Mechanisms of Graft Rejection: Lessons Learned from Pathology

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Mechanisms of Graft Rejection Lessons Learned
from Pathology

• Lorraine C. Racusen, M.D.
• The Johns Hopkins University
• Baltimore

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Rejection as an Inflammatory/Immune Process
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Cells Involved in/Diagnostic ofAcute Rejection
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Acute Rejection - cell-mediated

• The effector cells
• Morphology - mononuclear
• lymphocytic
• Immunophenotyping
• CD8 gt CD4 - ?/?, ?/?
• CD45RO gt RA
• perforin/granzyme/CD57 - cytotoxic cells
• Other cells - eosinophils
• plasma cells

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Acute Rejection - antibody mediated

• Effectors
• Complement
• Neutrophils
• Platelets

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Tissue Targets of the Acute Rejection Reaction
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Acute Rejection - cell-mediated

• The targets
• Vessels - arteries
• capillaries
• Parenchymal - tubules
• ducts
• myocardium
• hepatocytes
• acini
• bronchi
• crypts

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Antibody-mediated rejection

• The target
• Endothelium of arteries, capillaries
• HLA antigens - class I, class II,
• Endothelial antigens

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Antibody - mediated rejection

• Morphologic clues may lead to diagnosis
• Marginating cells - neutrophils, mononuclear
• Early/severe arteritis/fibrinoid necrosis
• Thromboses
• Hemorrhage/infarction
• Complement deposition

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Molecular mechanisms of Acute Rejection
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Acute Rejection - cell mediated

• The molecules
• Antigens/neo-antigens - Class II, Class I
• Adhesion molecules - V-CAM, I-CAM
• Cytokines - IL - 2
• Demonstrable by immunohistology, PCR

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Antibody-mediated rejection

• The molecules
• Antibodies - IgG (esp. IgG3), IgM
• Complement - new focus on C3d, C4d

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Mechanisms of Tissue Injury
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Acute Rejection

• Mechanisms of Tissue Injury
• Organ - Cytotoxicity
• Ischemia
• Cells - Sublethal Injury
• Necrosis
• Apoptosis
• Severity - Reversible
• Irreversible

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Concept of Tissue Priming for Rejection
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Acute Rejection - cell-mediated

• Targeting mechanisms
• ? or new expression of HLA antigens - DR
• ? expression of adhesion molecules
• I-CAM-1
• VCAM-1
• ? IFN-?, 1L-2 receptors

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Corollary Not all leukocytic infiltrates in
allografts are a response to allo-antigen
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Inflammation in the Allograft

• Pre-existing
• Ischemia
• Infection
• bacterial
• viral
• Drug reaction
• Neoplastic - PTLD
• Non-specific
• Acceptance reaction

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Acceptance Reactions

• Recognizable in experimental models
• T-lymphocytes and monocyte/macrophages
• no vasculitis, may be tubulitis
• less T cell activation, apoptosis than rejection
• ? interferon, ? IL-10 compared to rejection
• Cytotoxic cells present
• NOT BEING RECOGNIZED CLINICALLY

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Criteria for diagnosis of rejection
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Morphologic Bases of Diagnosis of Rejection
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The concept of subclinical rejection
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Morphologic predictors - of refractory
rejection of later functional loss
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Cells Involved in Chronic Rejection
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Acute Rejection

• Pathologic Findings Predicting Refractory
  Rejection
• Intimal arteritis
• Severe acute glomerulitis
• Necrotizing arteritis
• Interstitial hemorrhage
• Numerous eosinophils, plasma cells,
• monocyte/macrophages
• CD8 - rich infiltrate

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Cells involved in Chronic Rejection
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Chronic Rejection

• The Cells
• Monocyte/macrophage - IL2R
• Fibroblast/myofibroblast
• T cells - CD4

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Tissue Targets of Chronic Rejection
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Chronic Rejection

• The targets
• Parenchymal elements
• most closely correlated with outcome
• the final common pathway
• Arteries
• lesions often not sampled on Bx
• Capillary lesions
• better sampled

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Molecular Mechanisms of Chronic Rejection
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Chronic Rejection

• The Molecules
• Fibrogenic Factors
• TGF, FGF, PDGF
• Macrophage-associated
• RANTES, MCP-1, IL-6
• Cytokines
• IFN, TNF

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Molecular Pathology of Acute and Chronic
Rejection
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Not all chronic change in the allograft
represents a chronic alloimmune response
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Causes of fibrosis in the allograft

• Chronic rejection
• Infection
• Drug toxicity
• Atherosclerosis/hypertensive
• vascular disease
• Obstruction
• Recurrent disease
• Donor-related

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Early Prediction

• Rejection too patchy a process for biopsy to be
  useful

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Critical Pathologic Data

• Nature of infiltrates
• Localization of infiltrates
• Predictive features
• Differential diagnoses
• Molecular milieu