Basic Immunobiology of Kidney Allograft Rejection

Donor's MHC Molecules as a Main Target of Recipient Immune System

Histocompatibility molecules are encoded by an array of genes on chromosome 6 and now completely sequenced. A consortium of laboratories has determined the sequence of 3,673,800 nucleotides on chromosome 6 that encode the genes of the MHC [1]. MHC class 1 molecules consist of a transmembrane protein that is noncovalently attached to a molecule of b-2 microglobulin and a short peptide. MHC class 1 molecules are encoded by three loci: HLA-A, HLA-B, and HLA-C. They are expressed at the surface of almost all the cells of the body (except for red blood cells and the cells of the central nervous system). Class 2 molecules consist of two transmembrane polypeptides. They are represented by alpha (a) chain and beta (b) chain. The a and b chains are encoded by clusters of loci in the region of chromosome 6 designated HLA-D. In contrast to MHC class 1 molecules, MHC class 2 molecules are not as widely expressed in the body. However, cells at the site of inflammation strongly express MHC class 2 molecules and provide a powerful stimulus to the immune system. The core function of MHC molecules is to "present" antigenic peptides to the T cells of the immune system. The peptides— usually about nine amino acids long—are bound by noncovalent forces in the a groove at the surface of the MHC molecule.

Alloantigen Recognition

Transplanted organs express donor MHC molecules, resulting in two pathways of antigen recognition (allorecog-nition) by T cells: direct and indirect. Allorecognition refers to T cell recognition of genetically encoded polymorphisms between members of the same species. The primary targets of the immune response to allogeneic tissues are MHC molecules on donor cells. Direct and indirect pathways of T-cell allorecognition are mediated by different antigen-presenting cells (APCs), and their cellular mechanisms are distinct. The direct pathway consists of recipient T cells recognizing intact donor MHC molecules expressed on donor cells. Allorecognition via the indirect pathway requires that recipient APCs process the donor-MHC antigens before presenting them to recipient T cells. The direct pathway is more closely associated with acute allograft rejection, and the indirect pathway with chronic rejection. Transplantation of a vascular organ induces MHC sensitization by direct stimulation of circulating host immune cells that encounter donor MHC antigens on allograft cell surfaces.

T-Cell Activation

T-cell activation is essential for allograft rejection. T-cell activation is associated with nuclear translocation of specific transcription factors that regulate expression of genes critical for T-cell function. NF-kB plays the central role in this process. The activation of T cells is a key start mechanism of immune response and requires two distinct, but synergis-tic, signals. The first signal is provided by a specific antigen and is delivered via the T-cell receptor. The second signal (costimulatory signal) is not antigen specific. Indeed, many T-cell molecules may serve as receptors for costimulation. The most well characterized costimulatory molecule is CD28, which has two ligands (B7-1 [CD80] and B7-2 [CD86]) that are expressed primarily on APCs. Another molecule, CTLA-4, is similar to CD28 and is also expressed on T cells. Although CTLA-4 binds B7-1 and B7-2, it transmits an inhibitory signal that serves to terminate the immune response.

Cellular and Humoral Mechanisms of Allograft Rejection

One or more attacks of acute cellular (Figure 1) or humoral (antibody-mediated) rejection (Figure 2) usually occur in almost half of the kidney transplant recipients despite active immunosuppressive strategies. Until recently, most studies on the mechanisms of renal allograft rejection have focused on the central role of T cells and of other cellular mechanisms of tissue injury. It has been established that CD4 T cells are crucial in initiating most acute rejection episodes, and that alloactivated CD4 T cells, cytotoxic CD8 T cells, monocytes/macrophages, and NK (natural killer) cells play a major role in cell-mediated mechanisms that eventually result in allograft destruction. Perforin and

Endothelial Graft Rejection
Figure 1 Acute cellular rejection. Lymphocytes (L) infiltrate beneath endothelium (E) with edema of intima (I) and subintimal layers (B). (H x E, original magnification 100x.) (see color insert)
Figure 2 Acute humoral rejection. Fibrinoid necrosis (N) of the thickened arterial wall surrounded by polymorphonuclear and lymphoid cell infiltrates (L). (H x E, original magnification 400x.) (see color insert)

granzyme B are two proteins that are present in the cytoplasmic granules of cytotoxic T cells and NK, cells which are an integral part of the effector mechanisms of cellmediated allograft rejection. In recent years, it has also become increasingly appreciated that detection of anti-MHC donor specific antibodies (DSA) de novo after transplantation is associated with rejection due to antibody-mediated effector mechanisms of tissue injury. The identification of the complement fragment C4d as a specific marker for humoral rejection in peritubular capillaries (PTCs) of renal allograft biopsies has helped to define and characterize these syndromes.

Cytokines and Cell Adhesion Molecules in Transplant Immunity

Cytokines are any of numerous low-molecular-weight proteins that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells. A diversity of cytokines, each with many functions, is involved in an immune response. While IL-12 facilitates differentiation towards the Th1 phenotype and IL-4 towards the Th2 phenotype, other cytokines such as INF-8 and IL-2 secreted by the Th1 cells promote cell-mediated immune responses, and IL-4, IL-6, and IL-7 released by Th2 cells are important in B cell maturation. IL-2 and IFN-g play crucial roles in graft rejection. They are important for recruitment, activation, and proliferation of various leukocytes, for the induction or upregulation of cell adhesion molecules and MHC molecules, and for mediating communication between leukocytes and parenchymal cells. Therefore, IL-2 has been studied as a potential target for suppression of graft rejection. The complexity of the cytokine network, particularly the plethora of cytokines and their overlapping functions, is a major obstacle in achieving this objective.

Cell adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion

Table I The Role of Some Cytokines and Chemoattractive Molecules in Renal Transplant Rejection.

Cytokine

Function in allograft rejection

IL-1

Causes neointimal formation and pathogenesis of chronic rejection

IL-2

Enhances all types of allograft rejection

IL-4

Promotes a delay in vasculopathy in the graft

IL-5

Mediates transplant vasculopathy

IL-10

Prevents ischemia-reperfusion injury and decreases acute rejection

IL-15

Activates allospecific CD8 T cells during acute rejection

IL-16

Plays an activation role rather than an inhibition of anti-graft reaction

IL-17

Stimulates early alloimmune responses

IL-18

Plays the activation role in acute rejection

IFN-g

Promotes acute rejection of kidney allografts

TNF-a

Participates in pathogenesis of acute and chronic rejection

TGF-ß1

Expression is linked with chronic vasculopathy

VEGF

Influences adhesion and migration of leukocytes across the endothelium

MCP-1

Associated with premature kidney graft failure

ICAM-1 and VCAM-1

Early leukocyte and lymphocyte recruitment in the microvasculature of rejecting

allograft, costimulation T cell activation

PDGF

Mediates mesenchymal cell proliferation in chronic rejection

M-CSF

Promotes macrophage recruitment and proliferation

molecule-1 (VCAM-1), are also key regulatory molecules in immune responses. They are important in migration and localization of leukocytes into tissues as well as in a variety of cell-to-cell interactions that include signaling between cells and even cell-mediated cytotoxicity. The expression of these molecules, which occurs in a sequential fashion, is important for orchestrating the various steps in graft rejection, though the actual sequence of events and their underlying mechanism is not yet clear. A brief summary of the role of some cytokines involved in allograft rejection is given in Table I.

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