Graft Rejection
المؤلف:
Mary Louise Turgeon
المصدر:
Immunology & Serology in Laboratory Medicine
الجزء والصفحة:
5th E, P449-450
2025-10-30
49
Organs vary with respect to their susceptibility to rejection based on inherent immunogenicity (Box 1), which is influenced by factors such as vascularity.
Box1. Immunogenicity of Different Transplant Tissues
The role of sensitized lymphocytes and antibodies in graft rejection differs and is influenced by the type of organ trans planted. Lymphocytes, particularly recirculating small lymphocytes, are effective in shortening graft survival. Cell-mediated immunity is responsible for the rejection of skin and solid tumors. However, humoral antibodies can also be involved in the rejection process. The complexity of the action and interaction of cellular and humoral factors in grafts is considerable. Five possible categories of graft rejection have been demonstrated in human kidney transplant rejection—hyperacute, accelerated, acute, chronic, and immunopathologic (Table 1).
Table1. Categories and Characteristics of Graft Rejection Based on Immune Destruction of Kidney Grafts
First-Set and Second-Set Rejections
Skin transplantation is the most common experimental model for transplantation research (Fig. 1). Rejection of skin and solid tumors can be divided into first-set and second-set rejections. Activation of cellular immunity by T cells is the predominant cause of the first-set allograft rejection. Lymphocytes can directly attack cellular antigens to which they are sensitized by previous exposure or by cytotoxic lymphokines. The primary role of lymphocytes in first-set rejection is consistent with the histology of early reaction and shows infiltration by mononuclear cells, with very few polymorphonuclear leukocytes or plasma cells. Sensitization occurs within the first few days of transplantation, and the tissue is lost in 10 to 20 days.
Fig1. Hyperacute rejection results from placement of tissue in an animal already possessing antibodies to antigens of grafted tis sue. Second-set rejection is an accelerated first-set reaction and is seen in animals that have already rejected tissue at least once. (Adapted from Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)
When sensitized lymphocytes are already present because of prior graft rejection, an accelerated rejection of tissue results from regrafting, called second-set rejection. Lymphocytes from a sensitized animal transferred to a first-graft recipient will accelerate rejection of the graft. Graft rejection is primarily a T cell function, with some assistance from antibodies.
Hyperacute Rejection
Hyperacute reactions are caused entirely by the presence of preformed humoral antibodies in the host, which react with donor tissue cellular antigens. These antibodies are usually anti-A–related or anti-B–related antibodies to the ABO blood group systems or antibodies to class I MHC antigens (hyper sensitivity type II). Potential recipients harboring antibodies to HLA-A, HLA-B, and HLA-C (class I) but not HLA-DR (class II) antigens are at high risk for this process.
The interaction of cellular antigens with antibodies activates the complement system and leads to grafted cell lysis and clot ting in the grafted tissue. Kidney allografts can be rejected by the hyperacute rejection process within minutes of transplantation. The irreversible kidney damage of hyperacute rejection is characterized by sludging of erythrocytes, development of microthrombi in the small arterioles and glomerular capillaries, and infiltration of phagocytic cells.
Genetically altered pig organs could be available for trans plantation into human beings within 2 years, but it is likely to be at least 5 years before full-scale studies can begin. Future xenotransplantation will depend on overcoming problems of hyperacute rejection. In hyperacute rejection, the recipient of the organ produces xenoreactive antibodies, which lodge on the cells lining the blood vessels of the new organ and trigger the release of complement. This release triggers inflammation, swelling, and ultimately blockage of the blood vessels, leading to death of the organ.
Accelerated Rejection
Accelerated rejection is comparable to the second-set rejection phenomenon observed in animal models. In these cases, retransplantation is less severe than hyperacute rejection and is considered to be accelerated rejection. Accelerated rejection is caused by activation of the T cell–mediated response.
Acute Rejection
Acute rejection can result after the first exposure to alloantigens. In this reaction, donor antigens select reactive T cell clones and initiate visible manifestation of rejection within 6 to 14 days. The early processes in acute rejection appear to be T cell–mediated; however, later aspects may involve antibodies and complement.
Acute rejection is equivalent to a first-set allograft rejection in experimental animals and is primarily mediated by cells, as in accelerated rejection. Immunopathologic changes include the presence of immune complex deposition and other hyper sensitivity reactions already present in the recipient.
Acute rejection takes place when there is HLA incompatibility. Recipient T cells can respond to donor peptides presented by a recipient MHC or to donor MHC molecules themselves. The better the HLA match, the more successful are the prospects for nonrejection. Because of the shortage of organs and the huge demand for organs, partially mismatched organs (e.g., kidneys) may be used. The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci. Despite mismatching, 1-year survival with five mismatches was almost 80% because of the effect of potent immunosuppressive drugs.
A recipient may respond to minor histocompatibility antigens. Minor antigens are encoded by genes outside the HLA. These minor histocompatibility antigen mismatches are not detected by standard tissue typing techniques but may cause rejection despite a good HLA match. Up to one third of transplants can be rejected because of minor antigens.
Acute early rejection, which occurs up to about 10 days after transplantation, is histologically characterized by dense cellular infiltration and rupture of peritubular capillaries. It appears to be a cell-mediated hypersensitivity reaction involving T cells. In comparison, acute late rejection occurs 11 days or more after transplantation in patients suppressed with prednisone and azathioprine. In kidney allografts, acute late rejection is probably caused by the binding of immunoglobulin, presumably antibody and complement, to the arterioles and glomerular capillaries, where they can be visualized by immunofluorescent techniques. These immunoglobulin deposits on the vessel walls include platelet aggregates in glomerular capillaries, which cause acute renal shutdown. The possibility of damage to antibody-coated cells through antibody-dependent, cell-mediated cytotoxicity (ADCC) may also take place.
Chronic Rejection
Chronic rejection occurs in most graft recipients. The process results in a slow but continual loss of organ function over months or years. However, chronic rejection is often responsive to various immunosuppressive therapies.
In kidney allografts, this insidious rejection is associated with subendothelial deposits of immunoglobulin and the C3 component of complement on the glomerular basement mem branes. This may occasionally be an expression of an underlying immune complex disorder that may have originally necessitated the transplantation, or it may result from complex formation with soluble antigens derived from the grafted kidney.
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