Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection
Daniel R. Goldstein, … , Shizuo Akira, Fadi G. Lakkis
Daniel R. Goldstein, … , Shizuo Akira, Fadi G. Lakkis
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1571-1578. https://doi.org/10.1172/JCI17573.
View: Text | PDF
Article

Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection

Abstract

The Toll-like receptors (TLRs) are recently discovered germline-encoded receptors on APCs that are critically important in innate immune recognition of microbial pathogens. However, their role in solid-organ transplantation is unknown. To explore this role, we employed a skin allograft model using mice with targeted deletion of the universal TLR signal adaptor protein, MyD88. We report that minor antigen–mismatched (HY-mismatched) allograft rejection cannot occur in the absence of MyD88 signaling. Furthermore, we show that the inability to reject these allografts results from a reduced number of mature DCs in draining lymph nodes, leading to impaired generation of anti–graft-reactive T cells and impaired Th1 immunity. Hence, this work demonstrates that TLRs can be activated in a transplant setting and not solely by infections. These results link innate immunity to the initiation of the adaptive alloimmune response.

Authors

Daniel R. Goldstein, Bethany M. Tesar, Shizuo Akira, Fadi G. Lakkis

×

Figure 5

Options: View larger image (or click on image) Download as PowerPoint
Impaired Th1 immune but intact Th2 immune responses in MyD88–/– recipien...
Impaired Th1 immune but intact Th2 immune responses in MyD88–/– recipients of male allografts. WT and mutant mice were grafted with corresponding male allografts, and draining lymph nodes were isolated 14 days after transplantation. Gene expression for IFN-γ (a) and IL-4 (b) was quantified using real-time PCR and reported as fold increase compared with that of naive mice in each group. The results show that in comparison to WT counterparts, MyD88–/– recipients had impaired upregulation of IFN-γ gene expression (5.5-fold vs. 23-fold increase, *P = 0.0002). However, IL-4 gene expression was equally well expressed (4.0-fold vs. 3.14-fold increase, **P = 0.6). Experiments were repeated in triplicate.