heparitin-sulfate and Graft-vs-Host-Disease

In addition to reduced-intensity conditioning, which has expanded the eligibility for hematopoietic cell transplantation (HCT) to older patients, increased availability of alternative donors, including HLA-mismatched unrelated donors, has increased access to allogeneic HCT for more patients. However, acute graft-versus-host disease (GVHD) remains a lethal complication, even in HLA-matched donor-recipient pairs. The pathophysiology of GVHD depends on aspects of adaptive immunity and interactions between donor T-cells and host dendritic cells (DCs). Recent work has revealed that the role of other immune cells and endothelial cells and components of the innate immune response are also important. Tissue damage caused by the conditioning regimen leads to the release of exogenous and endogenous "danger signals". Exogenous danger signals called pathogen-associated molecular patterns and endogenous noninfectious molecules known as damage-associated molecular patterns (DAMPs) are responsible for initiating or amplifying acute GVHD by enhancing DC maturation and alloreactive T-cell responses. A significant association of innate immune receptor polymorphisms with outcomes, including GVHD severity, was observed in patients receiving allogeneic HCT. Understanding of the role of innate immunity in acute GVHD might offer new therapeutic approaches.

Topics: Acute Disease; Adenosine Triphosphate; Allografts; Dendritic Cells; Graft vs Host Disease; Heat-Shock Proteins; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; HMGB1 Protein; Humans; Hyaluronic Acid; Immunity, Innate; Isoantigens; Molecular Targeted Therapy; Nod Signaling Adaptor Proteins; Polymorphism, Genetic; S100 Proteins; Signal Transduction; T-Lymphocytes; Toll-Like Receptors; Transplantation Conditioning

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.

Topics: Animals; Cell Proliferation; Dendritic Cells; Female; Flow Cytometry; Graft vs Host Disease; Hematologic Neoplasms; Heparitin Sulfate; Humans; Luciferases; Lymphocyte Depletion; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Stem Cell Transplantation; Survival Rate; T-Lymphocytes; Toll-Like Receptor 4; Transplantation, Homologous

In this issue of Blood, Brennan et al report that a noninfectious damage-associated molecular pattern (DAMP), heparan sulfate (HS),(1) aggravates graft-versus-host disease (GVHD) and that this enhanced severity can be dampened by administration of serine protease inhibitor α-1 antitrysin (AAT).(2)

Topics: Animals; Female; Graft vs Host Disease; Hematologic Neoplasms; Heparitin Sulfate; Humans; Male; Stem Cell Transplantation; T-Lymphocytes; Toll-Like Receptor 4

Veno-occlusive disease (VOD) is a regimen-related toxicity that occurs in the early phase of hematopoietic stem cell transplantation (HSCT). Therapeutic modalities for established VOD are limited, and severe VOD characterized by multiple organ failure is associated with a fatal prognosis despite intensive supportive care.. We analyzed the data of 95 consecutive allogeneic HSCT for childhood hematological malignancies, and assessed the efficacy of our VOD prophylaxis regimen based on danaparoid (n = 48), comparing with historical control regimen based on dalteparin (n = 47).. Eight patients (danaparoid cohort in one; dalteparin cohort in seven) developed VOD on day +30 (median onset, day +22; range, day +11 to day +28) after HSCT. The probability of developing VOD for the danaparoid cohort was 2% (95% CI, 0-6%) and that of the dalteparin cohort was 15% (95% CI, 5-26%). In the Cox hazard proportional model, the danaparoid cohort had a significant advantage over the dalteparin cohort for the prophylaxis of VOD (hazard ratio (HR), 0.0; 95% CI, 0.0-0.3; P < 0.01) without increasing hemorrhagic events.. Our findings suggest that danaparoid may have promise for the prophylaxis of VOD after allogeneic HSCT and further randomized studies are warranted.

Topics: Adolescent; Child; Child, Preschool; Chondroitin Sulfates; Dermatan Sulfate; Female; Fibrinolytic Agents; Follow-Up Studies; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Heparitin Sulfate; Hepatic Veno-Occlusive Disease; Humans; Infant; Male; Prognosis; Retrospective Studies; Survival Rate; Transplantation, Homologous

Adiponectin, a fat cell-derived protein, has been attracting considerable attention because of its antidiabetic and antiatherogenic activities. The aim of the present study is to identify molecules physiologically associating with adiponectin and to understand how the protein displays diverse biological activities.. We used an expression cloning method combined with enzyme-linked immunosorbent assay to clone adiponectin-binding proteins from the MS-5 complementary DNA library.. We successfully isolated two chemokines, stromal cell-derived factor-1 (SDF-1) and CCF18, and verified that adiponectin bound to them via its globular head. Adiponectin bound with various chemokines in vitro, such as macrophage-inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemoattractant protein-1 (MCP-1), suggesting that the protein had a feature commonly to bind to the chemokine family. The middle part of chemokines, dispensable for interacting with their receptors, was found to be important for the adiponectin binding. Although the interaction of adiponectin to SDF-1 affected neither the SDF-1-CXCR4 binding nor the SDF-1 signaling in Jurkat cells, adiponectin and heparin mutually interfered in their association to SDF-1 and MCP-1 in vitro, implying that their association might influence the distribution of adiponectin and SDF-1 in inflammatory sites. Indeed, both adiponectin and SDF-1 was positively immunostained in vascular walls in guts from acute graft-vs-host disease patients. In addition, peripheral blood of adiponectin-deficient mice contained more hematopoietic progenitors than that of wild-type mice.. Adiponectin may be involved in regulation of inflammation via binding to specific chemokines. Additionally, the interaction possibly enables adiponectin to gather and play its role in inflammatory sites.

Topics: Acute Disease; Adiponectin; Animals; Chemokines; Cloning, Molecular; Graft vs Host Disease; HeLa Cells; Hematopoietic Stem Cells; Heparitin Sulfate; Humans; Inflammation; Intestinal Diseases; Intestinal Mucosa; Intestines; Jurkat Cells; Mice; Mice, Knockout; Protein Binding; Signal Transduction