Modulating the conformation of the TIR domain by a neoteric MyD88 inhibitor leads to the separation of GVHD from GVT

Abstract

Graft-versus-host disease (GVHD) remains the least curable complication after allogeneic bone marrow transplantation (BMT). Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critically involved in the toll-like receptor (TLR) signaling pathway. The Toll/IL-1 receptor (TIR) domains of MyD88 and TLR are interactional modules responsible for sorting and signaling via direct or indirect TIR–TIR interactions, which can contribute to all phases of GVHD progression. Here, we describe the mechanisms of the novel MyD88 inhibitor, TJ-M2010-5, and the discovery of its immunosuppressive properties in the context of GVHD and the graft-versus-tumor (GVT) effect in a fully MHC-mismatched murine model. TJ-M2010-5 potentially interrupted the conformation of the TIR domain through its predicted DD loops, BB loops, and Poc site, and inhibited the homodimerization of MyD88, the LPS-stimulated activation of dendritic cells, and the priming of donor allogeneic T cell proliferation in a dose-dependent manner. Oral administration of TJ-M2010-5 ameliorated the inflammatory environment, decreased the number of apoptotic cells, increased tissue repair in GVHD target organs, and suppressed lethal GVHD. Further, protection against GVHD by TJ-M2010-5 did not abrogate a GVT effect against SP2/0, a myeloma cell line. Our data define the mechanisms of actions and provide novel insight into the potential clinical uses of TJ-M2010-5 for GVHD prevention.