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MOLECULAR MECHANISMS OF GRAFT REJECTION

Courtesy of: http://www-ermm.cbcu.cam.ac.uk

The direct and indirect pathways of antigen presentation. In the direct pathway, MHC molecules on donor APCs from the graft tissue present graft-derived peptides to host T-cells. In the indirect pathway, host APCs take up graft proteins and present donor-derived processed peptides on host MHC molecules to host T-cells.

 

The molecular mechanisms of graft rejection are based on recognition of foreign transplanted cells by the expression of polymorphic, codominant genes. These genes code for protein molecules which are found on the surfaces of cells called antigens. Due to polymorphism, it is rare to find a donor and recipient with matching surface antigens. Major histocompatibility complex (MHC) molecules are responsible for the most rapid rejection reactions. They are encoded by the MHC complex, a region of genes on chromosome 6 in human. These MHC molecules which present foreign peptides are in turn presented to recipient T-cells in two different ways, direct and indirect presentation.

 

 

Direct Presentation

Normally, host T-cell receptors (TCRs) recognize foreign peptides presented on self MHC molecules. In direct presentation, these host TCRs recognize foreign MHC-peptide combination presented by donor antigen presenting cells (APCs). The T cell is able to recognize and respond to the foreign MHC molecule because there are enough similarities between the self and non-self MHC molecules. The T cell, however, is able to determine that the MHC molecule is non-self. Studies have shown that TCR's are capable of recognizing foreign MHC molecules with some, but not other, bound peptides. This suggests that the particular peptide plays a role in determining whether or not its binding MHC molecule will be recognized.

Most rejection episodes are elicited through direct presentation. It is shown in many clinical studies that allographs are identified more readily, and responded to with more vigor than normal non-self antigens. This increased responsiveness is due in part to the fact that most host T-cells have the capability of recognizing a single foreign MHC molecule. This is due to several factors:

  • The MHC is extremely polymorphic in nature; many different amino acid residues can be found on a single MHC molecule. If a T-cell recognizes even one of those residues, it can target that particular MHC molecule. Therefore, several different classes of T-cells may recognize a single MHC molecule.
  • The surface of each foreign cell can have up to 105 copies of each MHC molecule with each molecule forming a complex with a distinct peptide. In this way, a single foreign cell has the potential to activate many different T-cells.

Indirect Presentation

Indirect presentation is the mechanism in which recipient APCs are able to process the donor antigens and present the resulting foreign peptides to T-cells using self-MHC molecules. The host APCs digest the foreign antigens through phagocytosis. The peptides from the digested complex are presented by host MHC molecules to either CD4+ or CD8+ T-cells. This intermediate pathway is termed "cross priming" because one cell, the host APC, presents the antigens of another cell from the graft, to activate, or "prime" T-lymphocytes. Due to the polymorphic nature of the MHC molecules, they are digested into a wide range of peptides, each of which are recognized by different host T-cells. In this case, the foreign MHC molecules are handled in in a manner simular to a other foreign antigen.

Other surface molecules that function in antigen presentation that are not included in the MHC group are classified as minor histocompatibility antigens. They are usually processed and presented indirectly to host T-cells by host APCs and MHC molecules.

 

Rejection Mechanisms
cellular mechanisms molecular mechanisms