Accelerated Onset and Increased Severity of Acute Graft-Versus-Host Disease Following Adoptive Transfer of DR6-Deficient T Cells

Abstract

DR6 is a recently identified member of the TNFR family. In a previous study, we have shown that DR6 KO mice have enhanced CD4+ T cell proliferation and Th2 cytokine production. Acute graft-vs-host disease (GVHD) results from the activation and expansion of alloreactive donor T cells following bone marrow transplantation. In this article, we demonstrate that the transfer of donor T cells from DR6 KO mice into allogeneic recipient mice in a parent into an F1 model of acute GVHD results in a more rapid onset of GVHD with increased severity. Recipients of DR6 KO T cells exhibit earlier systemic symptoms of GVHD, more rapid weight loss, earlier histopathological organ damage in the thymus, spleen, and intestines, and earlier mortality. The rapid onset of GVHD in these mice may be attributable to the enhanced activation and expansion of DR6 KO CD4+ and CD8+ T cells. Our findings support the hypothesis that DR6 serves as an important regulatory molecule in T cell immune responses. The identification and use of DR6 ligands and/or agonistic Abs to DR6 may represent useful therapeutics in the treatment of T cell-mediated diseases such as GVHD.

CCR6 regulates CD4+ T-cell–mediated acute graft-versus-host disease responses

“…The more severe pathology in WT T-cell recipients could be due to a simple mass effect, as increasing the donor T-cell inoculum in a transplantation leads to more severe GvHD, with greater morbidity and mortality (Liu et al 18 …”

Clinical Significance of Bcl–2 Gene Expression for the Prognosis and Monitoring of Acute Graft–versus–host–disease (Agvhd) in Allo–hsct

“…Острая форма реакции «трансплантат против хо зяина» (оРТПХ) остается одним из тяжелых ослож нений аллогенных трансплантаций стволовых гемо поэтических клеток (аТСГК) [5]. Несмотря на исполь зование различных препаратов и терапевтических схем профилактики и лечения частота встречаемос ти данного осложнения остается на очень высоком уровне [6].…”

Signaling Activated by the Death Receptors of the TNFR Family

“…Phenotype of DR6 knockout mice also suggests involvement of DR6 in the regulation of the immune response. Both CD4+ T and B lymphocytes from DR6-/-mice hyperproliferate and grafted DR6-/-T cells trigger accelerated and more severe graft-vs-host disease (GVHD) [94][95][96][97] . Despite the pronounced hematopoietic phenotype, discovery of the DR6 ligand came from the neuronal shore.…”