TLR Engagement Prevents Transplantation Tolerance

Abstract

In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4 + /FoxP3 + regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.

The Innate Immune System in Allograft Rejection and Tolerance

“…Additional studies have focused on the role of TLRs and inflammation in tolerance induction. Two groups have reported that long-term graft survival in a highly immunogenic, fully allogeneic skin transplant model can be achieve with costimulatory blockade if both host and recipient are MyD88 deficient (51,52). In one of these reports, Walker et al (51) provide evidence to support a model in which absence of MyD88 impairs DC production of IL-6, in turn rendering alloreactive T cells more susceptible to suppression by CD4 ϩ CD25 ϩ regulatory T cells (Tregs).…”

“…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.…”

“…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.…”

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

“…We and others have also shown that engagement of single TLRs, receptors that recognize molecular patterns expressed by viruses, fungi, parasites, and bacteria, is sufficient to prevent transplantation tolerance by anti-CD154 mAb (15)(16)(17). Conversely, elimination of the TLR adaptor MyD88 facilitated the induction of transplantation tolerance to skin allografts (15,17). Together, these experiments underscore the importance of the TLR/MyD88 pathway in the ability to prevent transplantation tolerance (18).…”

“…This is thought to occur via direct activation of cross-reacting alloreactive T cells by viral Ags (7,9) or upon bystander activation of allospecific T cells (9,12). We and others have also shown that engagement of single TLRs, receptors that recognize molecular patterns expressed by viruses, fungi, parasites, and bacteria, is sufficient to prevent transplantation tolerance by anti-CD154 mAb (15)(16)(17). Conversely, elimination of the TLR adaptor MyD88 facilitated the induction of transplantation tolerance to skin allografts (15,17).…”