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The ANoimmune Response and Allograft Rejection

Allograft rejection is conventionally divided into three syndromes according to the time of its occurrence; each of these has a different pathogenesis. Acute rejection may involve cellular or humoral mechanisms, although the former usually predominate. Pharmacological immunosuppression based on the calcineurin inhibitors has been effective in the control of acute cellular rejection, which is one of the most common problems early after organ transplantation, but it has had less impact on the other forms of rejection.

Hyperacute rejection was first described in renal transplantation (Williams et al. 1968; Patel and Terasaki 1969; Terasaki et al. 1971) and it has subsequently been recognised to occur in other types of transplant (Smith et al. 1993; Choi et al. 1999; Scornik et al. 1999). Preformed antibodies against antigens of either the ABO blood group system or human leukocyte antigens (HLA) bind to the endothelium of the allograft causing endothelial activation. This causes complement binding and intravascular coagulation which leads to the rapid destruction of the graft (Wu et al. 2003). This rapid form of rejection can be prevented by ABO matching between the recipient and donor and by screening transplant candidates for anti-HLA antibodies; those who have such antibodies must also undergo a lymphocytotoxic cross match against the donor before a transplant can be safely performed (Smith et al. 1993). When hyperacute rejection does occur, it requires specific treatment aimed at both the removal of the preformed antibodies and preventing the synthesis of further antibody (Bittner et al. 2001; Pierson et al. 2002).

Acute rejection typically first occurs within the first 3 months of transplantation but may occur later. It is predominantly a cellular process (Hall et al. 1978; Rosenberg et al. 1987) and is initiated by helper T cells which recognise either foreign HLA on the surface of cells within the graft (direct recognition) or antigens from the allograft which have been processed by antigen-presenting cells (APCs) of the host (indirect recognition) (Hornick and Lechler 1997). Direct recognition appears to be the most important mechanism in acute rejection. Thus, the T cell plays a central role in orchestrating the immune response to the allograft (Fig. 1) (Rose and Hutchinson 2003).

Fig. 1 Role of the helper T cell in orchestration the alloimmune response. Activation of CD4+ T cells results in Th1 or Th2 cells, production of their characteristic cytokine profiles and maturation of effector mechanisms. APC, antigen-presenting cell; MHC, major histocompatibility complex; IFN, interferon; TNF, tumour necrosis factor; iNOS inducible nitric oxide synthase; M0, macrophage; IL, interleukin. (Reproduced by permission from Rose et al. 2003)

Fig. 1 Role of the helper T cell in orchestration the alloimmune response. Activation of CD4+ T cells results in Th1 or Th2 cells, production of their characteristic cytokine profiles and maturation of effector mechanisms. APC, antigen-presenting cell; MHC, major histocompatibility complex; IFN, interferon; TNF, tumour necrosis factor; iNOS inducible nitric oxide synthase; M0, macrophage; IL, interleukin. (Reproduced by permission from Rose et al. 2003)

Antibody IFNy Cytotoxicity

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Antibody IFNy Cytotoxicity

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Fig. 2 Steps in the T cell activation cascade. Simplified model of the events which occur during T cell activation. The early, calcium-dependent, phase of activation begins when the T cell receptor (TCR) binds to a complementary MHC class II molecule with an associated peptide in its antigen-presentation grove 'Signal 1'. Full activation also requires a second signal ('Signal 2') which is caused by binding between complementary adhesion molecules on the surface of the antigen-presenting cell and the T cell. Signal transduction from the TCR occurs via the CD3 complex. Subsequent intracellular signalling involves the inositol triphosphate/diacylglycerol pathway and mobilisation of intracellular calcium. This leads to activation of the protein phosphatase calcineurin. Calcineurin dephos-phorylates the nuclear factor of activated T cells (NFAT) allowing its active moiety to translocate to the nucleus and so bind to the promoter regions of various genes encoding cytokines such as interleukin-2 (IL-2), regulatory proteins and the IL-2 receptor. The pattern of cytokine expression depends on the nature of the T cell (Th1 or Th2) and can lead to either recruitment of cytotoxic T cells and other effector cells or to the provision of help to B cells for antibody production. The expression of IL-2 leads to autocrine stimulation of the T cell. Binding of IL-2 to its receptor initiates a second sequence of intracellular signals involving the mammalian target of rapamycin (TOR) which leads to DNA synthesis and replication and which culminates in cell division. The sites of action of various immunosuppressive agents are shown. Polyclonal antithymocyte globulin is shown as binding to the common leukocyte antigen (CD45) although, in reality, it contains antibodies which bind to many different T cell antigens. Abbreviations: IL, interleukin; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T cells; TCR, T cell receptor; TOR, target of rapamycin; IFN, interferon. (Reproduced by permission from Banner and Lyster 2003)

Binding of the receptor of an alloreactive helper T cell to allogeneic HLA will, if coupled to a secondary signal caused by binding between adhesion molecules on the surface of the T cell and the APC, lead to activation of the T cell via a cascade of intracellular signals (Fig. 2) (Sayegh and Turka 1998). Once activated, alloreactive helper T cells act as a cytokine producing 'engine' which leads to amplification of the immune response through both cell division and the recruitment of other cells (Banner and Lyster 2003). T cells produce a series of cytokines including interleukin (IL)-2, IL-3, IL-4, tumour necrosis factor-a, granulocyte-macrophage colony-stimulating factor and interferon-g (Wiederrecht, Lam et al. 1993). The effector mechanisms which lead to the destruction of the graft include: the action of cytotoxic T cells which induce target cell necrosis in an MHC-restricted manner via molecules such as granzyme and perforin as well as by inducing apoptosis through the binding of Fas to Fas-ligand (Russell and Ley 2002); less-specific (i.e. non-MHC-restricted) cell killing will also occur by the recruitment of activated macrophages, natural killer cells and eosinophils (Adams and Hamilton 1984; Doody et al. 1994).

Acute humoral rejection is an antibody-mediated phenomenon that is less frequent than cellular rejection. It is caused by the production of antibody directed against antigens in the graft either de novo or as an anamnestic response leading to the resynthesis of a previously formed antibody. Antibody binding to the graft leads to complement-mediated injury with prominent vascular features (acute 'vascular' rejection) (Cherry et al. 1992; Bohmig et al. 2001; Feucht 2003). In severe rejection, cellular and humoral mechanisms often co-exist (Abe, Sawada et al. 2003). Once established, this type of rejection cannot be controlled by conventional immunosuppression based on the calcineurin inhibitors and requires additional specific treatment to remove the antibody and inhibit its resynthesis (Grandtnerova et al. 1995; Hickstein et al. 1998; Garrett et al. 2002).

Chronic rejection is a multifactorial process which is driven by both immune and non-immune mechanisms. Episodes of acute cellular rejection and the formation of alloreactive antibody as well as autoimmune antibodies against non-polymorphic antigens all appear to play a role (Rose and Hutchinson 2003). Immunosuppression based on calcineurin inhibitors has an indirect influence on these processes by reducing the incidence of acute rejection and reducing T cell help to B cells for de novo antibody synthesis. However, it has not overcome the problem of chronic rejection, which remains one of the commonest long-term complications of organ transplantation.

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