In order to elicit antigraft immune responses, alloantigens from the graft are transported by dendritic cells to draining lymph nodes, where they are recognized by alloreactive T cells (Fig. 1). The dendritic cells that present alloantigens also provide costimulators and can stimulate helper T cells as well as alloreactive CTLs. The effector T cells that are generated circulate back to the transplant and mediate rejection.

Fig1. Immune response against transplants. Graft antigens that are expressed on donor dendritic cells or captured by recipient dendritic cells are transported to peripheral lymphoid organs where alloantigen-specific T cells are activated (the sensitization step). The T cells migrate back into the graft and destroy graft cells (rejection). Antibodies are also produced against graft antigens and can contribute to rejection (not shown). The example shown is that of a kidney graft, but the same general principles apply to all organ grafts.

T cells in allograft recipients may recognize unprocessed donor MHC molecules on the surface of graft cells, or they may recognize peptides derived from donor MHC molecules bound to recipient MHC molecules on the surface of recipient APCs (Fig. 2). These two pathways of presentation of graft antigens have different features and names.

Fig2. Direct and indirect recognition of alloantigens. A, Direct alloantigen recognition occurs when T cells bind directly to intact allogeneic major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs) in a graft, as illustrated in Fig. 10.8. B, Indirect alloantigen recognition occurs when allogeneic MHC molecules from graft cells are taken up and processed by recipient APCs, and peptide fragments of the allogeneic MHC molecules are presented by recipient (self) MHC molecules. Recipient APCs also may process and present graft proteins other than allogeneic MHC molecules.

• Direct allorecognition. Most tissues contain dendritic cells, and when the tissues are transplanted, the dendritic cells in the graft may migrate to secondary lymphoid organs of the recipient. When naïve T cells in the recipient recognize donor allogeneic MHC molecules on these graft-derived dendritic cells, the T cells are activated; this process is called direct recognition (or direct presentation) of alloantigens. Direct recognition stimulates the development of alloreactive T cells (e.g., CTLs) that can then directly recognize the allogeneic MHC molecules on cells of the graft and destroy the graft.

 • Indirect allorecognition. Graft cells (or alloantigens) may be ingested by recipient dendritic cells and transported to draining lymph nodes. Here, donor alloantigens are processed and presented by self MHC molecules on the recipient APCs. This process is called indirect recognition (or indirect presentation) and is similar to the cross-presentation of tumor antigens to CD8+ T cells, discussed earlier. If alloreactive CTLs are induced by the indirect path way, these CTLs are specific for donor alloantigens displayed by the recipient’s self MHC molecules on the recipient’s APCs, so they cannot recognize and kill cells in the graft (which, of course, express donor MHC molecules). When graft alloantigens are recognized by the indirect pathway, the subsequent rejection of the graft likely is mediated mainly by alloreactive CD4+ T cells. These T cells may enter the graft together with host APCs, recognize graft antigens that are picked up and displayed by those APCs, and secrete cytokines that injure the graft by an inflammatory reaction. Indirect allorecognition by host CD4+ T cells also contributes to stimulating production of host antibodies that bind to graft MHC molecules, as discussed later.

We do not know the relative importance of the direct and indirect pathways of allorecognition in T cell- mediated rejection of allografts. The direct pathway may be most important for CTL-mediated acute rejection, and the indirect pathway may play a greater role in chronic rejection, as described later.

T cell responses to allografts require costimulation, but which stimuli in grafts enhance the expression of costimulators on APCs is unclear. As with tumors, graft cells may undergo necrosis, perhaps in the period of ischemia before the transplant is done, and substances released from the injured and dead cells activate APCs by innate immune mechanisms. As we discuss later, blocking costimulation is one therapeutic strategy for promoting graft survival.

The mixed lymphocyte reaction (MLR) is an in vitro model of T cell recognition of alloantigens. In this model, T cells from one individual are cultured with leukocytes of another individual, and the responses of the T cells are assayed. The magnitude of this response is proportional to the extent of the MHC differences between these individuals and is a rough predictor of the outcomes of grafts exchanged between these individuals.

Although much of the emphasis on allograft rejection has been on the role of T cells, it is clear that alloantibodies also contribute to rejection. Most of these antibodies are helper T cell–dependent high-affinity antibodies. In order to produce alloantibodies, recipient B cells recognize donor alloantigens and then process and present peptides derived from these antigens to helper T cells (that may have been previously activated by recipient dendritic cells presenting the same donor alloantigen), thus initiating the process of antibody pro duction. This is a good example of indirect presentation of alloantigens, in this case by B lymphocytes. 

مواضيع ذات صلة

Immune Mechanisms of Graft Rejection

Transplantation Antigens

Glycans and Immunity

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens

Cancer Immunotherapy: Immune Checkpoint Blockade

Cancer Immunotherapy: Adoptive T Cell Therapy

Cancer Immunotherapy: Passive Immunotherapy With Monoclonal Antibodies

Evasion of Immune Responses by Tumors

PROCESS OF PHAGOCYTOSIS

GRANULOCYTIC CELLS

B Cell Epitope Binding Predictions