Q4 LONG ANSWER 10M ★ High-yield

Describe the types and mechanisms of transplant rejection. Add a note on graft-versus-host disease.

Pathology · 2nd Professional — Para-Clinical

Definition and Terminology

Transplant rejection is the immune destruction of grafted tissue, caused by the recipient recognising the donor’s major histocompatibility (HLA) antigens as foreign.

Graft	Definition	Rejection
AUTOgraft	Same individual — skin graft, coronary vein graft	None
ISOgraft (syngeneic)	Identical twin	None
ALLOgraft	Same species, different individual — the usual clinical case	Yes
XENOgraft	Different species	Violent and immediate

Mechanisms of Recognition

Direct pathway — recipient T cells recognise intact donor MHC on donor dendritic cells carried in the graft; responsible for acute rejection
Indirect pathway — recipient antigen-presenting cells process donor MHC and present it as peptide; responsible for chronic rejection
CD8 cells kill graft cells directly; CD4 cells cause a delayed-type reaction and help B cells make antibody

Types of Rejection

Type	Onset	Mechanism	Morphology	Treatment
Hyperacute	Minutes to hours — on the operating table	Pre-formed antibodies (type II) from previous transfusion, pregnancy or transplant; also ABO incompatibility	The graft becomes cyanotic and mottled; widespread thrombosis, fibrinoid necrosis and neutrophil infiltration; cortical necrosis	None — the graft must be removed. Prevented by cross-matching
Acute — cellular	Days to weeks (or any time if immunosuppression lapses)	T cell-mediated (type IV)	Interstitial mononuclear infiltrate; tubulitis — lymphocytes invading tubular epithelium; endothelialitis	Responds well to high-dose steroids
Acute — humoral (vascular)	Days to weeks	Donor-specific antibody; C4d deposition in capillaries	Necrotising vasculitis, fibrinoid necrosis, thrombosis	Plasma exchange, intravenous immunoglobulin, rituximab
Chronic	Months to years	Combined immune and non-immune injury; the indirect pathway	Progressive intimal fibrosis narrowing the arteries ("graft arteriosclerosis"); interstitial fibrosis and tubular atrophy; glomerulopathy	Largely irreversible — the chief cause of late graft loss

CLINICAL PEARL

Acute rejection is treatable; chronic rejection is not. The difference is that acute rejection is an active cellular attack that immunosuppression can suppress, whereas chronic rejection is established scarring and vascular narrowing — the tissue has already been replaced by fibrous tissue. This is why prompt recognition and treatment of acute episodes protects long-term function.

Graft-versus-host Disease

The reverse situation — immunocompetent donor T cells attack the recipient
Three requirements — the graft must contain immunocompetent cells, the recipient must be immunosuppressed, and there must be an HLA difference
Occurs chiefly after allogeneic bone marrow transplantation, and after transfusion of non-irradiated blood into an immunosuppressed patient
Target organs — skin (rash), liver (jaundice) and gut (diarrhoea)
Chronic form resembles systemic sclerosis, with skin fibrosis and sicca symptoms
Prevented by HLA matching, immunosuppression, and irradiation of blood products for at-risk recipients

Immunosuppression

Drug	Mechanism	Chief toxicity
Corticosteroids	Broad anti-inflammatory	Diabetes, osteoporosis, infection
Ciclosporin, tacrolimus	Calcineurin inhibitors — block IL-2 production	Nephrotoxicity, hypertension, tremor
Azathioprine, mycophenolate	Antiproliferative — inhibit lymphocyte division	Marrow suppression
Sirolimus	MTOR inhibitor	Impaired wound healing
Antithymocyte globulin, basiliximab	Antibody-mediated depletion or blockade	Serum sickness, infection

Corneal and Other Privileged Grafts

Tissue	Why rejection is limited	Practice
Cornea	Avascular and alymphatic; anterior chamber-associated immune deviation	Over 90% survival at one year without matching or systemic immunosuppression; rejection rises sharply if the cornea becomes vascularised
Cartilage and bone graft	Avascular; often used as a non-viable scaffold	No immunosuppression needed
Heart valve (homograft)	Treated and largely acellular	No immunosuppression
Liver	Relatively tolerogenic — large size and dual blood supply	Lower immunosuppression than kidney; ABO matching still required

Immune privilege is not absolute — it depends on the tissue remaining avascular and on the absence of prior sensitisation

Applied Aspects

ABO compatibility and a negative lymphocyte cross-match are mandatory before transplantation; HLA matching improves long-term survival
The kidney is the commonest transplanted organ, and living related donation predominates in India
Graft biopsy is the only way to distinguish rejection from drug nephrotoxicity, since both present as a rising creatinine
Long-term immunosuppression causes infection and malignancy — particularly skin cancer and Epstein–Barr-driven post-transplant lymphoproliferative disorder
The cornea is the most successful graft because it is avascular and immunologically privileged; matching is usually unnecessary
Non-adherence to immunosuppression is a leading cause of late graft loss, and in India cost is a major contributor to it
Panel reactive antibody testing measures how sensitised a recipient is, and a highly sensitised patient may wait years for a compatible organ
Brain-stem death certification underpins deceased donor transplantation, and its legal framework in India is the Transplantation of Human Organs Act
Xenotransplantation is limited by hyperacute rejection against galactose-alpha-1,3-galactose, and by the risk of transmitting animal retroviruses
The graft-versus-leukaemia effect means that some GVHD after marrow transplantation actually reduces relapse, so complete suppression is not the goal
Calcineurin inhibitor nephrotoxicity mimics rejection in a renal graft, and only biopsy with drug levels can separate them — the commonest diagnostic problem in transplant medicine
Chronic rejection has no effective treatment, so the whole strategy is prevention: adequate immunosuppression, control of blood pressure and lipids, and prompt treatment of acute episodes
Living donation predominates in India, and deceased donation remains limited by low consent rates and by the logistics of organ retrieval
Cytomegalovirus is the commonest opportunistic infection after transplantation, and prophylaxis or pre-emptive monitoring is routine
Commercial organ trading is prohibited, and the law requires authorisation committee approval for unrelated donation
The waiting list far exceeds supply, which is why deceased donor programmes and public awareness matter as much as surgical technique

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