TLR Agonists Abrogate Costimulation Blockade-Induced Prolongation of Skin Allografts

101

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.

Section: Discussionmentioning

confidence: 95%

Section: Linical Data Support a Correlation Between Viral Infectionsmentioning

confidence: 99%

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

Wang¹,

Chen

Ahmed³

et al. 2008

101

“…Conversely, other studies show that despite costimulatory receptor blockade, challenge with TLR agonists such as LPS and CpG DNA at the time of allotransplantation prevents tolerance induction (52,54). Using donor-specific transfusion and CD154 Ab with a one-time TLR agonist challenge, Thornley et al (54) found that blockade of skin graft tolerance induction by TLR stimulation was associated with prevention of alloreactive CD8 ϩ T cell apoptosis.…”

Section: Examining Prr Signaling In Allotransplantationmentioning

confidence: 99%

“…Using donor-specific transfusion and CD154 Ab with a one-time TLR agonist challenge, Thornley et al (54) found that blockade of skin graft tolerance induction by TLR stimulation was associated with prevention of alloreactive CD8 ϩ T cell apoptosis. Moreover, Chen et al (52) found that blockade of heart graft tolerance induction by administering CpG DNA along with CD154 Ab occurred in conjunction with a reduced ratio of Tregs to effector T cells at the graft site.…”

Section: Examining Prr Signaling In Allotransplantationmentioning

confidence: 99%

The Innate Immune System in Allograft Rejection and Tolerance

LaRosa

Rahman

Turka

2007

168

121

As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a “rediscovery” of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely. This review will give an overview of recent studies and emerging concepts of how the cellular components of the innate immune system participate in the immune response to solid organ transplantation. These important studies highlight the complex interplay between diverse cells of the immune response and provide the basis for optimal strategies of tolerance induction.

“…TLR activation, however, provokes an inflammatory response, cytokine secretion, and APC maturation that is independent of the interaction between CD154 and CD40 (1). We have previously shown that TLR activation can bypass costimulation blockade, activate adaptive immunity, and impair allograft survival (13).…”

Section: Type 1 Ifn Mediates Cross-talk Between Innate and Adaptive Imentioning

confidence: 99%

Type 1 IFN Mediates Cross-Talk between Innate and Adaptive Immunity That Abrogates Transplantation Tolerance

Thornley

Phillips

Beaudette-Zlatanova

et al. 2007

Self Cite

TLR activation of innate immunity prevents the induction of transplantation tolerance and shortens skin allograft survival in mice treated with costimulation blockade. The mechanism by which TLR signaling mediates this effect has not been clear. We now report that administration of the TLR agonists LPS (TLR4) or polyinosinic:polycytidylic acid (TLR3) to mice treated with costimulation blockade prevents alloreactive CD8+ T cell deletion, primes alloreactive CTLs, and shortens allograft survival. The TLR4- and MyD88-dependent pathways are required for LPS to shorten allograft survival, whereas polyinosinic:polycytidylic acid mediates its effects through a TLR3-independent pathway. These effects are all mediated by signaling through the type 1 IFN (IFN-αβ) receptor. Administration of IFN-β recapitulates the detrimental effects of TLR agonists on transplantation tolerance. We conclude that the type 1 IFN generated as part of an innate immune response to TLR activation can in turn activate adaptive immune responses that abrogate transplantation tolerance. Blocking of type 1 IFN-dependent pathways in patients may improve allograft survival in the presence of exogenous TLR ligands.