Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Abstract

Exposure to certain viruses and parasites has been shown to prevent the induction of transplantation tolerance in mice via the generation of cross-reactive memory T cell responses or the induction of bystander activation. Bacterial infections are common in the perioperative period of solid organ allograft recipients in the clinic, and correlations between bacterial infections and acute allograft rejection have been reported. However, whether bacterial infections at the time of transplantation have any effect on the generation of transplantation tolerance remains to be established. We used the Gram-positive intracellular bacterium Listeria monocytogenes (LM) as a model pathogen because its effects on immune responses are well described. Perioperative LM infection prevented cardiac and skin allograft acceptance induced by anti-CD154 and donor-specific transfusion in mice. LM-mediated rejection was not due to the generation of cross-reactive T cells and was largely independent of signaling via MyD88, an adaptor for most TLRs, IL-1, and IL-18. Instead, transplant rejection following LM infection was dependent on the expression of the phagosome-lysing pore former listeriolysin O and on type I IFN receptor signaling. Our results indicate that bacterial exposure at the time of transplantation can antagonize tolerogenic regimens by enhancing alloantigen-specific immune responses independently of the generation of cross-reactive memory T cells.

The composition of the microbiota modulates allograft rejection

“…These pathways have been previously associated with transplant rejection, as NF-κB inhibition in DCs with decoy oligodeoxyribonucleotides has been shown to promote allograft survival (16). Similarly, type I IFN therapy has been associated with liver rejection in the clinic (17), and viral and bacterial infections that induce a type I IFN response were reported to prevent the induction of transplantation tolerance (18)(19)(20). Peritoneal and splenic mononuclear phagocytes have been shown to require signals from the microbiota to elicit NK cell priming and antiviral immunity, including expression of type I IFN genes, and to promote an activating epigenetic transcriptional landscape for cytokine production (21,22).…”

Alloantibodies Prevent the Induction of Transplantation Tolerance by Enhancing Alloreactive T Cell Priming

“…Administration of anti-K d mAbs, but not isotype control mAbs, to anti-CD154/DST-treated recipients on the day of skin transplantation resulted in the acute rejection of the skin allografts (MST = 12 d; p = 0.0013) (22). To confirm that the rejection was not due to the presence of contaminating endotoxin (23)(24)(25), anti-K d mAbs were denatured by heating for 10 min at 100˚C and then injected into anti-CD154/DST-treated B6 recipients. In addition, anti-K d mAbs injected into B6 recipients of C3H skin grafts (H-2 k ) treated with anti-CD154/C3H-DST.…”

Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling

“…New evidence now hints at an important role of the innate immune system in the development of organ rejection (Goldstein et al, 2003;Palmer et al, 2006;de Groot et al, 2008;Wang et al, 2008). The innate immune system recognizes pathogen-associated molecular patterns by pattern recognition receptors (Medzhitov et al, 1997).…”