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W Fanslow

Publications and source records attributed to W Fanslow.

12 recordsLinked to original sources
PubMed2001

Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin.

CD40 is a member of the tumor necrosis factor receptor family and was first identified with a monoclonal antibody raised against bladder carcinoma. Recombinant human CD40L has been shown previously to have a direct antitumor effect on an ovarian cancer cell line and ovarian carcinoma cells isolated from ascites fluid. We show here that rhuCD40L inhibits the growth of several ovarian adenocarcinomas derived from surgical specimens and grown as xenografts in severe combined immunodeficient mice. Two 14-day treatment cycles were more effective than one. This effect is apparently not mediated by natural killer cells, because blocking natural killer cell activity by antiasialo GM-1 did not diminish this effect. In addition to suppression of tumor growth, treatment with rhuCD40L resulted in an increased expression of FasL, an increase in apoptosis, and histological changes including increased fibrosis and areas of tumor destruction. Using this model, we examined the efficacy of rhuCD40L in combination with chemotherapeutic agents. The antitumor effect of rhuCD40L in combination with 4 mg/kg cisplatin (CDDP) was increased over the effect of CDDP alone. Furthermore, rhuCD40L increased the efficacy of a suboptimal dose of CDDP (2mg/kg) such that it matched that of high-dose CDDP alone. These data suggest a role for rhuCD40L therapy in combination with platinum based regimens for primary treatment of epithelial ovarian tumors.

Animals↗
PubMed2001

ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells.

New members of the extended MHC class I-like family were identified based on their ability to bind human cytomegalovirus glycoprotein UL16 and/or their mutual homology. Soluble UL16 binding proteins (ULBP) competed with each other for binding to NK cells. Treatment of human and mouse NK cells with ULBP led to increased production of cytokines/chemokines, proliferation, cytotoxic activity and up-regulation of activation-associated surface molecules. The presence of ULBP during the stimulation phase of the CTL assay caused increased cytotoxic activity. Addition of soluble recombinant UL16 protein inhibited the biological activities mediated by ULBP, suggesting the existence of a novel mechanism utilized by CMV to evade elimination by the host immune system.

Animals↗
PubMed2001

ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.

The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB. The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB. The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16. The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell-resistant target cells confers susceptibility to NK cell cytotoxicity. Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus-infected cells might evade attack by the immune system.

Amino Acid Sequence↗
PubMed1999

Synergistic action of fms-like tyrosine kinase 3 ligand and CD40 ligand in the induction of dendritic cells and generation of antitumor immunity in vivo.

Daily treatment of mice with fms-like tyrosine kinase 3 ligand (Flt3L) leads to a significant increase in the number of dendritic cells and induces antitumor immunity. Here, we show that Flt3L and CD40 ligand (CD40L) synergize in the generation of immune responses against two poorly immunogenic tumors, leading to complete tumor rejection in a high proportion of mice. Rechallenge of the Flt3L + CD40L-treated mice with the immunizing tumor resulted in complete inhibition of tumor growth, indicating that these animals had developed long-lasting antitumor immunity. In addition, we demonstrate that endogenous CD40L plays a critical role in antitumor immunity, since blockade of CD40-CD40L interactions in vivo prevents the generation of antitumor immunity in therapeutic and vaccination protocols. Dendritic cells generated in mice treated with Flt3L alone or in combination with CD40L were equally potent in stimulating allogeneic T cells and expressed similar levels of MHC class II, CD80, and CD86. However, mice treated with Flt3L + CD40L had significantly more dendritic cells than mice treated with either of the cytokines alone, suggesting that CD40L promotes the proliferation and/or survival of dendritic cells generated by Flt3L treatment. Dendritic cells generated in this manner are likely to be involved in the priming of antitumor immune responses.

Adjuvants, Immunologic↗
PubMed1998

Recombinant CD40L treatment protects allogeneic murine bone marrow transplant recipients from death caused by herpes simplex virus-1 infection.

Posttransplant infection associated with host immune deficiency is the major cause of nonrelapse mortality of human bone marrow transplant recipients. In a new murine model of posttransplant infection, allogeneic bone marrow transplant recipients were infected with herpes simplex virus-1 (HSV-1) via intraperitoneal inoculation 12 weeks after transplantation. Allogeneic transplant recipients with graft-versus-host disease (GVHD) had significantly increased mortality from HSV-1 encephalitis, with deficiencies of both specific anti-HSV-1 antibody and total serum IgG2a. GVHD mice displayed a Th2 cytokine profile (increased interleukin-4 [IL-4] and decreased interferon-gamma) and decreased lipopolysaccharide (LPS) responses, suggesting that both T-cell and B-cell defects contributed to the impaired production of antibody. Because passive transfer of hyperimmune serum protected mice from HSV-1 infection, we hypothesized that CD40 ligand (CD40L), which induces B-cell maturation, would protect mice from HSV-1 infection. CD40L-treated GVHD mice showed elevated IgG2a levels and increased survival compared with vehicle-treated transplant recipients.

Animals↗
PubMed1996

Complete nucleotide sequence of the mouse CTLA8 gene.

The gene encoding the mouse cytotoxic T-lymphocyte-associated antigen 8 (CTLA8) has been cloned and its complete nucleotide (nt) sequence determined. Sequence and polymerase chain reaction (PCR) analysis indicated that the published CTLA8 sequence[Rouvier et al., J. Immunol. 150 (1993), 5445-5456] was of rat rather than mouse origin. The mouse CTLA8 gene contains two exons and one intron. The 5'flanking region contains several consensus motifs for binding to transcription factors and the 3' untranslated region (UTR) has AU-rich motifs associated with RNA instability. The putative exon sequences predict that the full-length mouse CTLA8 molecule contains 147 amino acids (aa) and shares 88% aa identity with rat CTLA8 and 57% aa identity to HSV13, an open reading frame (ORF) from herpesvirus saimiri (HVS).

Animals↗
PubMed1996

Molecular pathology of the X-linked hyper-immunoglobulin M syndrome: detection of wild-type transcripts in a patient with a complex splicing defect of the CD40 ligand.

The X-linked hyper-immunoglobulin M syndrome (XHIM) is a primary immune deficiency disorder characterized by an inability to produce immunoglobulin isotypes other than immunoglobulin M (IgM) and IgD. Recently, a B-cell surface antigen (CD40) and its conjugate T-cell counterstructure (CD40 ligand) were shown to mediate immunoglobulin isotype switching in the presence of cytokines such as interleukin 4. Most patients with XHIM have been shown to have mutations of the extracellular domain of the CD40 ligand. Here we describe a novel point mutation of an intronic splice acceptor site which results in a complex splicing defect of the CD40 ligand in a patient with XHIM. In addition to two species of deleted transcripts, wild-type transcripts were also detected in this individual. The demonstration of wild-type CD40 ligand transcripts may be an explanation for previous observations suggesting that some XHIM patients are able to undergo immunoglobulin isotype switching in vivo.

Adolescent↗
PubMed1995

Epstein-Barr virus-induced human B-cell lymphoma arising in HuPBL-SCID chimeric mice: characterization and the role of CD40 stimulation in their treatment and prevention.

The transfer of human peripheral blood lymphocytes (huPBL) from EBV-seropositive donors into mice with severe combined immune deficiency (SCID) has been shown previously to result in the generation of human EBV-induced B-cell lymphomas. These lymphomas are similar to the aggressive lymphomas that arise clinically in immunocompromised individuals. We have assessed the p53 status of these human B-lymphomas and the clonality of cell lines established from tumors growing in the huPBL-SCID mice. While the lymphoma cell lines were demonstrated to be pauciclonal by Southern analysis, none of the lines demonstrated mutated p53 as determined by immunoprecipitation studies using antibodies specific for mutant p53. The cell lines were all positive for CD40, a marker present on normal and neoplastic B cells. Antibodies to CD40 significantly inhibited the growth of these EBV-transformed B-cell lymphomas both in vitro and in vivo. When partially purified human B cells were incubated with either anti-CD40 or anti-IgM in the presence of EBV-containing supernatants in vitro, only anti-CD40 prevented transformation by EBV. Treatment of huPBL-SCID mice with anti-CD40 also prevented the occurrence of the EBV lymphomas. However, long-term human B-cell engraftment was not inhibited as determined by the presence of serum human immunoglobulin in the chimeric mice. Overnight incubation of the huPBL with anti-CD40 did not prevent the incidence of lymphomas in huPBL-SCID chimeras suggesting that continuous exposure to anti-CD40 is required. These studies suggest that anti-CD40 may be of significant clinical use in the treatment or prevention of EBV-induced B-cell lymphomas.

Animals↗
PubMed1988

The influence of hepatocellular function on NK and T cell tumoricidal activity.

Recent studies by this group have demonstrated that hepatocellular integrity is important in the preservation of host cellular immune function. This study evaluated the effect of experimental hepatocellular dysfunction (EHD) on host antineoplastic defense mechanisms. In nonspecific immune studies, we examined the effect of EHD on Wistar Furth (WF) natural killer (NK) cell cytotoxicity; in specific immune studies, we assessed WF C3H/HeJ lymphocytic responsiveness to both T cell mitogen and unmodified syngeneic fibrosarcoma. In concurrent studies, we evaluated the effect of EHD on interleukin-2 (IL-2) synthesis, an important NK and T cell trophic factor. WF rats and C3H/HeJ mice were assigned to three groups: EHD induced by bile duct ligation, sham, and normal control (NC). At day 21 serum bilirubin, WF NK cytotoxicity to YAC-1 tumor cells, WF and C3H/HeJ lymphocytic responsiveness to phytohemagglutinin (PHA) and syngeneic MCA-fibrosarcoma (MCA-F), and WF T-helper IL-2 production were determined in respective groups. Serum total bilirubin was elevated in EHD rats and mice with respect to controls (p less than 0.01). Wistar Furth cytotoxicity to the YAC-1 tumor cells was depressed in EHD animals with respect to sham and NC groups at 12.5:1 (p less than 0.01), 25:1 (p less than 0.05), 50:1 (p less than 0.05), and 100:1 (p less than 0.05) effector/target cell ratios. WF T cell responsiveness to PHA was depressed in EHD with respect to controls (p less than 0.01). C3H/HeJ lymphoproliferative response to MCA-F tumor antigen was also depressed in EHD animals when compared with control groups with the addition of 12.5 X 10(3) (p less than 0.05) and 50 X 10(3) (p less than 0.05) MCA-F cells. These impairments in NK and T cell function in EHD could not be attributed to diminished IL-2 production (EHD vs sham and NC: 112,141 +/- 5232 vs 106,691 +/- 1419 and 120,759 +/- 3248 cpm, respectively). These results demonstrate that hepatocellular failure compromises NK and T cell tumoricidal function, an effect not resultant on diminished T helper IL-2 production.

Animals↗