Erosion of Transplantation Tolerance After Infection

Area of Science:

• Immunology
• Transplantation Biology

Background:

• Operational allograft tolerance is crucial for long-term graft survival.
• Infections can compromise established tolerance, leading to graft rejection.

Purpose of the Study:

• To investigate the impact of Listeria monocytogenes infection on established heart allograft tolerance in a mouse model.
• To understand how bystander immune responses during infection affect the stability of allograft tolerance.

Main Methods:

• A mouse model of heart allograft transplantation was used to establish operational tolerance.
• Tolerant mice were infected with Listeria monocytogenes to assess the impact on allografts.
• Graft-infiltrating cells and gene expression profiles were analyzed post-infection.
• Functional assessment of tolerance was performed using anti-PD-L1 treatment.

Main Results:

• Listeria monocytogenes infection induced full rejection in 40% of tolerant recipients.
• Infection led to increased graft-infiltrating cells and loss of the tolerance gene signature.
• While the tolerance signature partially restored by day 30, a subset of tolerance-associated genes remained downregulated.
• Anti-PD-L1 treatment induced rejection in infected tolerant mice, but not in non-infected controls, indicating functional erosion of tolerance.

Conclusions:

• Infection-induced bystander immune responses can erode even robust operational allograft tolerance.
• Tolerance exists on a continuum and can be functionally compromised by non-specific immune activation.
• These findings highlight the vulnerability of long-term allograft survival to intercurrent infections.