Transplantation Immunology CHAPTER 21 antigens on the graft, and( 2)an effector stage, in which im- Langerhans cells and endothelial cells lining the blood ves- mune destruction of the graft takes place sels. Both of these cell types express class I and class II MHC antigens. SENSITIZATION STAGE Recognition of the alloantigens expressed on the cells of During the sensitization phase, CD4+ and CD8+ T cells rec- a graft induces vigorous T-cell proliferation in the host. ognize alloantigens expressed on cells of the foreign graft This proliferation can be demonstrated in vitro in a and proliferate in response. Both major and minor histo- lymphocyte reaction(see Figure 21-4c). Both dendrit compatibility alloantigens can be recognized. In general, the and vascular endothelial cells from an allogeneic graft response to minor histocompatibility antigens is weak, al- host T-cell proliferation. The major proliferating cell is the though the combined response to several minor differences CD4* Tcell, which recognizes class Il alloantigens ectly can sometimes be quite vigorous. The response to major histo- alloantigen peptides presented by host antigen-presenting compatibility antigens involves recognition of both the donor cells. This amplified population of activated TH cells is MHC molecule and an associated peptide ligand in the cleft of thought to play a central role in inducing the various effector the MHc molecule. The peptides present in the groove of mechanisms of allograft rejection allogeneic class I MHC molecules are derived from proteins synthesized within the allogeneic cell. The peptides present EFFECTOR STAGE in the groove of allogeneic class II MHC molecules are gener- A variety of effector mechanisms participate in allograft re- ally proteins taken up and processed through the endocytic jection(Figure 21-6). The most common are cell-mediated athway of the allogeneic antigen-presenting cell reactions involving delayed-type hypersensitivity and ctl A host TH cell becomes activated when it interacts with an mediated cytotoxicity: less common mechanisms are antibody antigen-presenting cell(APC)that both expresses an appro- plus-complement lysis and destruction by antibody-dependent priate antigenic ligand-MHC molecule complex and pro cell-mediated cytotoxicity (ADCC). The hallmark of graft ides the requisite co-stimulatory signal. Depending on the rejection involving cell-mediated reactions is an influx of tissue, different populations of cells within a graft may func- T cells and macrophages into the graft. Histologically, the in- tion as APCs. Because dendritic cells are found in most tis- filtration in many cases resembles that seen during a delayed- sues and because they constitutively express high levels of type hypersensitive response, in which cytokines produced class II MHC molecules, dendritic cells generally serve as the by DTh cells promote macrophage infiltration(see Figure major APC in grafts. APCs of host origin can also migrate 14-15). Recognition of foreign class I alloantigens on the into a graft and endocytose the foreign alloantigens(both graft by host CD8 cells can lead to CTL-mediated killing(see major and minor histocompatibility molecules) and present Figure 14-4). In some cases, CD4 Tcells that function as class them as processed peptides together with self-MHC mole- II MHC-restricted cytotoxic cells mediate graft rejection. In each of these effector mechanisms, cytokines secreted In some organ and tissue grafts( e. g, grafts of kidney, thy. by TH cells play a central role(see Figure 21-6). For example, mus, and pancreatic islets), a population of donor APCs IL-2, IFN-Y, and TNF-s have each been shown to be impor- called passenger leukocytes has been shown to migrate from tant mediators of graft rejection. IL-2 promotes T-cell pro- the graft to the regional lymph nodes. These passenger leuko- liferation and generally is necessary for the generation of cytes are dendritic cells, which express high levels of class II effector CTls(see Figure 14-1). IFN-y is central to the devel MHC molecules( together with normal levels of class I MHc opment of a DTH response, promoting the influx of macro- molecules)and are widespread in mammalian tissues, with phages into the graft and their subsequent activation into the chief exception of the brain. Because passenger leuko- more destructive cells. TNF-B has been shown to have a di- cytes express the allogeneic MHC antigens of the donor graft, rect cytotoxic effect on the cells of a graft. A number of cyto- they are recognized as foreign and therefore can stimulate kines promote graft rejection by inducing expression of class immune activation of T lymphocytes in the lymph node. In Ior class II MHC molecules on graft cells. The interferons(a, some experimental situations, the passenger cells have been B, and Y), TNF-o and TNF-B all increase class I MHC ex- shown to induce tolerance to their surface antigens by dele- pression, and IFN-y increases class II MHC expression as tion of thymic T-cell populations with receptors specific for well. During a rejection episode the levels of these cytokines them. Consistent with the notion that exposure to donor increase, inducing a variety of cell types within the graft to cells can induce tolerance are data showing that blood tran- express class I or class II MHC molecules. In rat cardiac allo- fusions from the donor prior to tra grafts, for example, dendritic cells are initially the only cells ceptance of the graft that express class II MHC molecules. However, as an allograft Passenger leukocytes are not the only cells involved in im- reaction begins, localized production of IFN-y in the graft mune stimulation. For example, they do not seem to play any induces vascular endothelial cells and myocytes to express role in skin grafts. Other cell types that have been implicated class II MHC molecules as well, making these cells targets for in alloantigen presentation to the immune system include CTl attackantigens on the graft, and (2) an effector stage, in which im￾mune destruction of the graft takes place. SENSITIZATION STAGE During the sensitization phase, CD4+ and CD8+ T cells rec￾ognize alloantigens expressed on cells of the foreign graft and proliferate in response. Both major and minor histo￾compatibility alloantigens can be recognized. In general, the response to minor histocompatibility antigens is weak, al￾though the combined response to several minor differences can sometimes be quite vigorous. The response to major histo￾compatibility antigens involves recognition of both the donor MHC molecule and an associated peptide ligand in the cleft of the MHC molecule. The peptides present in the groove of allogeneic class I MHC molecules are derived from proteins synthesized within the allogeneic cell. The peptides present in the groove of allogeneic class II MHC molecules are gener￾ally proteins taken up and processed through the endocytic pathway of the allogeneic antigen-presenting cell. A host TH cell becomes activated when it interacts with an antigen-presenting cell (APC) that both expresses an appro￾priate antigenic ligand–MHC molecule complex and pro￾vides the requisite co-stimulatory signal. Depending on the tissue, different populations of cells within a graft may func￾tion as APCs. Because dendritic cells are found in most tis￾sues and because they constitutively express high levels of class II MHC molecules, dendritic cells generally serve as the major APC in grafts. APCs of host origin can also migrate into a graft and endocytose the foreign alloantigens (both major and minor histocompatibility molecules) and present them as processed peptides together with self-MHC mole￾cules. In some organ and tissue grafts (e.g., grafts of kidney, thy￾mus, and pancreatic islets), a population of donor APCs called passenger leukocytes has been shown to migrate from the graft to the regional lymph nodes. These passenger leuko￾cytes are dendritic cells, which express high levels of class II MHC molecules (together with normal levels of class I MHC molecules) and are widespread in mammalian tissues, with the chief exception of the brain. Because passenger leuko￾cytes express the allogeneic MHC antigens of the donor graft, they are recognized as foreign and therefore can stimulate immune activation of T lymphocytes in the lymph node. In some experimental situations, the passenger cells have been shown to induce tolerance to their surface antigens by dele￾tion of thymic T-cell populations with receptors specific for them. Consistent with the notion that exposure to donor cells can induce tolerance are data showing that blood tran￾fusions from the donor prior to transplantation can aid ac￾ceptance of the graft. Passenger leukocytes are not the only cells involved in im￾mune stimulation. For example, they do not seem to play any role in skin grafts. Other cell types that have been implicated in alloantigen presentation to the immune system include Langerhans cells and endothelial cells lining the blood ves￾sels. Both of these cell types express class I and class II MHC antigens. 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￾lymphocyte reaction (see Figure 21-4c). Both dendritic cells and vascular endothelial cells from an allogeneic graft induce host T-cell proliferation. The major proliferating cell is the CD4+ T cell, which recognizes class II alloantigens directly or alloantigen peptides presented by host antigen-presenting cells. This amplified population of activated TH cells is thought to play a central role in inducing the various effector mechanisms of allograft rejection. EFFECTOR STAGE A variety of effector mechanisms participate in allograft re￾jection (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 in￾filtration 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-, and TNF- have each been shown to be impor￾tant mediators of graft rejection. IL-2 promotes T-cell pro￾liferation and generally is necessary for the generation of effector CTLs (see Figure 14-1). IFN- is central to the devel￾opment of a DTH response, promoting the influx of macro￾phages into the graft and their subsequent activation into more destructive cells. TNF- has been shown to have a di￾rect 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 (, , and ), TNF-, and TNF- all increase class I MHC ex￾pression, and IFN- 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- in the graft induces vascular endothelial cells and myocytes to express class II MHC molecules as well, making these cells targets for CTL attack. Transplantation Immunology CHAPTER 21 487