Transplantation tolerance and its outcome during infections and inflammation

Abstract

Summary Much progress has been made towards understanding the mechanistic basis of transplantation tolerance in experimental models, which includes clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells that mediate infectious tolerance and linked-suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, but the basis for these challenges are beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long-periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable lifelong tolerance in transplant recipients.

Cytotoxic potential of decidual NK cells and CD8+ T cells awakened by infections

“…Uncontrolled placental viral (and bacterial) infections also provide a pro-inflammatory milieu that can alter the stability and function of Treg and the activation status of dNK and CD8+ EM dT (Chong and Alegre, 2014). Infections can result in enhanced alloreactivity, resistance to tolerance induction and destabilization of established tolerance.…”

“…Infections can result in enhanced alloreactivity, resistance to tolerance induction and destabilization of established tolerance. Similarly, infections in transplant recipients have been associated with failure to induce transplant tolerance and allograft rejection even after long periods of transplant tolerance (Chong and Alegre, 2014; Wang et al, 2010). …”

The Critical Role of Innate Immunity in Kidney Transplantation

“…Some T cells specific for microbial peptides presented by self-major histocompatibility complex (MHC) molecules can cross-react with allogeneic MHC, while bacterial superantigens can directly activate large populations of T cells. Therefore, infections experienced before transplantation can give rise to memory alloreactive T cells that may be more resistant to immunosuppression than naïve T cells [47]. Infections occurring late after transplantation may, in theory, elicit pro-inflammatory signals that activate tolerant T cells by enabling their escape from immunosuppression and/or peripheral mechanisms of tolerance, thereby precipitating rejection [48].…”

New insights into the mechanisms of Treg function

“…It is clear that exposure to infections and environmental antigens generates effector/memory T cells that cross-react with alloantigens. These effector/memory T cells make up a significant part of the alloimmune response and are relatively resistant to immunosuppressive and tolerogenic regimens [22,23]. Importantly, unlike naïve T cells, effector/memory T cells can directly migrate to the allograft to mount rejection, without prior activation in SLO [24,25].…”