The antigens of allografts that serve as the principal targets of rejection are proteins encoded in the MHC. Homologous MHC genes and molecules are present in all mammals; the human MHC is called the human leukocyte antigen (HLA) complex. It took more than 20 years after the discovery of the MHC to show that the physiologic function of MHC molecules is to dis play peptide antigens for recognition by T lymphocytes . Recall that every person expresses six class I HLA alleles (one allele of HLA-A, -B, and -C from each parent) and usually six or seven class II HLA alleles (one allele of HLA-DQ and HLA-DP and one or two of HLA-DR from each parent). MHC genes are highly polymorphic, with over 12,000 HLA alleles among all humans, encoding about 2800 HLA-A proteins, 3500 HLA-B proteins, 2500 HLA-C proteins, 1800 HLA-DRβ proteins, 800 DQβ proteins, and 700 DPβ proteins. Because of this tremendous polymorphism, two unrelated individuals are very likely to express several HLA proteins that are different from, and therefore appear foreign to, each other. Because the genes in the HLA locus are tightly linked, all the HLA genes from each parent are inherited together, as a haplotype, in a Mendelian pattern, and therefore the chance that two siblings will have the same MHC alleles is 1 in 4.

The reaction to allogeneic MHC antigens on another individual’s cells is one of the strongest immune responses known. T cell receptors (TCRs) for antigens have evolved to recognize MHC molecules, which is essential for surveillance of cells harboring infectious microbes. As a result of positive selection of developing T cells in the thymus, mature T cells that have some affinity for self MHC molecules survive, and many of these will have high affinity for self MHC displaying foreign peptides. Allogeneic MHC molecules containing peptides derived from the allogeneic cells may look like self MHC molecules plus bound foreign peptides (Fig. 1). Therefore, recognition of allogeneic MHC molecules in allografts is an example of an immunologic cross-reaction.

Fig1. Recognition of allogeneic major histocompatibility complex (MHC) molecules by T lymphocytes. Recognition of allogeneic MHC molecules may be thought of as a cross-reaction in which a T cell specific for a self MHC molecule–foreign peptide complex (A) also recognizes an allogeneic MHC molecule whose structure resembles that of the self MHC molecule–foreign peptide complex (B and C). Peptides derived from the graft or recipient (labeled self-peptide) may not contribute to allorecognition (B), or they may form part of the complex that the T cell recognizes (C). The type of T cell recognition depicted in B and C is direct allorecognition.

There are several reasons why recognition of allogeneic MHC molecules results in strong T cell reactions. Many clones of T cells, including memory T cells generated from prior infections, that are specific for different foreign peptides bound to the same self MHC molecule may cross-react with any one allogeneic MHC molecule, regardless of the bound peptide, as long as the allogeneic MHC molecule resembles complexes of self MHC plus foreign peptides. As a result, many self MHC–restricted T cells specific for different peptide antigens may recognize any one allogeneic MHC molecule. Also, the process of negative selection in the thymus eliminates cells that strongly recognize self MHC, but there is no mechanism for selectively eliminating T cells whose TCRs have a high affinity for allogeneic MHC molecules because these are never present in the thymus. Furthermore, a single allogeneic graft cell will express thousands of MHC molecules, every one of which may be recognized as foreign by a graft recipient’s T cells. By contrast, in the case of an infected cell, only a small fraction of the self MHC molecules on the cell surface will carry a foreign microbial peptide recognized by the host’s T cells. The net result of these features of allorecognition is that the frequency of alloreactive T cells in any individual is about 1000-fold greater than the frequency of T cells that recognize any one microbial antigen.

Although MHC proteins are the major antigens that stimulate graft rejection, other polymorphic proteins also may play a role in rejection. Non-MHC antigens that induce graft rejection are called minor histocompatibility antigens, and most are normal cellular proteins that differ in sequence between donor and recipient. These polymorphic proteins yield peptides that are presented by the recipient’s MHC molecules and trigger a T cell response. The rejection reactions that minor histocompatibility antigens elicit usually are not as strong as reactions against foreign MHC proteins. 

مواضيع ذات صلة

Immune Mechanisms of Graft Rejection

Induction of Immune Responses Against Transplants

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