Daniela Santoli

Antitumor activity of a human cytotoxic T-cell line (TALL-104) in brain tumor xenografts

Malignant glioma in adults and primitive neuroectodermal tumors/medulloblastomas in children are the most common malignant primary brain tumors that either respond poorly to current treatment or tend to recur. Adoptive therapy with TALL-104 cells-an IL-2-dependent, major histocompatibility complex nonrestricted, cytotoxic T-cell line-has demonstrated significant antitumor activity against a broad range of implanted or spontaneously arising tumors. This study investigates distribution of systemically and locally administered TALL-104 cells and their efficacy in effecting survival of a rat model of human brain tumor. In vitro, TALL-104 cells showed significant cytotoxic activity when added to human glioblastoma cell lines U-87 MG, U-251 MG, and A1690; the medulloblastoma cell lines DAOY, D283 Med, and D341 Med; and the epidermoid cancer cell line A431. In brain tumor-bearing rats, the amount of fluorescent dye-labeled TALL-104 cells in brain increased after they were given by intracarotid injection as compared with i.v. cell administration. However, TALL-104 cells rapidly decreased to low levels within 1 h after intracarotid injection. This finding suggests that TALL-104 cells given systemically may not invade brain or tumor tissues, but rather may remain in the vascular system, making this approach less efficient for brain tumor treatment. In a model of athymic rats engrafted with human A431 carcinoma brain tumor, repetitive local administration of TALL-104 cells directly into the tumor bed resulted in a significant increase in survival time compared with control animals. Therefore, local therapy with TALL-104 cells may be a novel and highly effective treatment approach for malignant brain tumors.

Persistent parainfluenza type 1 (6/94) infection of brain cells in tissue culture

SummaryA state of persistent infection with parainfluenza type 1 virus (6/94 strain) was established in cultures of human and bovine brain cells. Following primary infection of human brain cells, viral cytopathic effect (CPE) and hemadsorption (HAD) depended on the multiplicity of infection. After persistent infection was established the virus rapidly became cell-associated; no CPE occurred and no viral antigen was detectable by HAD, immunofluorescence (FA), or immunoprecipitation. Infectious virus could be recovered only by fusion or cocultivation. This was in marked contrast with infected bovine brain cells, where, following primary infection, little or no CPE occurred. A productive infection rapidly evolved and persisted without CPE, but with 100 per cent HAD and FA positive cells.

Interactions of the allogeneic effector leukemic T cell line, TALL-104, with human malignant brain tumors

TALL-104 is a human leukemic T cell line that expresses markers characteristic of both cytotoxic T lymphocytes and natural killer cells. TALL-104 cells are potent tumor killers, and the use of lethally irradiated TALL-104 as cellular therapy for a variety of tumors has been explored. We investigated the interactions of TALL-104 cells with human brain tumor cells. TALL-104 cells mediated increased lysis of a panel of brain tumor cells at low effector-to-target ratios over time. We obtained evidence that TALL-104 cells injured glioma cells by both apoptotic and necrotic pathways. A 7-amino actinomycin D flow cytometry assay revealed that the percentages of both apoptotic and necrotic glioma cells increased after TALL-104 cell/glioma cell coincubations. Fluorescent microscopy studies and a quantitative morphologic assay confirmed that TALL-104 cell/glioma cell interactions resulted in tumor cell apoptosis. Cytokines are secreted when TALL-104 cells are coincubated with brain tumor cells; however, morphologic analysis assays revealed that the soluble factors contained within clarified supernates obtained from 4 h coincubates added back to brain tumor cell cultures did not trigger the glioma apoptosis. TALL-104 cells do not express Fas ligand, even upon coincubation with glioma targets, which suggests that the Fas/Fas ligand apoptotic pathway is not likely responsible for the cell injury observed. We obtained evidence that cell injury is calcium dependent and that lytic granule exocytosis is triggered by contact of TALL-104 cells with human glioma cells, suggesting that this pathway mediates glioma cell apoptosis and necrosis.

Abnormalities of T-cell subpopulations in the blood and thymus of patients with myasthenia gravis

Abstract Subpopulations of T cells were quantitated in the blood and thymus of patients with myasthenia gravis. As compared to healthy donors, an increase in T lymphocytes bearing receptors for IgG (T G ) was found in the blood of 10 of 28 patients. T G and T M (T cells bearing receptors for IgM) cells were found in thymuses without thymoma.

Establishment of continuous multiple sclerosis brain cultures after transformation with PML-SV40 virus ☆

PML-SV40 virus was used to transform cells from explants and monolayer subcultures of human brain derived from biopsies or autopsies of MS cases, as well as from 1 case of Jakob-Creutzfeldt disease (JC), 1 case of amyotrophic lateral sclerosis (ALS) and several cases without CNS disease. The success of transformation depended on the growth condition of the culture at the time of infection but at present at least 14 cell lines, 10 derived from MS, 2 from JC, 1 from ALS and 1 from a normal non-CNS patient are maintained in continuous culture.

SCID Mice as a Model for Human Leukemias

The murine severe combined immunodeficiency (SCID) mutation, first reported in 1983 by Bosma and coworkers,1 affects a component of the recombinase system used in common by T and B lymphocytes to assemble the genes that code for the variable regions of antigen receptors.2–4 As a result, SCID mice are severely deficient in T-cell receptor (TCR)- and immunoglobulin receptor (IgR)-bearing lymphocytes, lack serum Ig, do not respond to immunologic in vitro assays testing for B- or T-cell function, and histopathologically, show severe lymphopenia in all lymphoid tissues.1 Despite the impairment in Band T-lymphocyte differentiation, SCID mice have normal natural killer (NK) cell function, and their hematopoietic microenvironment is intact as it contains normally functioning antigen-presenting cells and is able to promote the differentiation of normal stem cells into functionally competent T and B lymphocytes.1,5–7 Because of these characteristics, SCID mice have been excellent models for the propagation of human xenografts, superior to and more convenient than regular or splenectomized nude mice. The recognition that SCID mice are able to support the growth of human cells has led to a blooming of literature on the construction of SCID mouse-human chimeras. While the usefulness of the SCID mouse for studying murine and human hematopoiesis is addressed in other sections of this book, this chapter deals exclusively with the engraftment of human leukemias in this model system. Prior to the discovery of SCID mice, transfer of primary patient leukemia cells or established leukemic cell lines into nude mice had resulted in either engraftment failure, or in some cases, in the production of myelosarcomas, localized solid tumors, or ascites, all of which do not reflect the normal course of the disease in humans.8–16

Immunotherapy and Gene Therapy for Breast Cancer

To this day, surgery, chemotherapy, hormonal therapy, and radiation therapy remain the main forms of treatment for breast cancer. Although these approaches reduce the risk of death and can induce complete remissions in most patients, many tumors will recur as metastatic lesions. In recent years, novel therapies have been developed that work independently or in conjunction with conventional treatments to minimize side effects and enhance therapeutic efficacy. At least two areas have emerged in which the biology of breast cancer is most likely to have a therapeutic impact. The first area involves growth factors and their receptors, the second revolves around neoangiogenesis. In addition, cell- and gene-based approaches are being evaluated in the clinic that have either a direct tumoricidal function or act by stimulating the immune system against the patient’s own tumor cells. This chapter reviews the current status of these new therapies and some of the new products that are being evaluated for clinical toxicity and preliminary efficacy.

OPPOSING EFFECTS OF INTERFERON ON NATURAL KILLER AND TARGET CELLS

Publisher Summary This chapter discusses opposite effects of the interferon on natural killer (NK) cells and target cells. The effector cells (natural killer cells) have been identified as Fc receptor-bearing lymphocytes that have no surface immunoglobulin and that do not form high-affinity rosettes with sheep red blood cells. Evidence that the major histocompatibility complex plays a role in the genetic control of natural killer cell activity has been obtained both in man and mice. While normal fibroblasts are unable to induce interferon, most of the tumor-derived cell lines and of human lymphoid cell lines transformed by Epstein–Barr virus induce human lymphocytes to produce high levels of interferon starting a few hours after mixture. Interferon has been reported to increase both specific and nonspecific cell-mediated cytotoxicity of mouse lymphocytes. Two antagonistic effects of interferon on human natural killer cell-mediated cytotoxicity are considered: (1) interferon strongly enhances the activity of human cyto-toxic lymphocytes and (2) it abolishes almost completely the susceptibility of certain target cell lines to lysis. The mechanism inhibiting lysis of target cells seems specific for natural killer cells.