Figure

Aspects of the rejection response. A, The immune response cascade. Rejection is a complex and redundant response to grafted tissue. The major targets of this response are the major histo-compatibility complex (MHC) antigens, which are designated as human leukocyte antigens (HLAs) in humans. The HLA region on the short arm of chromosome 6 encompasses more than 3 million nucleotide base pairs. It encodes two structurally distinct classes of cell-surface molecules, termed class I (HLA-A, -B, and -C) and class II (-DR, -DQ, -DP).

B, Overview of rejection events. T cells recognize foreign antigens only when the antigen or an immunogenic peptide is associated with a self-HLA molecule on the surface of an accessory cell called the antigen-presenting cell (APC). Helper T cells (CD4) are activated to proliferate, differentiate, and secrete a variety of cytokines. These cytokines increase expression of HLA class II antigens on engrafted tissues, stimulate B lymphocytes to produce antibodies against the allograft, and help cytotoxic T cells, macrophages, and natural killer cells develop cytotoxicity against the graft.

C, Possible mechanisms for allorecognition by host T cells. In the direct pathway, T cells recognize intact allo-MHC on the surface of donor cells. The T-cell response that results in early acute cellular rejection is caused mainly by direct allorecognition. In the indirect pathway, T cells recognize processed alloantigens in the context of self-APCs. Indirect presentation may be important in maintaining and amplifying the rejection response, especially in chronic rejection. IFN-7—interferon gamma; IL-1—interleukin-1; IL-2R—inter-leukin-2 receptor; NK—natural killer. (Panel A adapted from [3]; with permission; panel C adapted from [4]; with permission.)

Indirect allorecognition

Direct allorecognition

CD8+

cytotoxic cell Th cell

Indirect allorecognition

CD8+

cytotoxic cell Th cell

(Class I-derived peptide presented by responder class II molecule)

Taken up and processed by host antigen-presenting cell

Responder antigen-presenting cell

Taken up and processed by host antigen-presenting cell

CD8+ cytoxic cell

Th cell

(Class I-derived peptide presented by responder class II molecule)

CD8+ cytoxic cell

Th cell

Allogeneic (stimulator) antigen presenting cell

Responder antigen-presenting cell

Allogeneic (stimulator) antigen presenting cell

0 Class I stimulator Q Class II haplotype Q Class III responder haplotype ^ P2 microglobulin

0 0

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