CONTENTS
Review
- Components of the IFN-g Signaling Pathway in Tumorigenesis
George Blanck (Department of Biochemistry and Molecular Biology, Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, FL 33612, USA)Abstract. Many features of the interferon g (IFN-g) signaling pathway would suggest that it is anti-tumorigenic. The IFN-g signaling pathway leads to apoptosis and to the expression of immune function proteins that could cooperate with T cells in the destruction of tumor. Various lines of experimental approaches have in general supported the hypothesis the IFN-g signaling pathway is anti-tumorigenic. However, data also indicate that the idea that the IFN-g signaling pathway is exclusively anti-tumorigenic is too simplistic. Also, to date, very little of the knowledge regarding the anti-tumor effects of the IFN-g pathway has been useful in the prognosis or therapy for cancer. This review summarizes the current state of knowledge regarding the IFN-g signaling pathway in tumorigenesis, with an emphasis on MHC class II induction in tumor cells and the induction of apoptosis in tumor cells. The review also indicates some future areas of investigation that offer hope for applying this knowledge in reducing cancer mortality.
Keywords: interferon gamma; tumorigenesis; apoptosis; MHC; interferon regulatory factor-1; retinoblstoma protein.
- Modulation of Pulmonary Innate Immunity during Bacterial Infection: Animal Studies
Marcus J. Schultz1,2 and Tom van der Poll1,3 (1Laboratory of Experimental Internal Medicine, 2Department of Intensive Care Medicine, 3Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands)Abstract. Both the increasing number of immunocompromised patients susceptible to pneumonia, and the development of bacterial resistance are significant problems related to the treatment of pneumonia. The primary outcome of treatment for pneumonia is to tip the balance to a successful host response. An ideal approach would be the combination of immunomodulation and conventional antimicrobial therapy for the treatment of pneumonia. It is of increasing importance to understand the components of innate immunity, before immunomodulatory therapy can be applied to patients. Much of our knowledge of the role of alveolar macrophages, cytokines and chemokines in the pathogenesis of pneumonia is derived from animal studies on experimental pneumonia. This article summarizes current information on the role of an alveolar macrophage (AM) and AM-derived mediators in host defense against pneumonia.
Keywords: innate immunity; pneumonia; alveolar macrophages; cytokines; immunotherapy.
- CD28 Costimulatory Molecule – Expression, Structure and Function
Dorota Boćko1, Agata Kosmaczewska1, Lidia Ciszak1, Renata Teodorowska1 and Irena Frydecka1,2 (1Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, 2Department of Hematology, Medical University, Wrocław, Poland)Abstract. T cell activation is a key event triggering an antigen specific immune response of the organism. The process is induced primarily by signal generated by direct interaction of T cell receptor (TCR) with antigen bound to major histocompatibile complex (MHC) on antigen presenting cell (APC). Although the signal is critical to excite immune response, however additional, costimulating signal is required. The major second signal is generated by interaction of CD28 molecule expressed on most T lymphocytes with its natural ligands CD80 and CD86 located on APCs. Signal excited by CD28 triggering involves multiple second messenger cascades, leading to activation of transcription factors and finally results in cell proliferation, cytokine production, and generation of effector function. The importance of CD28-delivered costimulatory signals was proven in experiments with CD28-deficient mice. T cells from these mice exhibit, impaired pattern of cytokine secretion, defects in T cell dependent antibody production. Certain forms of immunopathology might result from the aberrant regulation of CD28 expression.
Keywords: T cell activation; CD28 molecule; costimulation.
- Mast Cells and Inflammation
Michael Stassen1, Lothar Hültner2, Christian Müller1 and Edgar Schmitt1 (1Institute of Immunology, Johannes Gutenberg-University, Mainz, Germany, 2GSF-National Research Center for Environment and Health. Institute of Clinical, Molecular Biology and Tumor Genetics, Munich, Germany)Abstract. Mast cells have long since been recognized as potent producers of a large panel of biological highly active mediators such as biogenic amines, arachidonic acid metabolites, cytokines and chemokines, but most of their biological functions had been elusive and speculative. By taking advantage of mast cell-deficient mice, the role of mast cells in a variety of experimental settings can now be studied in detail and such approaches have dramatically altered and enlarged our knowledge about mast cell biology and function. Herein we will focus on the role of mast cells in inflammatory reactions of diverse origin such as delayed type hypersensitivity, atopy, immune complex-mediated inflammation and innate immune responses. From a current point of view, there is no doubt that the most outstanding and beneficial feature of mast cells is their recently uncovered ability to rapidly induce a life-saving inflammatory response upon encountering microbes and microbial constituents. Nevertheless, the picture is also emerging that mast cells are deeply involved in the induction and maintenance of a variety of severe allergic and autoimmune diseases. However, a deeper understanding of their activation and immune-modulatory capacity might open a new window for the development of curative strategies.
Keywords: mast cells; inflammation; IgE-independent activation; innate immune response.
- The Role of Dendritic Cells in Neurodegenerative Diseases
Pablo Iribarren, You-Hong Cui, Yingying Le and Ji Ming Wang (Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA.)Abstract. Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the induction of adaptive immune responses. The presence of DCs in the central nervous system (CNS) and the active participation of the immune system in a variety of neurodegenerative diseases have been demonstrated. This review will discuss recent findings pertinent to DCs and other antigen presenting cells in CNS in health and disease states.
Keywords: dendritic cells; neurodegenerative diseases; CNS.
- Active Vaccination after Allogeneic Bone Marrow Cell Transplantation: a New Option in the Immunotherapy Cancer?
Margot Zöller1, 2 and Siegfried Matzku2, 3 (1Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany, 2Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany, 3Department of Oncology, Biomedical Research, Merck KGaA, Darmstadt, Germany)Abstract. The concept of immunotherapy of cancer has been evoked more than a century ago by W. Coley. Yet, it is only recently that the state of knowledge allows for molecularly defined therapeutic approaches and much effort will still be required to place immunotherapy beside of surgery, chemotherapy and radiation as a forth option. In this review, we will strongly focus on two aspects: active therapeutic vaccination, because it is our belief that this approach will provide a major breakthrough and the potential efficacy of combining active vaccination with allogeneic bone marrow cell transplantation. It lately could be established in clinical trials that allogeneic bone marrow cell transplantation does not require myeloablative conditioning. Only non-myeloabaltive conditioning, which avoids the high toxicity of the conventional approach, allows the recruitment of elderly patients and patients in poor health condition. Concerning active vaccination protocols we will address the questions 1) what the targets (i.e. the antigens) of immunotherapeutic approaches could be; 2) how to achieve an optimal confrontation of the immune system with these tumor-associated antigens; and 3) which response elements are needed for raising a therapeutically successful immune reaction against these. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myelablative conditioning to optimize the therapeutic setting for this likely very powerfull tool of cancer therapy. We will briefly summarize current considerations to improve engraftment, to reduce graft versus host disease while strengthening graft versus tumor reactivity. There is some hope that the latter can be „naturally” maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, the efficacy of active vaccination of the allogeneically reconstituted host will meet a pool of virgin T cells, which are tolerant towards the host, but not anergized towards tumor antigens presented by MHC molecules of the host. We only briefly will mention suportive regimen of immunomodulation and those hazards which one is most frequently confronted with in trials to attack tumors with the inherent weapon of immune defense. Though successful immunotherapy of cancer still remains far behind expectation, there is a solid basis to believe that by improving our understanding of molecular mechanisms of immunity, it may become a very powerful and less harmful tool than conventional therapies.
Keywords: tumor, vaccination, allogeneic, stem cell transplantation
Experimental Immunology
- A Two Step Procedure to Fractionate Mouse Testicular Macrophages with a Different Cytokine Profile
Krzysztof Bryniarski, Katarzyna Szewczyk, Maria Ptak, Małgorzata Bobek and Włodzimierz Ptak (Department of Immunology, College of Medicine, Jagiellonian University, Czysta 18, 31-121 Kraków, Poland)
Abstract. Cells isolated enzymatically from interstitial tissue of mouse male gonads are composed of macrophages, Leydig cells, and myofibroblasts. They can be separated on density gradients either by sedimentation (Ficoll) or flotation (Percoll) into several fractions according to different buoyant density containing mixtures of different cells. Macrophages (FcgR+, esterase+) present in cell mixtures can by highly enriched in a single step to 95% purity by rosetting with opsonized erythrocytes followed by sedimentation on Lymphoprep. Separate fractions of highly purified (over 95%) macrophages obtained by successive use of density gradients and rosetting differ significantly in the production of cytokines, such as cells from fractions at lower density produce little IL-6, cells from fractions at higher density are poor producers of TNF-alpha whereas TMf in intermediate fractions produce significant amounts of both cytokines. These differences may suggest that particular subpopulations of testicular macrophages play different biological roles in the testis.
Keywords: testicular macrophages; isolation; functional subpopulations; cytokine secretion; FcgR expression.