Effector Stage

A variety of effector mechanisms participate in allograft rejection (Figure 21-6). The most common are cell-mediated reactions involving delayed-type hypersensitivity and CTL-mediated cytotoxicity; less common mechanisms are antibody-plus-complement lysis and destruction by antibody-dependent cell-mediated cytotoxicity (ADCC). The hallmark of graft rejection involving cell-mediated reactions is an influx of T cells and macrophages into the graft. Histologically, the infiltration in many cases resembles that seen during a delayed-type hypersensitive response, in which cytokines produced by Tdth cells promote macrophage infiltration (see Figure 14-15). Recognition of foreign class I alloantigens on the graft by host CD8+ cells can lead to CTL-mediated killing (see Figure 14-4). In some cases, CD4+ T cells that function as class II MHC-restricted cytotoxic cells mediate graft rejection.

In each of these effector mechanisms, cytokines secreted by Th cells play a central role (see Figure 21-6). For example, IL-2, IFN-7, and TNF-p have each been shown to be important mediators of graft rejection. IL-2 promotes T-cell proliferation and generally is necessary for the generation of effector CTLs (see Figure 14-1). IFN-7 is central to the development of a DTH response, promoting the influx of macrophages into the graft and their subsequent activation into more destructive cells. TNF-p has been shown to have a direct cytotoxic effect on the cells of a graft. A number of cyto-kines promote graft rejection by inducing expression of class I or class II MHC molecules on graft cells. The interferons (a, p, and 7), TNF-a, and TNF-p all increase class I MHC expression, and IFN-7 increases class II MHC expression as well. During a rejection episode, the levels of these cytokines increase, inducing a variety of cell types within the graft to express class I or class II MHC molecules. In rat cardiac allo-grafts, for example, dendritic cells are initially the only cells that express class II MHC molecules. However, as an allograft reaction begins, localized production of IFN-7 in the graft induces vascular endothelial cells and myocytes to express class II MHC molecules as well, making these cells targets for CTL attack.

Effector Stage
FIGURE 21-6

Effector mechanisms (purple blocks) involved in allograft rejection. The generation or activity of various effector cells depends directly or indirectly on cytokines (blue) secreted by activated Th cells. ADCC = antibody-dependent cell-mediated cytotoxicity.

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