Effects of soy intake on sex hormone metabolism in premenopausal women.

Studies suggest that phytoestrogens in soy products may impart hormonal effects that protect women against breast cancer. Limited research suggests that intake of soy products high in isoflavonoid phytoestrogens affects sex hormone metabolism, but it is unknown whether phytoestrogens in soy have any effect on menstrual function or serum sex hormones in women on common hormone therapies, such as oral contraceptives (OC). We studied the effects of soy in 36 premenopausal women, 20 of whom used OC. Subjects consumed their normal diet for two menstrual cycles and added a soy beverage containing 20 g of protein and 38 mg of total isoflavones to their usual diet for another two menstrual cycles. No significant differences were observed in serum estrone, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prolactin, or progesterone concentrations with soy feeding in the non-OC or the OC group. No changes in menstrual cycle length or the urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone were seen with soy feeding in the non-OC or the OC group. Levels of urinary estrogen metabolites were significantly different between the non-OC and the OC group. Thus soy consumption had no significant effect on the menstrual cycle, serum sex hormones, or urinary estrogen metabolite ratio in premenopausal OC or non-OC users.

Irradiation of singly and doubly transduced murine neuroblastoma cells expressing B7-1 and producing interferon-gamma reduces their capacity to induce systemic immunity.

We have previously reported that immunization with low major histocompatibility complex (MHC) class I expressing murine neuroblastoma (neuro-2a) transduced with B7-1 fails to induce significant protection to wild-type tumor challenge. In this study we investigated whether B7-1 expressing neuro-2a cells can stimulate an effective T-cell response if they were cotransduced with the interferon-gamma (IFN-gamma) gene to upregulate MHC class I. Transfer of both the IFN-gamma and B7-1 genes into neuro-2a (N-2a/B7-1/IFN) almost completely abrogated the tumorigenic potential of this tumor and improved survival when compared with mice receiving the single transductants, N-2a/IFN and N-2a/B7-1. Rejection of N-2a/B7-1/IFN was mediated primarily by CD8+ T cells. When irradiated tumor cells were tested, IFN-gamma gene transfer into neuro-2a significantly increased immunogenicity, but transfer of the B7-1 gene did not. However, nonirradiated N-2a/B7-1, N-2a/IFN, and N-2a/B7-1/IFN cells were significantly more effective in eliciting systemic immunity against subsequent wild-type tumor challenge than their irradiated counterparts. N-2a/B7-1/IFN was more immunogenic than N-2a/B7-1 but not more than N-2a/IFN, indicating that B7-1 does not further increase immunogenicity of neuro-2a over that induced by IFN-gamma transduction. These findings should be considered when designing gene modified tumor vaccines for use in human trials.

B7-1 expression decreases tumorigenicity and induces partial systemic immunity to murine neuroblastoma deficient in major histocompatibility complex and costimulatory molecules.

Neuroblastoma may escape an immune attack by virtue of its low expression of surface accessory molecules essential in the antitumor response. Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector LB7-1SN to examine the influence of B7-1 expression on the immune response directed against a low major histocompatibility class (MHC) I and class II negative, B7-2, and ICAM-1 negative tumor. Using a retroperitoneal model for implantation of neuroblastoma in its natural site, we demonstrated that expression of B7-1 by neuro-2a reduces its tumorigenicity. Coinjection of B7-1-positive and -negative cells improved survival compared with mice receiving B7-1-negative cells alone. This was dependent on the ratio of B7-1+ to B7-1- neuro-2a cells injected. CD8+ and not CD4+ T-cell depletion significantly increased tumor-induced mortality in syngeneic A/J mice, indicating that B7-1 decreases tumorigenicity primarily by direct constimulation of CD8+ T cells. Rejection of N-2a/B7-1 tumors or preimmunization with irradiated N-2a/B7-1 cells die not increase protection to challenge with unmodified neuro-2a cells over mice vaccinated with N-2a/neo. Furthermore, cytotoxic T lymphocyte (CTL) precursor frequencies were not significantly higher after in vivo priming and in vitro stimulation with irradiated N-2a/B7-1 compared with N-2a/neo, indicating that B7-1 costimulation by the tumor, in the absence of adequate antigen presentation by MHC molecules, may limit the generation of effective CTLs.

Short-term ex vivo activation of splenocytes with anti-CD3 plus IL-2 and infusion post-BMT into mice results in in vivo expansion of effector cells with potent anti-lymphoma activity.

We investigated the proliferation and therapeutic utility of anti-CD3 activated splenocytes infused into mice following BMT. Using congenic mouse strains we demonstrated that splenocytes activated briefly ex vivo with anti-CD3 plus IL-2 (T-activated killer cells or T-AK) and infused intravenously following BMT had a greater expansion in blood, spleen and BM compared with splenocytes stimulated with IL-2 alone. T-AK cells recovered from blood, spleen and BM consisted predominantly of CD8+ T cells. A single infusion of T-AK cells given on day +1 post-syngeneic BMT and sustained in vivo with liposomal encapsulated IL-2, significantly increased survival of mice with BDL-2 lymphoma when compared with mice receiving saline and those treated with IL-2 liposomes alone. The anti-tumor effect of T-AK cells was significantly enhanced when IL-2 was given by continuous infusion compared with bolus injections. Depletion studies confirmed that the CD8+ T-AK cells were mainly responsible for the anti-tumor effect against BDL-2 lymphoma. Our findings demonstrate that brief ex vivo activation of splenocytes with anti-CD3 plus IL-2 results in in vivo proliferation of effector cells with potent anti-tumor activity following BMT.

Infusions of interleukin-1 alpha after autologous transplantation for Hodgkin's disease and non-Hodgkin's lymphoma induce effector cells with antilymphoma cytolytic activity.

We evaluated the cytolytic function, phenotypic characteristics, and cytokine levels of 22 patients with non-Hodgkin's lymphoma and 7 with Hodgkin's disease receiving interleukin-1 alpha (IL-1 alpha) following autologous bone marrow or peripheral blood stem cell transplantation. IL-1 alpha was given i.v. over 6 hr, between day 0 and day +13 posttransplant. On day +14, cells from patients receiving high-dose IL-1 alpha (3.0 micrograms/m2/day) had significantly enhanced killing of natural killer (NK)-sensitive and -resistant lymphoma targets compared to those treated with low-dose IL-1 alpha (0.1, 0.3, or 1.0 microgram/m2/day). The differences in cytolytic function between the two groups persisted but were not as striking on day +28. Patients receiving higher-dose IL-1 alpha had a significantly increased proportion of CD3+ T cells on days +14 and +28, while the proportion of CD16+ and CD56+ NK cells was decreased compared to those of patients treated with the lower dose. There were no detectable levels of IL-2, interferon-gamma, or tumor necrosis factor-alpha in the plasma of patients receiving IL-1 alpha posttransplant. However, higher-dose IL-1 alpha therapy was associated with significant increases in serum IL-6 levels in comparison to those in patients receiving low-dose IL-1 alpha. IL-1 alpha may increase cytolytic function post-bone marrow transplantation; it remains to be determined, however, whether this would have an impact on decreasing relapse rates of patients undergoing transplantation for lymphoma.