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PH-IM15

Graft rejection

Why the immune system attacks a transplanted organ: how T cells and antibodies recognise donor HLA, how hyperacute, acute and chronic rejection damage the graft, and how donor cells can attack the recipient instead.

By the end, you can

  • Describe HLA (MHC) class I and II molecules and why they differ so much between people.
  • Explain direct and indirect recognition of donor HLA, and how a person becomes sensitised.
  • Explain hyperacute and antibody-mediated rejection in terms of antibodies, complement and endothelium.
  • Explain T-cell-mediated rejection and the changes it causes in a kidney graft.
  • Describe chronic rejection and graft-versus-host disease.
  • Recognise the biopsy appearances, classifications and tests of rejection, including the Banff categories and C4d, and explain how immunosuppressants act on the steps of allorecognition and rejection.

What it is

Graft rejection is immune injury to transplanted tissue that the recipient recognises as foreign, mainly because of differences in HLA (human leucocyte antigen) molecules, the human major histocompatibility complex (MHC). It is classed by timing and mechanism: hyperacute (minutes to hours, preformed antibodies), acute (days to months, T cells or antibodies) and chronic (months to years, progressive narrowing of vessels and fibrosis). In graft-versus-host disease the direction is reversed: immune cells from the graft attack the recipient.

5 types to tell apart
Hyperacute rejection
Preformed antibodies against ABO blood group or donor HLA antigens bind the graft endothelium within minutes to hours; now rare because of blood group matching and crossmatching.
Acute T-cell-mediated rejection
Recipient T cells infiltrate the graft, most often in the first months.
Antibody-mediated rejection
Donor-specific antibodies, present before transplantation or made afterwards, injure the graft’s capillaries; it can be acute or chronic.
Chronic rejection
Slowly narrowing arteries and fibrosis over months to years; a leading cause of late graft loss.
Graft-versus-host disease
Donor T cells, chiefly after a haematopoietic stem-cell transplant, attack the recipient’s skin, gut and liver.

US spelling: leucocyte → leukocyte.

Normal function

HLA molecules: how T cells see self

T cells cannot see whole proteins. They recognise short peptides held in the groove of HLA molecules on cell surfaces. Class I molecules (HLA-A, -B and -C), on almost every nucleated cell, show peptides made inside the cell to CD8 cytotoxic T cells. Class II molecules (HLA-DR, -DQ and -DP), mainly on antigen-presenting cells such as dendritic cells, macrophages and B cells, show peptides taken up from outside to CD4 helper T cells.

The HLA genes are the most variable in the human genome, with thousands of versions in the population, so that people between them can present peptides from almost any microbe. Each person inherits one set (a haplotype) from each parent and expresses both; two siblings have a one-in-four chance of sharing both haplotypes, and unrelated people rarely match fully.

In the thymus, T cells that react strongly to the body’s own HLA carrying its own peptides are deleted, so T cells tolerate the body’s own tissues. Nothing has taught them to tolerate someone else’s HLA, and an unusually large share of T cells (in the usual estimate, 1–10%) reacts to any one foreign HLA type.