L. Binaglia

Modulation of colony-stimulating activity by interleukin 1 mice: opposing effects of combined treatment with indomethacin of prostaglandin E2

Following previous observations that interleukin 1 (IL-1) may have both positive and negative effects on the levels of circulating colony-stimulating factors (CSF) in mice, we have investigated the impact of human rIL-1 beta administration on serum concentrations of colony-stimulating activity (CSA, as defined by biossay) and macrophage-specific colony-stimulating factor (CSF-1, measured by RIA). In addition, we have studied the effects of IL-1 administered in conjunction with indomethacin or prostaglandin (PG) E2. Besides confirming the finding that exogenous IL-1 leads to a rapid increase in CSF detection, we obtained evidence that IL-1 may also result in the production of cyclo-oxygenase pathway products that down-regulate the IL-1-induced burst in CSA and CSF-1 levels. While co-treatment of mice with indomethacin led to a further increase in CSF detection, the combined exposure to IL-1 and PGE2 resulted in a significant impairment of the stimulatory activity of IL-1.

Modulation of circulating colony-stimulating activity in mice : combined effects of IL-1 and bacterial or indomethacin treatment

We have investigated the effects of interleukin 1 (IL-1) administration on circulating levels of colony-stimulating activity (CSA) in intact or neutropenic mice. Intact or cyclophosphamide-treated mice received human rIL-1 beta according to different regimens, and their sera were assayed for CSA at 4, 24 or 48 h. The results indicated that (1) cyclophosphamide alone significantly increased the level of circulating CSA, (2) administration of IL-1 to intact or neutropenic mice resulted in a biphasic pattern of CSA response, an early burst at 4 h being followed at 24-48 h by a significant decrease. In nongranulocytopenic mice, the combined treatment with IL-1 and bacterial cells also resulted in a biphasic pattern of CSA response. However, when IL-1 was administered in concurrence with the cyclo-oxygenase inhibitor indomethacin, sustained CSA levels could be observed for a prolonged period of time. These data expand upon our previous observations on modulation of CSA by IL-1 in granulocytopenic mice, and further support the concept that IL-1 may have both positive and negative effects on the expression of circulating CSA.

Chemical Xenogenization of Experimental Tumors by Antineoplastic Drugs

The antigenic phenotype of experimental tumors can be modified through procedures that either directly -and rather transiently, as a rule- affect the membrane structures of the cell or involve stable, often hereditary, changes in the cell biology (e.g., the genetic code). The term of chemical xenogenizationwas introduced by our group to indicate the appearance of tumor-associated transplantation antigens in murine tumors subjected to chemical treatment, and thus rendered antigenically foreign to the host of origin (Puccetti et al., 1987). Bonmassar et al. (1970) had indeed found that murine leukemia cells, on repeated in vivo exposure to the antitumor agent dacarbazine, would become increasingly immunogenic, eventually acquiring a degree of foreignness capable of resulting in tumor cell rejection by the histocompatible host.

Cell-mediated immunity to chemically xenogenized tumors—VI. The effect of cell treatment with retroviral env antisense oligonucleotides

The occurrence of aberrant, retrovirus-related proteins is a common finding in immunogenic clones of the triazene-xenogenized L5178Y lymphoma line (L5178Y/DTIC). In clone D-cells, newly expressed 80 kDa antigens related to xenotropic murine leukemia virus env gene products induce specific humoral and cell-mediated responses and possess biologic activity in vivo. To further clarify the relationship between immunogenic properties of clone D and retroviral gene expression, tumor cells were treated in vitro with antisense oligonucleotides complementary to xenotropic and/or polytropic env sequences of murine leukemia virus. The cells were then assayed for expression of antigens recognized by humoral and cell-mediated responses with specificity for clone D. The results demonstrated that inhibition of env mRNA translation adversely affected the expression of immunogenic determinants in the xenogenized tumor cells.