Sunjida Ahmed

Natural killer activity of peripheral-blood mononuclear cells in breast cancer patients

Natural killer (NK) activity of immune cells plays a central role in host defense against cancer and virus-infected cells. Natural cytotoxic activity of peripheral-blood mononuclear cells was assessed by a Calcein-AM release assay in 89 subjects. In the present study, we here demonstrated that NK activities of peripheral-blood mononuclear cells (PBMCs) from breast cancer patients were significantly lower as compared with that of healthy individuals. There were significant differences in the NK activities of PBMCs from HER2-negative breast cancer patients as compared with HER2-positive patients. Our results suggest that NK activity of PBMCs is lower in breast cancer indicating a role for immunological natural host defense mechanisms against cancer.

An HIV protease inhibitor, ritonavir targets the nuclear factor-kappaB and inhibits the tumor growth and infiltration of EBV-positive lymphoblastoid B cells

Epstein‐Barr Virus (EBV)‐associated immunoblastic lymphoma occurs in immunocompromised patients such as those with AIDS or transplant recipients after primary EBV infection or reactivation of a preexisting latent EBV infection. In the present study, we evaluated the effect of ritonavir, an HIV protease inhibitor, on EBV‐positive lymphoblastoid B cells in vitro and in mice model. We found that it induced cell‐cycle arrest at G1‐phase and apoptosis through down‐regulation of cell‐cycle gene cyclin D2 and antiapoptotic gene survivin. Furthermore, ritonavir suppressed transcriptional activation of NF‐κB in these cells. Ritonavir efficiently prevented growth and infiltration of lymphoma cells in various organs of NOD/SCID/γcnull mice at the same dose used for treatment of patients with AIDS. Our results indicate that ritonavir targets NF‐κB activated in tumor cells and shows anti‐tumor effects. These data also suggest that this compound may have promise for treatment or prevention of EBV‐associated lymphoproliferative diseases that occur in immunocompromised patients.

Hodgkin's lymphoma cells are efficiently engrafted and tumor marker CD30 is expressed with constitutive nuclear factor-κB activity in unconditioned NOD/SCID/γcnull mice

As there are very few reproducible animal models without conditioning available for the study of human B‐cell‐type Hodgkins lymphoma (HL), we investigated the ability of HL cells to induce tumors using novel NOD/SCID/γcnull (NOG) mice. Four human Epstein–Barr virus‐negative cell lines (KM‐H2 and L428 originated from B cells, L540 and HDLM2 originated from T cells) were inoculated either subcutaneously in the postauricular region or intravenously in the tail of unmanipulated NOG mice. All cell lines successfully engrafted and produced tumors with infiltration of cells in various organs of all mice. Tumor cells had classical histomorphology as well as expression patterns of the tumor marker CD30, which is a cell surface antigen expressed on HL. Tumor progression in mice inoculated with B‐cell‐type, but not T‐cell‐type, HL cells correlated with an elevation in serum human interleukin‐6 levels. Tumor cells from the mice also retained strong nuclear factor (NF)‐κB DNA binding activity, and the induced NF‐κB components were indistinguishable from those cultured in vitro. The reproducible growth behavior and preservation of characteristic features of both B‐cell‐type and T‐cell‐type HL in the mice suggest that this new xenotransplant model can provide a unique opportunity to understand and investigate the mechanism of pathogenesis and malignant cell growth, and to develop novel anticancer therapies. (Cancer Sci 2005; 96: 466–473)

Mouse serum factor(s) down-modulate the CD4 and CXCR4 molecules on human T cells conferring resistance to HIV infection in NOG mice

Human cells have developed innate immunity, exploiting several means to block virus infection, and viruses have evolved diverse strategies to resist these. We show here that the human immunodeficiency virus 1 (HIV-1) could neither progressively infect engrafted human leukemic T cells nor repress their growth in NOG mice. However, ED-40515(−) cells infected with HIV-1 before inoculation were found to significantly delay the onset of tumor growth and increased the survival period of NOG mice. ED-40515(−) tumor cells showed resistance to HIV-1 which was apparently correlated with the down-regulation of CD4 and CXCR4 molecules in NOG mice. Serum from three different mouse strains, including NOG, retained a suppressive effect on the CD4 molecule of ED-40515(−) cells in vitro. ED-40515(−) cells obtained from mice re-expressed CD4 and CXCR4 molecules upon in vitro culture and were again successfully infected with HIV-1. These findings indicate that HIV-1 may initially successfully delay or regress tumor growth in NOG mice, but eventually fails to do so because of the evolution of HIV-resistant cells due to a rapid down-modulation of CD4 and CXCR4. Our data also demonstrated that some unknown soluble factor(s) present in mouse serum was responsible for conferring resistance to HIV infection to human T cells.