Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models.
ABSTRACT Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.
Article: NK cells in immunotolerant organs.[show abstract] [hide abstract]
ABSTRACT: Organs such as the liver, uterus and lung possess hallmark immunotolerant features, making these organs important for sustaining self-homeostasis. These organs contain a relatively large amount of negative regulatory immune cells, which are believed to take part in the regulation of immune responses. Because natural killer cells constitute a large proportion of all lymphocytes in these organs, increasing attention has been given to the roles that these cells play in maintaining immunotolerance. Here, we review the distribution, differentiation, phenotypic features and functional features of natural killer cells in these immunotolerant organs, in addition to the influence of local microenvironments on these cells and how these factors contribute to organ-specific diseases.Cellular & Molecular Immunology advance online publication, 8 April 2013; doi:10.1038/cmi.2013.9.Cellular & molecular immunology 04/2013; · 2.99 Impact Factor
Article: Circulating Cytokines and Nitric Oxide are Involved in the Inhibition of Neutrophil Migration in Patients with Uterine Cervical Neoplasia.[show abstract] [hide abstract]
ABSTRACT: To verify if patients with cervical neoplasia produce mediators that reduce leukocyte function. Control neutrophils incubated with normal serum or serum from pre-invasive or invasive neoplasia patients were assayed for chemotaxis. Mediators were assayed in serum and in leukocyte supernatants. Experiments were also performed in random patients after surgery. Neutrophils incubated with patient sera, but not normal sera, failed to migrate towards the chemoattractants. In invasive neoplasia compared to controls, IL-6 and IL-8, and IL-10 and TNF-α were elevated in serum and in neutrophil supernatants, respectively. Nitrite levels were elevated in mononuclear cell supernatants from patients than controls. After surgery, serum cytokine levels were reduced, mainly in pre-invasive patients. Neutrophils treated with serum from pre-invasive patients undergone surgery had restored migration. Patients with cervical neoplasia produce mediators, predominantly induced by tumor cells, able to impair the inflammatory response at very early stages of disease.Clinical Medicine Insights: Oncology 01/2012; 6:233-42.
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ABSTRACT: Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.Cellular & Molecular Immunology advance online publication, 22 April 2013; doi:10.1038/cmi.2013.10.Cellular & molecular immunology 04/2013; · 2.99 Impact Factor