Jingwu Xu

Elevated Serum Transforming Growth Factor β1 Levels in Epstein-Barr Virus-Associated Diseases and Their Correlation with Virus-Specific Immunoglobulin A (IgA) and IgM

ABSTRACT Transforming growth factor β (TGF-β) is an immunosuppressive cytokine which can induce immunoglobulin A (IgA) switch and Epstein-Barr virus (EBV) replication in latently infected cells. Here we report elevated serum levels of TGF-β in various EBV-associated diseases correlating positively with EBV-specific IgA titers and negatively with IgM titers, suggesting a role for this cytokine in the pathogenesis of these diseases.

Thrombin induces apoptosis in human tumor cells.

Thrombin is a serine protease that is produced during the coagulation process and plays an essential role for hemostasis, thrombosis and wound healing. It is a potent activator of platelets, induces proliferation of a wide variety of normal and malignant human cells, and enhances their invasiveness and metastatic potential. We studied the effect of thrombin on the proliferation of a wide variety of human tumor cells and report here that, at low concentrations, thrombin induces proliferation of these cells. However, at higher concentrations, thrombin inhibited their proliferation. We show that this inhibition of cell proliferation was due to apoptosis of the tumor cells. The thrombin‐mediated apoptosis was inhibited significantly by its specific inhibitor, hirudin. Furthermore, no consistent pattern of induction and/or modulation of p53, p21 and bcl‐2 was observed in the thrombin‐mediated apoptosis. To our knowledge, this is the first report to describe the pro‐apoptotic effects of thrombin on human tumor cells and may have implications for chemotherapy in cancer patients and for the pathogenesis of AIDS as well. Int. J. Cancer 87:707–715, 2000.

Host's innate immune response to fungal and bacterial agents in vitro: up-regulation of interleukin-15 gene expression resulting in enhanced natural killer cell activity

Natural killer (NK) cells play an important role in the first line of defence against viral infections. We have shown earlier that exposure of human peripheral blood mononuclear cells (PBMC) to viruses results in rapid up‐regulation of NK cell activity via interleukin‐15 (IL‐15) induction, and that this mechanism curtails viral infection in vitro. By using Candida albicans, Escherichia coli and Staphylococcus aureus, we now show here that exposure of PBMC to fungi and bacteria also results in an immediate increase of NK cytotoxicity. Reverse transcriptase–polymerase chain reaction and Western blot analyses as well as the use of antibodies against different cytokines revealed that IL‐15 induction played a predominant role in this NK activation. These results indicate that IL‐15 is also involved in the innate immune response against fungal and bacterial agents.

Modulatory effects of human herpes virus‐7 on cytokine synthesis and cell proliferation in human peripheral blood mononuclear cell cultures

Human herpes virus‐7 (HHV‐7) infects cells of the immune system and thus may modulate their function. To investigate the potential immunomodulatory effects of this virus, we performed an in vitro study in which we investigated effects of HHV‐7 on the synthesis of several key immunomodulatory cytokines, i.e. tumor necrosis factor α (TNF‐α), interleukin‐2 (IL‐2), interferon‐γ (IFN‐γ), IL‐4, IL‐6, and transforming growth factor β (TGF‐β). This was examined after in vitro infection of human peripheral blood mononuclear cells (PBMC) with HHV‐7. We found elevated levels of TNF‐α, TGF‐β, and IFN‐γ in the supernatants of HHV‐7‐infected cells. By reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis, using cytokine‐specific primers, we found that levels of TNF‐α, TGF‐β, and IFN‐γ mRNA were increased in the infected cells. The HHV‐7 infection also significantly (P < 0.05) decreased the production of IL‐2 from activated, IL‐2‐producing PBMC. Furthermore, mitogen‐ and cytokine‐induced cellular proliferative responses of human PBMC were found to be significantly (P < 0.05) down‐regulated by this virus. On the other hand, HHV‐7 did not affect IL‐4 and IL‐6 synthesis. Overall, our results indicate that HHV‐7 infection causes significant immunomodulatory effects with regard to cytokine synthesis in these cells as well as inhibiting lymphocyte proliferation by various stimuli. J. Leukoc. Biol. 66: 822–828; 1999.

The Epstein‐Barr Virus (EBV) major envelope glycoprotein gp350/220‐specific antibody reactivities in the sera of patients with different EBV‐associated diseases

gp350 of Epstein‐Barr virus (EBV) induces a strong immune response in EBV‐infected individuals, but relatively little is known about the clinical relevance of this response in patients with different EBV‐associated malignancies and other diseases. Using our gp350‐expressing cell clones, we studied gp350‐specific humoral immune responses in the sera of individuals with nasopharyngeal carcinoma (NPC), chronic symptomatic EBV infection (CEI), Hodgkins disease (HD), acute infectious mononucleosis (IM) and healthy EBV‐seropositive individuals (HI). The titres of antibody‐dependent cellular cytotoxicity (ADCC) antibodies were highest in HI followed by CEI, HD and NPC. EBV‐neutralizing (NA) and gp350‐specific IgG antibody profiles in these conditions were: CEI > HI > NPC > HD, whereas IgA titres were the highest in NPC sera followed by CEI and HD. The sera from IM patients were found to be negative for gp350‐specific ADCC and IgA activities. Sera from HI were also negative for gp350‐specific IgA. A significant positive correlation was found between serum gp350 IgA and viral capsid antigen IgA and a significant negative one between IgM and ADCC titres. High IgA titres were also found in CEI and EBV‐genome positive HD in addition to NPC. Importantly, gp350‐specific IgA titres were of prognostic value in NPC patients. Our data provide new insights about the clinical relevance of gp350‐specific immune responses in these diseases. Int. J. Cancer (Pred. Oncol.) 79:481–486, 1998.© 1998 Wiley‐Liss, Inc.

Comparison of Human Immunodeficiency Virus (HIV)-Specific Infection-Enhancing and -Inhibiting Antibodies in AIDS Patients

ABSTRACT The humoral immune response of the human host against the human immunodeficiency virus (HIV) type 1 (HIV-1) envelope glycoproteins comprises virus-neutralizing antibodies (NAs), antibody-dependent cellular cytotoxicity-mediating (ADCC) antibodies, and infection-enhancing antibodies (IEAs). Because of their potential significance for the outcome of infection with this virus, we have studied the relative prevalence of NAs, ADCC antibodies, and IEAs in the sera of patients infected with HIV. Our results demonstrate that while ≥60% of serum samples are positive for NAs or ADCC antibodies, 72% of these serum samples mediate the enhancement of infection in the presence of complement. In patients with low CD4 counts, NA and ADCC antibody levels tend to decrease, while IEA levels increase. A significant positive correlation was found only between the presence of ADCC antibodies and the presence of antibodies that neutralized HIV-1 in the presence of complement. These results show that the anti-HIV-1 humoral immune response consists of a mixture of antibodies that may inhibit or enhance HIV infection and whose ratios may vary in different stages of the infection.

Preferential Localization of the Epstein-Barr Virus (EBV) Oncoprotein LMP-1 to Nuclei in Human T Cells: Implications for Its Role in the Development of EBV Genome-Positive T-Cell Lymphomas

ABSTRACT The Epstein-Barr virus (EBV)-encoded latent membrane protein-1 (LMP-1) is thought to play a role in the EBV-induced B-cell transformation and immortalization. EBV has also been implicated in certain human T-cell lymphomas; however, the phenotypic effects of the expression of this oncoprotein in T cells are not known. To learn whether LMP-1 also induces phenotypic changes in T cells, we stably expressed it in human cell lines of T and B lineages and 25 LMP-1-expressing T-cell clones and 7 B-cell clones were examined. Our results show for the first time that, in sharp contrast to B cells, LMP-1 preferentially localizes to nuclei in T cells and does not induce the phenotypic changes in these cells that it induces in B cells, does not associate with TRAF proteins, and does not arrest the cell cycle in the G2/M phase. A computer-assisted analysis revealed that LMP-1 lacks the canonical nuclear localization signal. Our results suggest that this oncoprotein may not play the same role in the lymphomagenesis of T cells as it does in B cells.