What is the mechanism of rejection of a heart transplant allograft in adult patients with a history of heart disease?

Mechanism of Heart Transplant Allograft Rejection

Heart transplant rejection occurs through two primary pathways: antibody-mediated rejection (AMR), where recipient antibodies target donor HLA antigens on the vascular endothelium triggering complement activation and tissue injury, and T-cell mediated cellular rejection involving direct lymphocyte infiltration and myocyte damage. 1

Antibody-Mediated Rejection (AMR) Mechanism

AMR develops when recipient antibody is directed against donor HLA antigens on the endothelial layer of the allograft, inducing fixation and activation of the complement cascade, resulting in tissue injury. 1

Pathophysiologic Cascade

• Complement activation serves as a key contributor to AMR pathogenesis, resulting in activation of both innate and adaptive immune responses. 1

• Complement and immunoglobulin are deposited within the allograft microvasculature, triggering an inflammatory process characterized by:

  • Endothelial cell activation 1
  • Upregulation of cytokines 1
  • Infiltration of macrophages 1
  • Increased vascular permeability 1
  • Microvascular thrombosis 1
  • This process ultimately manifests as allograft dysfunction 1

Temporal Presentation of AMR

• Hyperacute rejection occurs within 0 to 7 days after transplantation in patients sensitized to donor HLA antigens, caused by preformed donor-specific antibodies binding to endothelial cells. 1, 2

• Early AMR may occur during the first month after transplantation due to development of de novo donor-specific antibodies (DSA) or preexisting DSA, and tends to be associated with higher prevalence of allograft dysfunction and hemodynamic compromise. 1

• Late AMR occurs months to years after transplantation, with approximately 50% of heart transplant recipients who develop rejection >7 years after transplantation having evidence of AMR. 1

• AMR can present concurrent with cellular rejection in up to 24% of cases. 1, 3

Histopathologic Features of AMR

The vascular endothelium is the point of first contact for anti-donor antibody in the allograft and the primary locus of activity in AMR, with myocardial capillaries, arterioles, and venules being readily affected. 1, 3

Microscopic Findings

• Enlarged or swollen endothelial cells (both cytoplasm and nuclei) are consistently seen, reflecting endothelial activation as a consequence of intracellular signaling induced by antibody and subsequently complement binding to surface antigen epitopes. 1

• Vasculitis or leukocytes infiltrating through the endothelium into the vessel wall demonstrates active humoral immunity with antibody-dependent cytotoxicity, cytokine- and chemoattractant-mediated homing, and circulating monocyte recruitment. 1

• Intravascular thrombi can be seen in these vessels, particularly in severe manifestations. 1

• Interstitial edema and hemorrhage are also seen in AMR. 1

Cellular (T-Cell Mediated) Rejection Mechanism

Acute cellular rejection is primarily T-cell mediated, occurring days to months after transplantation, diagnosed by histological identification of interstitial leukocyte infiltration with various degrees of myocyte damage. 2

Allorecognition Pathways

• The trigger to cell-mediated rejection is allorecognition, where recipient T cells detect donor antigens through two distinct mechanisms: the direct pathway (recognition of intact foreign MHC molecules on donor cell surfaces) and the indirect pathway (donor MHC molecules processed and presented as peptides by host antigen presenting cells). 4

• Acute rejection is predominantly triggered by the direct pathway, although the indirect pathway can suffice if the direct pathway is blocked. 4

• The direct pathway is unlikely to contribute to chronic rejection as donor antigen presenting cells become depleted with time, while the indirect pathway shows association with chronic rejection. 4

Clinical Implications and Outcomes

• Subclinical AMR (complement deposition without allograft dysfunction) appears to be associated with poor outcomes, with patients having significantly worse cardiovascular mortality than those with isolated cellular rejection (21.2% versus 12.6%, P=0.009). 1

• Patients with subclinical AMR are more likely to develop cardiac allograft vasculopathy than control groups. 1

• The status of the graft itself plays a dominant role in defining the type of rejection even in the face of an established alloimmune response, with ischemia-reperfusion injury enhancing accumulation of effector T cells within the graft. 5