Erosion of Transplantation Tolerance after Infection #MMPMID27273890
Young JS; Daniels MD; Miller ML; Wang T; Zhong R; Yin D; Alegre ML; Chong AS
Am J Transplant 2017[Jan]; 17 (1): 81-90 PMID27273890show ga
Recent clinical studies suggest that operational allograft tolerance can be persistent, but long-term surviving allografts may be lost in a subset of patients, sometimes after episodes of infection. In this study, we examined the long-term impact of Listeria monocytogenes (Lm) infection on the quality of tolerance in a mouse model of heart allograft tolerance. 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 post-infection, graft-infiltrating cell numbers increased and exhibited a loss in the tolerance gene signature. By day 30 post-infection, the tolerance signature was broadly restored, but with a discernable 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 non-infected tolerant mice. Collectively, these observations demonstrate that tolerance, even if initially robust, exists as a continuum that can be eroded following by-stander immune responses that accompany certain infections.