T cells and of other cellular mechanisms of tissue injury. Over the years, it has been established that CD4 T cells are crucial in initiating most acute rejection episodes, and that alloactivated CD4T cells, cytotoxic CD8T cells, monocytes/macrophages and NK cells play a major role in cell-mediated mechanisms that eventually result in allograft destruction1. These research efforts in the cellular immunity of organ transplantation have been illustrated in a recent study by Li y cols., in with measurement of urinary mRNA encoding perforin and granzyme B was used as a noninvasive means of diagnosing acute renal allograft rejection2. Perforin and granzyme B are two proteins that are present in the cytoplasmic granules of cytotoxic T cells and NK cells which are an integral part of the effector mechanisms of cellmediated allograft rejection.


In recent years, however, it has become increasingly appreciated that detection of anti-HLA donor specific antibodies (DSA) de novo after transplantation is associated with specific «humoral syndromes» which are due predominantly, or in part, to antibodymediated effector mechanisms of tissue injury. The identification of the complement fragment C4d as a specific marker for humoral rejection in peritubular capillaries of renal allograft biopsies has helped to define and characterize these syndromes, which we have recently termed acute humoral rejection (AHR) and chronic humoral rejection (CHR)3-7. In this article, the three different clinical settings in which humoral immunity appears to play an important role in clinical kidney transplantation are reviewed. In addition, new therapeutic approaches to control the production or the detrimental consequences of alloantibodies are discussed in the light of our recent studies and those of others.

Hyperacute Rejection

The rejection of an allograft within minutes to hours after transplantation is termed «hyperacute rejection» (HAR). HAR is generally mediated purely by humoral mechanisms, that is by the binding of recipient's DSA to the donor graft vasculature which triggers complement activation. Both preformed DSA to HLA antigens or anti-ABO isohemagglutinins can result in «hyperacute rejection»8, 9. Preformed anti-HLA DSA have generally been induced by previous exposure to alloantigens through prior transplantations, pregnancies or multiple blood transfusions10. Anti-ABO blood group natural antibodies are present in recipients who receive a blood group-incompatible transplant 11. The detrimental effect of preformed DSA became apparent in the 1960s. In the presence of pre-existing DSA («positive crossmatch» at the time of renal transplantation), hyperacute destruction of grafted kidneys occurred almost inevitably8, 9. The histopathologic findings of HAR revealed intense neutro- philic infiltrate, edema, focal interstitial hemorrhage and thrombosis, and fibrin thrombi in capillaires associated in some cases with fibrinoid necrosis of small arteries. Importantly, the absence of a mononuclear cell infiltrate indicated that HAR was not due to cellmediated immunity.

This initial experience stimulated the requirement for demonstration of a pre-transplant «negative» crossmatch and, in most centers, ABO compatibility to perform kidney transplantation12, ...
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