Solid-organ transplant rejection reactions

Pathogenesis and renal transplant pathology

Robbins-based MD Pathology exam answer

Definition

Donor organ with non-self HLA antigens
                ↓
Recipient recognizes alloantigens
                ↓
Activation of recipient T cells and B cells
                ↓
Cell-mediated injury + antibody/complement-mediated vascular injury
                ↓
Graft dysfunction, fibrosis, vascular obliteration, or infarction

1. Immunologic basis of graft rejection

A. Major target antigens

Donor-recipient genetic disparity
                ↓
Main antigenic targets = donor HLA molecules
                ↓
Recipient immune system recognizes donor HLA as alloantigen
                ↓
Alloreactive T-cell and B-cell response

Why is allograft rejection so vigorous?

B. Alloantigen recognition pathways

Easy flowchart

                    DONOR HLA / DONOR ANTIGENS
                              │
          ┌───────────────────┴───────────────────┐
          │                                       │
          ▼                                       ▼
DIRECT ALLORECOGNITION                   INDIRECT ALLORECOGNITION
Donor APC presents intact                Recipient APC takes up donor
donor HLA to recipient T cell            HLA/proteins, processes them,
                                         and presents peptides on self HLA
          │                                       │
          ▼                                       ▼
Strong activation of recipient           Recipient CD4+ T-cell activation
CD8+ CTLs and CD4+ T cells               and B-cell help
          │                                       │
          ▼                                       ▼
Important in acute                       Important in chronic rejection
T-cell-mediated rejection                and alloantibody generation

Direct pathway

• Passenger donor dendritic cells/APCs in the graft present intact donor HLA molecules directly to recipient T cells.
• Activates:
  • CD8+ T cells to become cytotoxic T lymphocytes
  • CD4+ T cells, mainly Th1-type cytokine-producing effector cells
• Especially important in acute cellular rejection.

Indirect pathway

• Recipient APCs ingest donor HLA proteins or other donor antigens.
• Donor peptides are processed and presented by recipient self-HLA to recipient T cells.
• Promotes:
  • CD4+ T-cell cytokine response
  • B-cell activation and donor-specific alloantibody production
  • Fibrosis and vascular remodeling
• Has a major role in chronic rejection.

C. Effector mechanisms of graft injury

Activated recipient immune response
                │
     ┌──────────┼───────────┐
     │          │           │
     ▼          ▼           ▼
CD8+ CTLs   CD4+ Th1    B cells/plasma cells
     │          │           │
Kills graft  Cytokines:   Donor-specific antibodies
parenchymal  IFN-γ, TNF,        │
cells and    macrophage          ▼
endothelium  activation    Complement activation
     │          │                 │
     └──────────┴─────────────────┘
                ↓
Parenchymal damage + endothelial injury
                ↓
Inflammation, thrombosis, ischemia, fibrosis

2. Classification of graft rejection

Acute rejection is often a mixed process: both T-cell-mediated and antibody-mediated injury may coexist.

3. Hyperacute rejection

Pathogenesis

Prior sensitization of recipient
(transfusion / pregnancy / previous transplant)
                ↓
Preformed anti-ABO or anti-HLA antibodies in recipient blood
                ↓
Graft reperfused after transplantation
                ↓
Antibodies bind donor vascular endothelial antigens
                ↓
Classical complement activation + endothelial injury
                ↓
Platelet activation + coagulation + neutrophil recruitment
                ↓
Widespread thrombosis and ischemic infarction of graft

Timing

• Occurs immediately, usually minutes to hours after vascular anastomosis and restoration of blood flow.

Renal transplant morphology

Gross

Kidney becomes:
cyanotic + mottled + swollen + anuric

Microscopy

• Acute fibrinoid necrosis of arterioles and arteries
• Luminal narrowing or complete occlusion by platelet-fibrin thrombi
• Neutrophils in:
  • arterioles
  • glomeruli
  • peritubular capillaries
• Glomerular capillary thrombosis
• Diffuse ischemic cortical necrosis or infarction

Antibody + complement injury
            ↓
Vascular thrombosis
            ↓
Loss of perfusion
            ↓
Cortical infarction
            ↓
Nonfunctioning graft

Prevention

• ABO compatibility testing
• Donor-recipient crossmatch for preformed anti-donor antibodies

4. Acute rejection

General features

• Usually occurs within days to weeks after transplantation.
• Can also occur months or years later if immunosuppression is reduced or stopped.
• Important cause of early graft dysfunction.
• Includes:
  1. Acute T-cell-mediated rejection
  2. Acute antibody-mediated rejection

A. Acute T-cell-mediated rejection

Pathogenesis

Donor alloantigen recognition
                ↓
Recipient CD4+ and CD8+ T-cell activation
                ↓
          ┌─────┴─────┐
          │           │
          ▼           ▼
CD8+ CTLs         CD4+ Th1 cells
Direct graft      Cytokine secretion
cell killing      and macrophage activation
          │           │
          └─────┬─────┘
                ↓
Tubular, interstitial, and vascular injury

Mechanisms

• CD8+ CTLs directly kill graft tubular epithelial cells and endothelial cells.
• CD4+ T cells release cytokines that recruit and activate macrophages and other inflammatory cells.
• T cells may attack graft vessels, producing vascular rejection.

Renal transplant morphology

1. Tubulointerstitial pattern

Interstitial mononuclear infiltrate
                +
Lymphocytes within tubular epithelium
                ↓
TUBULITIS
                ↓
Tubular epithelial injury

• Dense interstitial mononuclear infiltrate
• Activated CD4+ and CD8+ lymphocytes
• Lymphocytes infiltrating tubular epithelium: tubulitis
• Focal tubular injury or tubular destruction

2. Vascular pattern

Lymphocytes attack endothelium of arteries/arterioles
                ↓
Endothelial swelling
                ↓
Lymphocytes beneath endothelium / within vessel intima
                ↓
ENDOTHELIITIS or INTIMAL ARTERITIS
                ↓
Vascular luminal narrowing and ischemic injury

• Severe cases may show vessel-wall necrosis.
• T-cell-mediated rejection without a humoral component often responds to immunosuppressive therapy.

B. Acute antibody-mediated rejection

Pathogenesis

Recipient B-cell activation against donor HLA
                ↓
Donor-specific anti-HLA antibodies
                ↓
Antibodies bind graft vascular endothelium
                ↓
Classical complement activation
                ↓
C4d deposition + endothelial activation/injury
                ↓
Neutrophilic microvascular inflammation
                ↓
Capillary injury, thrombosis, and graft dysfunction

Key diagnostic triad

1. Graft dysfunction
        +
2. Histologic microvascular injury
        +
3. Evidence of antibody action:
   donor-specific antibodies and/or C4d deposition

Renal transplant pathology

• Glomerulitis: inflammation in glomerular capillaries
• Peritubular capillaritis: inflammation of peritubular capillaries
• Endothelial injury and swelling
• C4d deposition in peritubular capillaries on immunohistochemistry
• Focal small-vessel thrombosis may occur

High-yield comparison

5. Chronic rejection

Definition

Pathogenesis

Persistent low-grade alloimmune injury
                │
      ┌─────────┴─────────┐
      │                   │
      ▼                   ▼
T-cell cytokines      Alloantibodies/endothelial injury
      │                   │
      ▼                   ▼
Fibroblast activation  Chronic vascular inflammation
VSMC proliferation     and remodeling
      └─────────┬─────────┘
                ↓
Intimal thickening + arterial narrowing
                ↓
Chronic ischemia
                ↓
Interstitial fibrosis + tubular atrophy
                ↓
Progressive graft failure

Mechanisms

• Predominantly driven by persistent T-cell responses, especially indirect allorecognition.
• T-cell cytokines stimulate:
  • fibroblasts to produce collagen
  • vascular smooth-muscle cells to proliferate
• Alloantibodies also contribute by producing chronic endothelial injury.
• Chronic rejection is relatively resistant to therapy and is a major cause of late graft loss.

Renal transplant pathology in chronic rejection

1. Graft arteriosclerosis

Chronic immune endothelial injury
                ↓
Concentric intimal thickening
                ↓
Progressive arterial luminal narrowing
                ↓
Chronic ischemia of renal parenchyma

• Diffuse intimal thickening of graft arteries
• Progressive narrowing or obliteration of vascular lumen
• This is the central vascular lesion of chronic rejection.

2. Interstitial fibrosis and tubular atrophy

Chronic vascular narrowing
        + persistent immune injury
                ↓
Tubular ischemic injury and loss
                ↓
Tubular atrophy
                ↓
Interstitial fibrosis

3. Transplant glomerulopathy

Chronic endothelial injury
                ↓
Remodeling of glomerular capillary wall
                ↓
Duplication / double contour of GBM
                ↓
Proteinuria and progressive graft dysfunction

• Glomerular basement membrane duplication is a classic lesion.
• Often linked to chronic antibody-mediated endothelial injury.

Exam one-liner

Chronic renal allograft rejection is characterized by graft arteriosclerosis, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy with duplication of glomerular basement membranes.

6. Final rapid-revision flowchart

SOLID ORGAN ALLOGRAFT
        ↓
Recipient recognizes donor HLA / ABO antigens
        ↓
 ┌────────────────────────────────────────────────────────┐
 │                 TYPE OF IMMUNE RESPONSE                 │
 └────────────────────────────────────────────────────────┘
        ↓
 ┌───────────────────┬───────────────────┬────────────────────┐
 │ HYPERACUTE        │ ACUTE             │ CHRONIC            │
 ├───────────────────┼───────────────────┼────────────────────┤
 │ Minutes-hours     │ Days-weeks         │ Months-years       │
 │ Preformed Ab      │ T cells ± Ab       │ T cells + Ab       │
 │ Complement        │ Cellular/humoral   │ Fibrosis/vasculopathy│
 │ Thrombosis        │ inflammation      │                     │
 └───────────────────┴───────────────────┴────────────────────┘
        ↓
KIDNEY LESIONS
        ↓
Hyperacute:
fibrinoid necrosis + thrombi + cortical infarction

Acute cellular:
interstitial infiltrate + tubulitis + endotheliitis

Acute antibody-mediated:
glomerulitis + peritubular capillaritis + C4d + thrombosis

Chronic:
graft arteriosclerosis + IF/TA + transplant glomerulopathy

7. MD exam conclusion