Erosion of Transplantation Tolerance After Infection.
Recent clinical studies suggest that operational allograft tolerance can be persistent, but long-term surviving allografts can be rejected in a subset of patients, sometimes after episodes of infection. In this study, we examined the impact of Listeria monocytogenes (Lm) infection on the quality of tolerance in a mouse model of heart allograft transplantation. Lm infection induced full rejection in 40% of tolerant recipients, with the remaining experiencing a rejection crisis or no palpable change in their allografts. In the surviving allografts on day 8 postinfection, graft-infiltrating cell numbers increased and exhibited a loss in the tolerance gene signature. By day 30 postinfection, the tolerance signature was broadly restored, but with a discernible reduction in the expression of a subset of 234 genes that marked tolerance and was down-regulated at day 8 post-Lm infection. We further demonstrated that the tolerant state after Lm infection was functionally eroded, as rejection of the long-term surviving graft was induced with anti-PD-L1 whereas the same treatment had no effect in noninfected tolerant mice. Collectively, these observations demonstrate that tolerance, even if initially robust, exists as a continuum that can be eroded following bystander immune responses that accompany certain infections.
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
J S
JS
Young
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.|Department of Biological Sciences, Chicago State University, Chicago, IL.
M D
MD
Daniels
Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
M L
ML
Miller
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
T
T
Wang
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
R
R
Zhong
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
D
D
Yin
Section of Rheumatology, Department of Medicine, The University of Chicago, Chicago, IL.
M-L
ML
Alegre
Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL.
A S
AS
Chong
D000818:Animals; D006084:Graft Rejection / Q000453:epidemiology / Q000276:immunology* / Q000821:virology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
animal models: murine; bacterial; basic (laboratory) research/science; immunosuppression/immune modulation; infection and infectious agents; tolerance: costimulation blockade; tolerance: experimental