Allografts are rejected by a process called allograft reaction. Graft rejection is the consequence of an immune response mounted by the recipient against the graft as a consequence of the incompatibility between tissue antigens of the donor and recipient.
The problem of rejection was first recognized when attempts to replace damaged skin on burn patients with skin from unrelated donors were found to be relatively unsuccess-ful. During a period of 1–2 weeks, the skin would undergo necrosis and peel off. The failure of such grafts led scientists like Peter Medawar and many others to study skin transplanta-tion in animal models. These experiments established that the failure of skin grafting was caused by an inflammatory reac-tion, now called as rejection. Results of several experimental studies imply that adaptive immune response is responsible for rejection.
Recognition of transplanted cells as self or foreign is deter-mined by polymorphic genes that are inherited from both parents and are expressed codominantly. MHC molecules are responsible for almost all strong rejection reactions. The rejec-tion reactions are mediated by T cells. Both CD4 and CD8 cells coordinate to bring about an effective and pronounced rejec-tion reaction. Nude mice, which lack a thymus, are incapable of launching an allogeneic immune response.
Histocompatibility is tissue compatibility as demonstrated in the transplantation of tissues or organs from one member to another of the same species (an allograft), or from one species to another (a xenograft).
The greater the match between donor and recipient, the more likely the transplant is to survive. For example, a six-antigen match implies sharing of two HLA-A antigens, two HLA-B anti-gens, and two HLA-DR antigens between donor and recipient. Even though antigenically dissimilar grafts may survive when a strong immunosuppressive drug, such as cyclosporine, is used; the longevity of the graft is still improved by having as many antigenic match as possible.
Allogeneic MHC molecules are presented for recognition by the T cells of a graft recipient in two distinctly different ways: (a) direct presentation and (b) indirect presentation.
Direct recognition of foreign MHC molecules is a cross-reaction of a normal T-cell receptor, which is selected to recog-nize a self-MHC molecule and foreign peptide, with an allogeneic MHC molecule and peptide. This is because an allogeneic MHC molecule with a bound peptide can mimic the determinant formed by a self-MHC molecule and a particular foreign peptide.
As many as 2% of an individual’s T cells are capable of recogniz-ing and responding to a single foreign MHC molecule, and this high frequency of T cells reactive with allogeneic MHC molecules is one reason that allografts elicit strong immune responses in vivo.
Indirect presentation: The “indirect presentation” involvesthe recognition of processed allogeneic MHC molecules but not an intact MHC molecule. It involves processing of donor MHC molecules by recipient APCs and presentation of derived pep-tides from the allogeneic MHC molecules in association with self-MHC molecules. Here the processed MHC molecules are recognized by T cells like conventional foreign protein antigens. Indirect presentation may result in allorecognition by CD4 T cells. This is because alloantigen is acquired primarily through the endosomal vesicular pathway and is therefore presented by class II MHC molecules. Some antigens of phagocytosed graft cells appear to enter the class I MHC pathway of antigen presen-tation and are indirectly recognized by CD8 T cells.
Cell-mediated graft rejection could occur in two stages:
I. A sensitization phase, in which antigen-reactive lympho-cytes of the recipient proliferate in response to alloantigens on the graft and
II. An effector stage, in which immune destruction of the graft takes place.
Recognition of the alloantigens expressed on the cells of a graft induces vigorous T-cell proliferation in the host. This proliferation can be demonstrated in vitro in a mixed lympho-cyte reaction. Both dendritic cells and vascular endothelial cells from an allogeneic graft induce host T-cell proliferation. The CD4 T cell is the major proliferating cell that recognizes class II alloantigens directly or alloantigen peptides presented by host APCs. This amplified population of activated TH cells is believed to play a key role in inducing the various effector mechanisms of allograft rejection.
· The most common are cell-mediated reactions involving delayed-type hypersensitivity and cytotoxic T lymphocyte (CTL)-mediated cytotoxicity.
· Less common mechanisms are antibody plus complement lysis and destruction by antibody-dependent cell-mediated cytotoxicity (ADCC).
An influx of T cells and macrophages into the graft is the hallmark of graft rejection involving cell-mediated reactions. Histologically, the infiltration in many cases resembles that seen during a delayed-type hypersensitive response, in which cytokines produced by TD and TH cells promote macrophage infiltration. Recognition of foreign class I alloantigens on the graft by host CD8 cells results in CTL-mediated killing. In some cases, CD4 T cells that function as class II MHC-restrict cytotoxic cells mediate graft rejection.
Rejection episodes, based primarily on the time elapsed between transplantation and the rejection episode, are traditionally classified as (a) hyperacute, (b) acute, and (c) chronic rejections.
Once the antibodies bind to the transplanted tissues, rejection can be caused either (a) by activation of the complement system, which results in the chemotactic attraction of granulocytes and the triggering of inflammatory circuits, or (b) by ADCC.
Pathological features of hyperacute rejection are following
· This is associated with the formation of massive intravascu-lar platelet aggregates leading to thrombosis, ischemia, and necrosis.
· The hyperacute rejection episodes are irreversible and invariably results in graft loss. With proper cross-matching techniques, this type of rejection is almost 100% avoidable.
· The hyperacute rejection by antibodies to all human cellular antigens is the major limitation of xenogeneic transplanta-tion (e.g., pig to human).
· When acute rejection takes place in the first few days after grafting, it may correspond to a secondary (second set) immune response. This indicates that the patient had been previously sensitized to the HLA antigens present in the organ donor (as a consequence of a previous transplant, pregnancy, or blood transfusions).
· When graft rejection occurs first week after grafting, it usually corresponds to a first-set (primary) response. Up to 70% of graft recipients experience one or more acute rejection episodes.
Acute rejection is predominantly mediated by T lymphocytes. CD4 helper T lymphocytes are believed to play the key role in acute rejection of the graft. This is because they release growth factors like IL-2 and IL-4 for the promotion of clonal expansion of CD8 lymphocytes and B cells.
In rejected organs, the cellular infiltrates contain mostly monocytes and T lymphocytes of both helper and cyto-toxic phenotypes, and lesser numbers of B lymphocytes, NK (natural killer) cells, neutrophils, and eosinophils. All these cells have the potential to play significant roles in the rejection process. The initial diagnosis of acute rejection is usually based on clinical suspicion:
· Functional deterioration of the grafted organ is the main basis for considering the diagnosis of acute rejection.
· Confirmation usually requires a biopsy of the grafted organ.
· Mononuclear cell infiltration in tissues of rejected graft tissue is characteristic finding.
· The measurement of cytokines (such as IL-2) in serum and in urine (in the case of renal transplants) is another diagnos-tic approach.
In most cases, acute rejection, if detected early, can be reversed by increasing the dose of immunosuppressive agents or by briefly administering additional immunosuppressants.