Aspects of the rejection response.
The immune responsecascade. Rejection is a complex and redundant response to graftedtissue. The major targets of this response are the major histo-compatibility complex (MHC) antigens, which are designated ashuman leukocyte antigens (HLAs) in humans. The HLA region onthe short arm of chromosome 6 encompasses more than 3 millionnucleotide base pairs. It encodes two structurally distinct classesof cell-surface molecules, termed class I (HLA-A, -B, and -C) andclass II (-DR, -DQ, -DP).
Overview of rejection events. T cells recognize foreign antigensonly when the antigen or an immunogenic peptide is associatedwith a self-HLA molecule on the surface of an accessory cell calledthe antigen-presenting cell (APC). Helper T cells (CD4) are activatedto proliferate, differentiate, and secrete a variety of cytokines. Thesecytokines increase expression of HLA class II antigens on engraftedtissues, stimulate B lymphocytes to produce antibodies against theallograft, and help cytotoxic T cells, macrophages, and natural killercells develop cytotoxicity against the graft.
Possible mechanisms for allorecognition by host T cells. In thedirect pathway, T cells recognize intact allo-MHC on the surface of donor cells. The T-cell response that results in early acute cellularrejection is caused mainly by direct allorecognition. In the indirectpathway, T cells recognize processed alloantigens in the context of self-APCs. Indirect presentation may be important in maintainingand amplifying the rejection response, especially in chronic rejection.IFN-
—interferon gamma; IL-1—interleukin-1; IL-2R—inter-leukin-2 receptor; NK—natural killer. (
Panel A adapted from
panel C adapted from
; with permission.)
AllogeneiccellShedallogeneicMHCTaken up andprocessed by hostantigen-presenting cellCD8+cytotoxic cellCD8+cytoxic cellTh cellTh cellResponder antigen-presenting cell
Peptide derived fromallogeneic MHC presentedon host MHCAllogeneic (stimulator)antigen presenting cellClass IstimulatorClass IIhaplotypeClass IIIresponderhaplotype
(Class I–derived peptidepresented by responderclass II molecule)
Indirect allorecognitionDirect allorecognition
B.OVERVIEW OF REJECTION EVENTS
Antigen-presenting cells trigger CD4 and CD8 T cellsBoth a local and systemic immune response developCytokines recruit and activate nonspecific cells and accumulate in graft, which facilitatesthe following events:Development of specific T cells, natural killer cells, or macrophage-mediated cytotoxicityAllograft destruction