Transplant immunology

Grafts and HLA

• Autograft (own tissue), isograft (identical twin), allograft (another person; most transplants), xenograft (another species, such as porcine valves).
• HLA genes lie on chromosome 6. Class I (HLA-A, B, C) is on all nucleated cells and presents to CD8 T cells; class II (HLA-DR, DP, DQ) is on antigen-presenting cells and presents to CD4 T cells. HLA-DR matching matters most for kidneys.
• HLA typing uses lymphocytes (now DNA-based typing from white cells, classically serological typing of lymphocytes), because they carry both classes in abundance.
• HLA genes pass from each parent as a block (haplotype). A sibling has a 1 in 4 (25%) chance of a full match, one in two of a half match; parents are usually half matches to their child.
• Pre-transplant tests: ABO compatibility; HLA typing; crossmatch (recipient serum against donor lymphocytes) to detect preformed anti-donor antibodies: a positive crossmatch forbids the transplant; panel-reactive antibodies measure sensitisation from pregnancy, transfusion or a previous graft.

Rejection

• C4d is a stable fragment of the classical complement pathway that binds covalently where antibody has activated complement, so it marks antibody-mediated damage.
• Cornea grafts succeed without matching because the cornea has no blood vessels or lymphatics, so donor antigens reach the immune system slowly; inflamed, vascularised corneas lose this privilege. The liver also tolerates mismatch well.

How immunosuppressants work

• Early calcineurin nephrotoxicity is afferent arteriolar vasoconstriction (endothelin, thromboxane up, prostaglandins and nitric oxide down), so GFR falls and recovers when the dose is reduced. Chronic use causes arteriolar hyalinosis and striped fibrosis. A rising creatinine after transplant may be drug toxicity rather than rejection; levels and biopsy decide.
• Tacrolimus and ciclosporin are metabolised by CYP3A4: clarithromycin, azoles, diltiazem and grapefruit juice raise levels (tremor, rising creatinine, hyperglycaemia); rifampicin, carbamazepine and phenytoin lower them and risk rejection.

Infections and cancers after transplant

Graft-versus-host disease

• Donor immunocompetent T cells attack the recipient, chiefly after allogeneic stem cell transplant, and after non-irradiated blood in an immunosuppressed host. Billingham requirements: the graft has immunocompetent cells, the host has antigens the donor lacks, and the host cannot reject the graft.
• Acute (classically within 100 days): skin rash including palms and soles, liver (cholestatic jaundice), gut (diarrhoea). Chronic: scleroderma-like skin, sicca, bronchiolitis obliterans.
• Prevention: HLA matching, ciclosporin or tacrolimus with methotrexate, T-cell depletion, irradiated blood components. Graft-versus-leukaemia is the beneficial side.
• After stem cell transplant, the neutrophil count is the first marker of engraftment.

Organ donation

• Brainstem death: coma of known cause; reversible causes excluded (drugs, hypothermia, metabolic, endocrine); absent pupillary, corneal, vestibulo-ocular, gag and cough reflexes, no motor response in cranial nerve territory, and a positive apnoea test, by two senior doctors.
• Pakistan's Transplantation of Human Organs and Tissues Act 2010 prohibits commercial organ trade. Cold ischaemia limits: kidney about 24–36 hours, liver about 12, heart 4–6.

Amyloidosis

• Extracellular deposits of misfolded proteins in beta-pleated sheets; Congo red stains them, with apple-green birefringence under polarised light; electron microscopy shows non-branching fibrils.

• Kidney: nephrotic syndrome with large kidneys. Heart: restrictive cardiomyopathy, a thick-walled ventricle with low-voltage QRS complexes (infiltration, not hypertrophy), preserved systolic function; cardiac failure is the commonest cause of death in AL amyloidosis.
• Liver: amyloid is laid down first in the space of Disse, compressing hepatocyte plates; bilirubin often stays normal. Spleen: sago (follicular) or lardaceous (diffuse).
• AL features: macroglossia, periorbital purpura, carpal tunnel syndrome, autonomic neuropathy, bruising from factor X binding.
• Diagnosis: abdominal fat pad aspirate is the simplest and safest sample (a negative result does not exclude it); rectal biopsy is the classic alternative; organ biopsy (kidney) when needed; serum free light chains for AL; SAP scintigraphy.
• Treatment: AL with plasma cell chemotherapy (bortezomib, daratumumab) or stem cell transplant; AA by controlling inflammation (colchicine for familial Mediterranean fever); ATTR with tafamidis.

Remember Antibodies already present reject in minutes, T cells in weeks, and fibrosis over years.

Exam trap Tacrolimus and sirolimus both bind FKBP-12, but tacrolimus blocks calcineurin while sirolimus blocks mTOR.

Exam trap A thick left ventricle with low-voltage QRS suggests amyloid, not hypertrophy.

How FCPS asks about this

• Graft cyanosed within 10 minutes: hyperacute rejection from preformed antibodies; prevented by crossmatch.
• Antibody-mediated rejection: C4d in peritubular capillaries; acute cellular rejection shows lymphocytic tubulitis.
• Drug mechanisms: mycophenolate inhibits IMP dehydrogenase; basiliximab targets CD25; sirolimus inhibits mTOR.
• Tacrolimus toxicity after clarithromycin: CYP3A4 inhibition; early ciclosporin nephrotoxicity is afferent vasoconstriction.
• Post-transplant viruses: CMV pneumonitis with owl's-eye inclusions; BK decoy cells; EBV in PTLD.
• HLA: typing on lymphocytes; 25% sibling match; B27 with ankylosing spondylitis.
• Amyloid: Congo red apple-green birefringence; fat pad aspirate; AL usually lambda; dialysis amyloid causes carpal tunnel.