IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 27. Transplantation and Rejection

DYNAMICS OF REJECTION

The speed of graft rejection depends partly on The Nature of the effector mechanisms (Fig. 27.12).

Class="center">

Fig. 27.12. The rate at which graft damage develops reflects the underlying rejection mechanism. Preformed Antibodies and presensitized lymphocytes induce much faster rejection compared with a primary, slower-developing response.

Hyperacute rejection. This type of rejection occurs extremely rapidly and is observed in patients whose Blood serum already contains antibodies directed against the graft. Anti-HLA antibodies are typically induced by prior blood transfusions, multiple pregnancies, or the rejection of previously transplanted Tissues. In addition, antibodies against ABO Blood Group Antigens can trigger hyperacute rejection. These preformed antibodies fix Complement, damaging the endothelial Cells lining the inner surface of Blood Vessels. As a result, the vascular wall becomes permeable to plasma and cells, leading to platelet aggregation and microcirculatory failure that cuts off the graft's blood supply (Fig. 27.13). To prevent hyperacute rejection, donor-recipient ABO compatibility must be strictly maintained, and crossmatching must be performed to detect cytotoxic anti-donor antibodies in the prospective recipient's serum.

Because of hyperacute rejection, cross-species organ transplantation from animals to humans is currently impossible, as humans possess natural IgM and IgG antibodies against animal cellular antigens. Intensive research is underway to find ways to prevent this response. Potential approaches include antibody depletion, complement exhaustion, or Introduction/32.html">Genetic Engineering OF source animals to produce Organs less susceptible to hyperacute rejection.

Fig. 27.13. Histology of hyperacute renal graft rejection. There is extensive Necrosis of the glomerular capillaries accompanied by marked interstitial Hemorrhage. The necrosis is preceded by heavy infiltration of the tissue by polymorphonuclear leukocytes, occurring within the first hour of graft revascularization. This photomicrograph shows changes developing 24–48 h later. H&E stain, ×200.

Acute rejection. This manifests days to weeks post-transplantation and is primarily driven by T-Cell activation followed by the deployment of various effector mechanisms (Figs. 27.14–27.16). When a transplant is performed in a patient presensitized to graft antigens, a secondary T-cell activation occurs, resulting in accelerated cell-mediated rejection. This accelerated response is particularly dramatic in Skin grafts (the "white graft" reaction), where the tissue is destroyed before vascularization can even begin (see Fig. 27.18).

Fig. 27.14. Skin sections from Strain A mice: normal animals (1) and skin grafts at 5 (2) and 12 (3) days post-transplantation onto CBA strain mice. By day 5, substantial infiltration (I) of the graft area by host mononuclear cells is evident. By day 12, the epithelium is completely destroyed and detached from the dermis, which is now devoid of cells; the infiltrating host cells have died from anoxia, although intense cellular migration is still visible in the graft bed between the dermis and the thin Muscle layer (panniculus carnosus). (Photomicrographs kindly provided by Prof. L. Brent.)

Fig. 27.15. Histology of acute renal graft rejection - I. Clusters of small lymphocytes and other cells within the graft interstitium. This cellular infiltration (I) is characteristic of acute rejection and appears before any clinical signs manifest. (G – glomerulus.) H&E stain, ×200.

Fig. 27.16. Histology of acute renal graft rejection - II. The left section shows vascular occlusion (V) (H&E stain), and the right section shows the end-stage of this process (van Gieson stain). (G – glomerulus.) ×140.

Fig. 27.17. Endothelial activation triggered by an immune reaction or viral infection leads to the release of various growth factors. Among these, TGF-$eta$ is particularly important as it drives graft fibrosis and contributes to The Development of arteriosclerosis. The obliteration of blood vessels supplying the graft occurs through the migration of intimal smooth muscle cells into the vessel wall, their proliferation, and the deposition of matrix components. A progressive reduction in the Blood supply to the graft tissues leads to fibrosis, clinically manifested as a gradual loss of graft function.

Fig. 27.18. The pattern of graft rejection depends on the development of immunological memory. A human skin allograft 5 days post-transplantation (1) is fully vascularized with actively dividing cells, but by 12 days (2) it is completely destroyed. A second ("second-set") graft from the same donor (shown here at 7 days post-transplantation) fails to vascularize and is rapidly destroyed (3). This demonstrates the establishment of immunological memory resulting from sensitization by the antigens of the first graft.

Chronic rejection. Given certain genetic disparities between donor and recipient and under the coverage of immunosuppressive therapy, graft rejection can unfold as a slow process spanning months or years. In this scenario, the walls of the graft vessels thicken progressively until their lumens are completely occluded. This chronic rejection can stem from multiple causes, such as a low-grade cell-mediated rejection response or the deposition of antibodies and antigen–antibody complexes within the transplanted tissue, leading to vascular endothelial cell damage or activation followed by inadequate tissue repair.

Chronic rejection is characterized by two major hallmarks: vascular obliteration (occlusion of graft vessels by proliferating smooth muscle cells migrating from the vessel wall, combined with Extracellular matrix protein deposits) and interstitial fibrosis (diffuse scar tissue formation within the graft). These processes are regulated by various growth factors, such as transforming growth factor $eta$ (TGF-$eta$), released as a consequence of immune-mediated or Other forms of graft injury (see Fig. 27.17). The half-life of a transplanted Kidney currently remains only 7–8 years, and no significant extension of this timeframe has been achieved over the past decade, despite the introduction of newer agents like cyclosporin A to manage acute rejection. There remains an urgent, unmet need for novel immunosuppressive agents to combat chronic graft rejection.

Damage to a transplanted organ can also arise from a recurrence of the original disease that necessitated the transplantation in the first place.