Abstract
Lung allograft rejection results in the accumulation of low–molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein, we investigated the use of 4-Methylumbelliferone (4MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4MU from days 20 to 30 after transplant was sufficient to significantly improve outcomes, characterized by a reduction in T cell–mediated lung inflammation and LMW-HA content and in improved pathology scores. In vitro, 4MU directly attenuated activation, proliferation, and differentiation of naive CD4+ T cells into Th1 cells. As 4MU has already been demonstrated to be safe for human use, we believe examining 4MU for the treatment of acute lung allograft rejection may be of clinical significance.
Highlights
Lung transplantation is the only therapy for end-stage lung disease, resulting in an improvement in overall quality of life and life expectancy [1]
Compared to control mice transplanted with an isograft donor lung, mice transplanted with allografts and treated with vehicle had noticeably worse post-transplant outcomes (Figure 1B) grossly characterized by reduced lung size and generalized diffuse erythema
We demonstrate that the accumulation of low molecular weight hyaluronic acid (LMW-HA) fragments is associated with tissue injury and acute allograft rejection
Summary
Lung transplantation is the only therapy for end-stage lung disease, resulting in an improvement in overall quality of life and life expectancy [1]. T-cells clonally expand, differentiate into effector cells, and subsequently migrate to sites of inflammation (e.g., the donor lung graft). CD4+ T-cells can differentiate into either Th 1 or Th2; Th1 cells are primarily associated with acute cellular rejection and produce IFNG, TNFA, and IL-2 that can stimulate the humoral response, increase expression of MHC on DCs and prime CD8+ T-cells, while CD8+ T-cells primed by both DCs and Th1 cells [5] differentiate into cytotoxic T-cells that directly kill target donor cells via secretion of perforin and granzyme B or cell-to-cell contact via the FAS/FASL pathway and are major contributors to graft rejection in murine models of allograft transplantation [6]. At the donor tissue site, effector T-cells can activate other immune cells including macrophages, neutrophils, eosinophils, and basophils.
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