CONTENTS
Review
- Integrating B Cell Homeostasis and Selection with BLyS
Susan Harless Smith and Michael P. Cancro (Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA)Abstract. The mechanisms that maintain a pool of B cells that is adequately diverse yet devoid of pathogenic autoreactivity remain poorly understood. B cells complete maturation after migrating to the periphery, where they transit several intermediate developmental stages prior to recruitment into the long-lived primary pool. Since B lineage commitment is not coupled to peripheral B cell numbers and most mature peripheral B cells are quiescent, the sizes of mature peripheral compartments are primarily determined by the proportion of immature B cells that survive transit through later developmental stages, coupled with the longevity of mature B cells themselves. Compelling evidence indicates that the B cell antigen receptor (BcR) plays an essential role in all of these processes, but further findings indicate a similar role for the recently described tumor necrosis factor family member, B lymphocyte stimulator (BLyS). Signaling through the BLyS receptor, Bcmd/BR3, controls B cell numbers in two ways: by varying the proportion of cells that complete transitional B cell development, and by serving as the primary determinant of mature B cell longevity. The striking congruence of BcR- and BLyS-mediated effects on B cell selection and survival suggests these pathways may be related. The recent discovery that BcR signaling is selectively coupled to Bcmd/BR3 expression links BcR- and BLyS-mediated activities in transitional and mature B cells, suggesting specificity-based selection and survival may be mechanistically similar processes.
Keywords: B lymphocytes; BLyS; homeostasis; development.
- PPARg – an Important Regulator of Monocyte/Macrophage Function
Andreas von Knethen and Bernhard Brüne (Department of Cell Biology, University of Kaiserslautern, Kaiserslautern, Germany)Abstract. Regulation of monocyte/macrophage function is important to coordinate immune responses. Their contact with invading pathogens activates signaling pathways that provoke pro-inflammatory gene expression and thus causing a locally restricted inflammation. Recently, the peroxisome proliferator activated receptorg (PPARg) has been identified to antagonize pro-inflammatory responses in monocytes/macrophages causing an anti-inflammatory and/or desensitized phenotype to predominate. For PPARg general mechanisms in facilitating the transition from a pro- to an anti-inflammatory phenotype have been elucidated. PPARg is a member of the nuclear receptor superfamily and activated upon endogenous as well as exogenous agonist binding. Here we focus on its role in monocyte/macrophage biology in affecting inflammation. Summarizing current information, a model is proposed, giving rise to potential new therapeutic possibilities for the treatment of diseases presumably involving PPARg-dependent regulatory circuits.
Keywords: inflammation; monocytes/macrophages.
- The Role of Autoimmunity in the Pathogenesis of Lung Allograft Rejection
David S. Wilkes (Departments of Medicine, Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA)Abstract. For many patients, lung transplantation is the only definitive treatment modality for different forms of end stage lung disease. However, the lung is rejected more often than any other type of solid organ allografts, and the five year survival is less than that of other transplanted organs. While alloimmunity directed against donor transplantation antigens is believed to be the key mechanism that mediates rejection responses, newer immunosuppressive regimens designed to abrogate alloimmune activation have not improved survival. Accordingly, these data suggest that other antigens are involved in rejection. Autoimmune responses, reported to occur during allograft rejection, could participate in graft destruction. This review article discusses the role of autoimmune responses to type V collagen ([col(V)], a minor collagen in the lung, in the pathogenesis of lung allograft rejection. By recognizing that lung transplant rejection involves both alloimmune and autoimmune responses, scientific investigation may uncover novel targets for therapeutic intervention that could prolong the life of the lung transplant recipient.
Keywords: lung transplantation; alloimmune response; autoimmune response; transplant rejection.
- Are NKT Cells Essential for Endotoxic Shock?
Masashi Emoto (Department of Immunology, Max-Planck-Institute for Infection Biology, Berlin, Germany)Abstract. Endotoxic shock is a major health threat caused by Gram-negative bacteria and their unique cell wall component, lipopolysaccharide which induces exaggerated production of proinflammatory cytokines? Although macrophages play a central role in the pathogenesis of endotoxic shock, NK1+ cells are also involved in this mechanism. NK1+ cells comprise two major populations, namely NK cells and NKT cells. It remains, however, elusive whether either NK cells, NKT cells or both are involved in induction of endotoxic shock. This review will focus on the relative contribution of these NK1+ cells to the pathogenesis of endotoxic shock.
Keywords: endotoxin shock, NK cell, NKT cell, IFN-g, lipopolysaccharide.
- Phage Therapy: a Reappraisal of Bacteriophages as Antibiotics
Jameel M. Inal (University Hospital Basel, Department of Research, Basel, Switzerland)Abstract. The concept of phage therapy to treat bacterial infections was born with the discovery of bacteriophage almost a century ago. After a chequered history its current renaissance is fuelled by the dangerous appearance of antibiotic-resistant bacteria on a global scale. As a mark of this renewed interest, the unanswered problems of phage therapy are now being addressed, especially for human use. Phage therapy in agricultural, food processing and fish farming industries is already successful and this review, whilst being aware of the potential drawbacks, emphasizes the need for further carefully controlled empirical data on its efficacy and safety in treating human and animal disease, especially in view of its numerous advantages over antibiotics. Finally the potential of phage therapy against bioterrorism and the emergence of second generation phage antibacterials based on phage-derived single-protein lysis systems are addressed.
Keywords: phage therapy; bacteriophage; antibiotic resistance.
- Considerations on Clinical Use of T Cell Immunotherapy for Cancer
Gregory E. Plautz, Peter A. Cohen and Suyu Shu (Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA)Abstract. The recognition by effector T lymphocytes of novel antigenic targets on tumor cells is the premise of specific targeted immunotherapy of cancer. With the molecular characterization of peptide epitopes from melanoma antigens, and more recently broadly expressed tumor antigens, there has been considerable enthusiasm for clinical evaluation of peptide tumor vaccines. Immunologic monitoring of vaccinated patients has demonstrated expansion of CD8+ T cells that react with the relevant peptide and, more importantly, with native tumor. In most instances however, vaccine-induced CD8+ T cell responses alone have not been sufficiently robust or sustained to translate into a high percentage of durable clinical responses. Vaccine strategies have also utilized dendritic cells (DCs) that have been modified to present tumor antigens. The superior antigen processing capacity and co-stimulatory function of DC convey a powerful stimulatory signal to both CD4+ and CD8+ T cells. Several strategies are attempting to broaden the immune response beyond single antigens by introducing the entire complement of tumor antigens into DCs. Adoptive immunotherapy is a promising strategy to recover tumor-reactive precursor T cells from patients, stimulate them to induce numerical expansion, and then re-infuse them. Ex vivo manipulation of the tumor-reactive T cells also permits cytotoxic therapy to be administered to the patient without damaging the effector cells. Recently, host lymphodepletion prior to adoptive transfer of effector T cells has resulted in an extremely high and sustained frequency of effectors that has achieved therapeutic efficacy against bulky metastatic disease in a substantial fraction of treated patients.
Keywords: tumor antigens, T lymphocyte, immunotherapy, dendritic cell.
Experimental and Clinical Immunology
- Time-Dependent Observations of Secretion Marker Levels in Nasal Secretion after Histamine and Methacholine Provocations
Małgorzata Pupek1, Wojciech Mikulewicz2, Jarosław Mielnik2,3, Bożena Batycka2 and Iwona Kątnik-Prastowska1 (1Department of Chemistry and Immunochemistry, Wrocław Medical University, Bujwida 44a, 50-345 Wrocław, Poland, 2Otolaryngology Department, Regional Hospital of Wrocław, Kamieńskiego 73a, 51-124 Wrocław, Poland, 3Department of Basic Medical Sciences, Wrocław Medical University, Kochanowskiego 14, 51-601 Wrocław, Poland)Abstract. Nasal provocation tests with histamine and methacholine were carried out in 25 healthy men on an effort to assess the dynamic changes of albumin, total IgA, secretory IgA and lactoferrin concentrations in the nasal secretion. The trials were performed with 0.5, 1, and 4 mg of histamine and 8, 16, 32 mg of methacholine. Each dose of histamine or methacholine was sprayed into a nose every second day, and with two days interval between two provocating agents. The nasal secretions were collected after saline spraying only forming baseline group and after 3, 10 and 15 minutes of the challenge agent administration. The baseline levels presented the following values: for albumin 257± 230 µg/ml, secretory IgA 608 ± 379 µg/ml, total IgA 1025 ± 423 µg/ml, and lactoferrin 213 ± 156 µg/ml. The increase of albumin level after nasal provocation, particularly significant after histamine administration (to 3713 ± 2311 µg/ml), indicates the incessant protein plasma leaking from the blood circulation to the nasal secretion. After administration of both provocating agents there was the significant gradual decrease of secretory IgA level, even below the baseline value. After the 2nd and the 3rd doses of methacholine and histamine spraying the concentration of secretory IgA decreased 2-3 times and was found to be 200-300 µg/ml, respectively. Also, lactoferrin concentration values decreased gradually after the 2nd and 3rd doses of methacholine and histamine to level close the baseline value. These observations suggest time and dose dependent, a non-specific dysfunction of local immunity response after nasal provocations.
Keywords: nasal challange, nasal secretion markers, lactoferrin, IgA, secretory IgA.
- Effect of Exogenous Opioid Peptides on TNF-a-induced Human Neutrophil Apoptosis in Vitro
Zofia Sułowska1, Ewa Majewska2, Henryk Tchórzewski1, 3 and Magdalena Klink1 (1Microbiology and Virology Center, Polish Academy of Sciences, Łódź, Poland, 2Department of Pathophysiology and Clinical Immunology, Medical University Łódź, Poland, 3Department of Clinical Immunology, Polish Mother`s Memorial Institute, Łódź, Poland)
Abstract. Polymorphonuclear leukocytes (neutrophils) apoptosis is an important mechanism regulating the life span and some functions of neutrophils at inflamed sites. The opioid peptides are present in the peripheral circulation and their concentrations rapidly increase as the result of stress and inflammation. The effect of opioid peptides such as met-enkephalin (M-ENK) and beta-endorphin (b-END) on tumor necrosis factor a (TNF-a)-induced apoptosis in human neutrophils in vitro was investigated. Neutrophils isolated from peripheral blood were cultured in the absence or presence of 10-6-1010 M of opioid peptides for 8, 12 and 18 hours. Features of apoptotic neutrophils were measured by flow cytometric method based on analysis of apoptotic nuclei (DNA content). We found that M-ENK and b-END enhanced both non-induced and TNF-a-induced neutrophil apoptosis in vitro in a dose-dependent manner. The effect of opioid peptides on modulation of neutrophil apoptosis was not reversed by opioid-receptor antagonist naloxone. The results suggest that M-ENK and b-END can regulate neutrophil life span via apoptosis and in this way may participate in resolution of inflammation.
Keywords: apoptosis, opioid peptides, human polymorphonuclear leukocytes (neutrophils), flow cytometry, TNF-a.