Graft rejection is caused principally by a T cell-mediated immune response to alloantigens expressed on the graft cells, primarily the MHC molecules (Fig. 1).

Fig1. Mechanisms involved in graft rejection.

The T cell response to MHC antigens involves recognition of both the donor MHC molecule as well as the associated peptide ligand present in the cleft of the MHC molecule.

- T he peptides present in the groove of allogeneic (i.e donor) class I MHC molecules are derived from proteins synthesized within the allogeneic cell

- The peptides present in the groove of allogeneic (i.e. donor) class II MHC molecules are generally proteins taken up and processed by the allogeneic APCs.

The process of graft rejection can be divided into two stages: (1) A sensitization phase-which involves alloantigen (mainly graft MHC molecules) presentation to recipient’s T cells and (2) An effector stage, in which immune destruction of the graft takes place due to activation of recipient’s T cells.

Sensitization Phase

T cells in the recipient may recognize donor alloantigens in the graft in two different ways: (1) direct pathway, and (2) indirect pathway; depending on what cells in the graft are displaying these alloantigens to the recipient T cells (Fig. 1).

Direct Pathway of Alloantigen

Presentation Many graft tissues contain antigen presenting cells (APCs, e.g. dendritic cells and macrophages) and when the tissues are transplanted, the APCs are also carried along with the graft to the recipients.

- The allogeneic MHC molecules on graft’s APCs are directly presented to the recipient’s helper T cells

- This pathway is responsible for most of the acute graft rejections mediated by cytotoxic T cells (described in effector phase).

Indirect Pathway of Alloantigen Presentation

This is similar to that for recognition of any foreign antigen by the host APCs.

- T he graft cells are ingested by recipient APCs, donor alloantigens are processed and presented by the MHC molecules present on recipient APCs to recipient’s helper T cells

- This pathway is responsible for most of the chronic rejection mediated by helper T cells via specialized form of chronic DTH reaction (described in effector phase).

Effector Phase

A variety of effector mechanisms participate in allograft rejection. The most common are cell-mediated reactions involving delayed-type hypersensitivity T cells and cytotoxic T cells.

- Delayed-type hypersensitivity: Activated helper T cells differentiate into T_DTH cells. Cytokines secreted from T_DTH (e.g. interferon-γ) activate macrophages which destroy the target graft cells by producing lytic enzymes

- Cytotoxic T cells: CD8+ TC cells kill the graft cells by recognizing the allogeneic MHC-I molecules

- Antibody-mediated mechanisms: Cytokines produced by helper T cells activate B cells to produce antibodies. Antibodies are also important in mounting immune response against the graft. They take a lead role in mediating hyperacute graft rejections; however, in acute and chronic rejections, they play a minor role. Antibody mediated destruction of the graft occurs by the following mechanisms:

* Complement-mediated lysis

* Antibody-dependent cell-mediated cytotoxicity (ADCC) via NK cell or macrophage mediated destruction.

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مواضيع ذات صلة

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Tumor Antigens

Factors Influencing Allograft Rejection

Types of Graft Rejection

Histocompatibility Antigens

Disorders of Phagocytosis

Combined Immunodeficiencies (B and T Cells Defects)

Cellular Immunodeficiency (T Cell Defects)

Neuropathies

Humoral Immunodeficiency (B Cell Defects)

Type IV Hypersensitivity Reaction

Type III Hypersensitivity Reaction