Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease

Abstract

Summary:Acute graft-versus-host disease (aGVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Recently, accumulating evidence indicates that the Fas/Fas ligand (FasL) system is implicated in the pathogenesis of aGVHD in murine models. We determined the serum levels of soluble FasL (sFasL) in BMT recipients using an enzyme-linked immunosorbent assay. The serum sFasL was suppressed during the period of myelosuppression following the preparative regimen and subsequently increased with hematopoietic reconstitution after BMT. In patients with aGVHD, the serum sFasL level was significantly higher than in those without aGVHD. In the mixed lymphocyte reaction assay, sFasL in the supernatants was increased with a significant correlation to the level of 3 H-thymidine uptake. Our findings suggest that the Fas/FasL system is activated by allogeneic stimulation and may have close correlation to the development of aGVHD in human BMT. Keywords: bone marrow transplantation; graft-versushost disease; Fas; soluble Fas ligand Allogeneic bone marrow transplantation (BMT) is a clinical treatment modality for a variety of hematologic diseases. Acute graft-versus-host disease (aGVHD) remains a main complication following BMT. The host-reactive T cells play a major role in the pathogenesis of GVHD, proven not only by studies of experimental murine BMT models but also by several clinical studies. 1,2 However, the precise mechanism of the development of tissue damage associated with aGVHD has not been clarified.Fas (Apo-1, CD95) is a member of the tumor necrosis factor (TNF) receptor family and transmits an apoptotic cell death signal upon ligation with Fas ligand (FasL). 3 Fas is expressed in target tissues of aGVHD including the skin, liver and intestine. 4 The involvement of the Fas/FasL system in the development of aGVHD has been demonstrated in murine BMT models. [5][6][7][8] Recipients transplanted from allogeneic FasL-defective mice exhibited less symptoms of aGVHD compared with those transplanted from allogeneic normal mice. 5 However, little information is available about the involvement of the Fas/FasL system in complications associated with human BMT.FasL is released from the T cell surface by metalloproteinase-mediated processing. 9 The soluble FasL (sFasL) is increased in the sera of some patients with large granular lymphocytic leukemia and natural killer cell lymphoma. 10 In the present study, we examined the serum sFasL levels in BMT recipients using the enzyme-linked immunosorbent assay (ELISA) to evaluate the implication of sFasL in clinical aGVHD. Patients and methods Patients and sera samplesWe retrospectively analyzed sera from 21 BMT recipients transplanted between June 1995 and November 1997. There were 17 males and four females with a median age of 33.0 years (range 17-47 years). Nine patients with chronic myelogenous leukemia, five with acute lymphoblastic leukemia, four with acute myeloblastic leukemia, two with myelodysplastic syndrome, and one with severe aplastic anemia were ...

Analysis of natural killer–cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease

“…[1][2][3] Characteristic findings are also the high levels of various cytokines, such as interleukin 6 (IL-6), IL-8, IL-10, IL-18, interferon ␥ (IFN-␥), and tumor necrosis factor ␣ (TNF-␣) and also high plasma concentrations of sCD25 and sCD95-ligand. [4][5][6] In some cases HLH may occur in patients of any age undergoing therapeutic immune suppression. In such cases, also defined as "secondary," immune suppressive treatment withdrawal may result in control of HLH.…”

Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell–induced apoptosis

“…1,2 Various genetic or acquired immunodeficiencies may be involved. [3][4][5] In addition to high levels of interleukin-6 (IL-6), IL-8, interferon-␥ (IFN-␥), IL-10, macrophage inflammatory protein-1␣ (MIP-1␣), macrophage-colonystimulating factor (M-CSF), and tumor necrosis factor-␣ (TNF-␣), very high plasma concentrations of sCD25, sCD95-ligand, 5,6 and IL-18 7 are characteristic. By contrast, the inflammatory marker IL-1␤ is not elevated.…”

Fas and Fas Ligand Expression in Maternal Blood and in Umbilical Cord Blood in Preeclampsia

“…We hypothesized that abnormal activation of the Fas-FasL pathway in pregnancy-related hypertension would result in increased amounts of the soluble forms of the Fas receptor or of FasL, as has been observed in other disease states linked with this pathway (4,6,25,26). We further hypothesized that surface expression of Fas or FasL might also be elevated in maternal or CB leukocytes in this disorder, because inflammation has been associated with up-regulated expression of these proteins (27).…”