Inhibition of TLR4 signaling prolongs Treg-dependent murine islet allograft survival

Abstract

Toll-like receptors (TLRs) provide an important link between innate and adaptive immune system. We hypothesized that the recognition of endogenous TLR4 ligands is occurring at the time of transplantation, and these innate signals drive the inflammation and affect alloimmune responses. We confirmed that early after transplantation of allogenic islets, transcripts for TLR4 as well as potential ligands were released or upregulated. In an allogenic islet transplantation model, genetic disruption of TLR4 on donor islets had no effect on allograft survival, whereas TLR4 deficiency in recipients lead to prolonged graft survival. Low dose rapamycin-treatment of TLR4 −/− recipients induced permanent engraftment of 45% islet graft (p=0.005) compared to WT recipients. This prolonged graft survival was dependent on the presence of CD4 + CD25 + Foxp3 + Treg. Naïve CD4 + CD25 − T cells cultured with the TLR4 ligand lipopolysaccharide showed enhanced IL-4, IL-6, IL-17, IFNγ secretion and inhibited TGFβ induced Foxp3 + Treg generation. Thus, inhibition of recipient TLR4 activation at the time of transplantation decreases proinflammatory signals and allows Treg generation.

Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

“…It has been reported that TLR4 signaling is involved in allograft survival through a Treg-dependent mechanism1819. We next determined the number of Tregs in the DLNs of mice treated with various lentiviral vectors.…”

“…Using small interfering RNA (siRNA) to silence the expression of the TLR signal adaptors MyD88 and TRIF prolongs allograft survival in a BALB/C to C57BL6 cardiac transplantation model18. In an islet transplantation model19, genetic disruption of TLR4 on donor islets had no effect on allograft survival, whereas TLR4 deficiency in recipients led to prolonged graft survival, which was dependent upon the presence of CD4 + CD25 + Foxp3 + Tregs. These two studies raised that silencing TLR signaling in organ transplantation generated Tregs, which facilitated graft survival.…”

Innate immunity in solid organ transplantation: an update and therapeutic opportunities

“…Interestingly, administration of an anti-CD25 antibody to these mice depleted Tregs and broke tolerance. There is accumulating evidence that TLR2 and TLR4 activation inhibits Treg activation [62, [70][71][72]. It is known that neither Tregs nor Th17 represent a terminally differentiated phenotype, given the plasticity of T-cell differentiation [73].…”

Roles of Toll-like receptors in transplantation

“…The addition of rapamycin further extended allograft survival and was associated with an increase in the numbers of CD4 þ CD25 þ FoxP3 þ regulatory T cells and Th2 deviation [27 & ]. TLR4 appears to play a significant role in experimental islet transplantation, as TLR4 deficiency in recipients [28] but not in donors [28,29] delayed rejection of graft across a major antigen mismatch [28]. In Goldstein et al's [24] original experiments, while MyD88 deficiency prevented rejection of skin allografts across a minor MHC mismatch, neither TLR2 nor TLR4 was found to be protective.…”