Questions: Graft Rejection: Acute, Chronic, and Hyperacute

Question 1

A kidney transplant recipient develops severe graft dysfunction within 3 hours of surgery. The organ appears dark and necrotic, with widespread vascular thrombosis. What is the most likely mechanism?

• A. CD8+ cytotoxic T cells rapidly killed graft endothelial cells through direct allorecognition
• B. Preformed antibodies against donor ABO or HLA antigens activated complement, triggering vascular thrombosis
• C. NK cells recognized missing self-MHC on donor cells and initiated cytotoxic killing
• D. An unusually rapid acute rejection response caused by prior sensitization from a previous transplant

Answer: (B)

The timing (minutes to hours) and the pattern (vascular thrombosis, necrosis) are hallmarks of hyperacute rejection. This requires preformed antibodies already circulating in the recipient before surgery — against ABO antigens or anti-HLA antibodies from prior transfusions, pregnancies, or transplants. These antibodies bind immediately to donor endothelium, fix complement, and cause rapid thrombosis and organ death. T cell-mediated acute rejection (options A and D) takes days to weeks to develop — the adaptive immune response requires time for clonal expansion. This scenario illustrates why pretransplant crossmatching is mandatory.

Question 2

Which type of graft rejection is most resistant to intensified immunosuppressive therapy once it is established?

• A. Hyperacute rejection — preformed antibodies are not affected by immunosuppression
• B. Acute rejection — T cells become refractory to calcineurin inhibitors over time
• C. Chronic rejection — involves fibrosis and vasculopathy with both immune and non-immune components
• D. All three types respond equally once adequate immunosuppressive levels are achieved

Answer: (C)

Chronic rejection is the leading cause of long-term graft loss and currently has no reliable treatment once established. It involves progressive transplant vasculopathy (fibrosis and thickening of graft vessel walls) driven by a combination of immune factors (ongoing low-grade T cell and antibody responses) and non-immune factors (ischemia-reperfusion injury, drug toxicity, recurrence of original disease). Unlike acute rejection, which responds well to high-dose corticosteroids and calcineurin inhibitors, chronic rejection progresses despite immunosuppression. Hyperacute rejection (A) is prevented, not treated; acute rejection (B) is the primary target of standard immunosuppression and responds well when caught early.

Question 3

Pretransplant crossmatch testing primarily aims to prevent hyperacute rejection by detecting preformed recipient antibodies against donor antigens.

• T. True
• F. False

Answer: True

Crossmatch testing mixes recipient serum with donor lymphocytes before surgery. If the recipient has preformed antibodies against donor HLA molecules, they will bind donor cells and produce a positive crossmatch — a contraindication to transplantation. This test directly screens for the preformed antibodies that cause hyperacute rejection. Together with ABO blood group compatibility, crossmatch testing has made hyperacute rejection rare in modern transplant medicine, though it was a common cause of immediate graft loss before these protocols were established.

Question 4

Chronic graft rejection is a purely immune-mediated process and can be fully prevented by maintaining adequate immunosuppression throughout the life of the graft.

• T. True
• F. False

Answer: False

Chronic rejection involves both immune and non-immune mechanisms, which is why it responds poorly to immunosuppression even when intensified. Non-immune contributors include ischemia-reperfusion injury at the time of transplant, nephrotoxicity from calcineurin inhibitors themselves, hypertension, dyslipidemia, and recurrence of the original kidney disease. Even perfectly controlled immune rejection doesn't eliminate these factors. This mixed etiology explains why chronic rejection is the leading cause of long-term graft failure despite excellent short-term results with modern immunosuppression — and why HLA matching (reducing the immune stimulus) matters more than simply increasing drug doses.

Question 5

Explain why HLA matching between donor and recipient reduces both acute and chronic rejection. Connect the mechanism to each type.

Model answer: HLA matching reduces the number of foreign allogeneic HLA molecules the recipient's immune system encounters. In acute rejection, T cells recognize donor MHC molecules as foreign alloantigens — each HLA mismatch represents a set of epitopes that can activate recipient T cell clones through direct or indirect allorecognition. More mismatches mean more T cell clones activated, a stronger and harder-to-control rejection response. In chronic rejection, ongoing low-grade immune responses against mismatched HLA molecules drive the progressive vasculopathy and fibrosis. Better HLA matching reduces the antigenic stimulus driving both processes: fewer foreign HLA molecules means weaker T cell activation, less antibody production against donor antigens, and slower accumulation of immune-mediated vascular damage. HLA matching thus improves both short-term rejection control and long-term graft survival.