title: Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation.
abstract: Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.
authors: Department of Surgery, Duke University, Durham, NC 27710, USA.
authors: Todd V
authors: TV
authors: Brennan
authors: Liwen
authors: L
authors: Lin
authors: Xiaopei
authors: X
authors: Huang
authors: Diana M
authors: DM
authors: Cardona
authors: Zhiguo
authors: Z
authors: Li
authors: Keith
authors: K
authors: Dredge
authors: Nelson J
authors: NJ
authors: Chao
authors: Yiping
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003713:Dendritic Cells; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000209:etiology* / Q000401:mortality; D019337:Hematologic Neoplasms / Q000150:complications* / Q000628:therapy; D006497:Heparan Sulfate / Q000009:adverse effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D014184:Transplantation, Homologous
chemical_list: D006497:Heparan Sulfate; D008156:Luciferases; D051197:Toll-Like Receptor 4