In Vitro Models: The Mixed Lymphocyte Reaction

Recognition of allogeneic MHC molecules can often lead to T cell-mediated graft rejection. A common model of direct T cell recognition leading to graft rejection is called the mixed leukocyte reaction (MLR). MLR is performed through culturing immature leukocytes derived from another individual with inhibited host lymphocytes. When the individuals the MHC antigens between the individuals differ, cell proliferation of the donor lymphocytes occurs. CD8+ cells differentiate into CTLs, and CD4+ cells differentiate into cytokine-producing helper T cells. Class I MHC, such as HLA-A, HLA-B, and HLA-C molecules are recognized by CD8+ CTLs. Class II MHC molecules, such as HLA-DR, HLA-DP, and HLA-DQ are recognized by CD4+. When the class I MHC alleles of both stimulator and responder cells are the same, few CTLs will be generated. Similarly, when class II MHC molecules are identical, few CD4+ T cells will be generated. Proliferation is thus a signal of mismatch in the HLA loci, and is an indicator of a bad donor-recipient match.

In Vivo Models: Stimulation of T Cells

For in vivo models, MHC molecules play an important role, as evident from supporting clinical transplantation trials. In cases in which the allografts differ at both class I and class II sites, recognition of the MHC molecules leads to activation of both CD8+ and CD4+ T cells. Some evidence supporting the importance of MHC molecules in rejection includes studies in which grafts between congenic strains of inbred animals were rejected when the only differences in the genes of the strains were those found in class I or class II MHC alleles. In another study, when the differences in MHC alleles were minimized between the donor and the recipient, rejection of human kidneys or bone marrow allografts was shown to be reduced.

APCs (Antigen Presenting Cells) are involved in graft rejection, with dendritic cells being the most important. APCs may enter the graft through blood supply and stimulate T cells, or directly enter into lymph nodes and activate T cells. Recipient APCs infiltrate the graft and pick up donor alloantigens. These cells are then transported to lymph nodes through the circulation, and work in activating lymphocytes where they are most concentrated. This leads to massive lymphocyte proliferation and eventual infiltration into the donor graft. The donor graft is thus rejected.