CONTENTS
Review
- Allergen-Specific T Lymphocytes as Targets for Specific Immunotherapy: Striking at the Roots of Type I Allergy
Barbara Bohle (Department of Pathophysiology, Division of Immunopathology, University of Vienna, Vienna, Austria)Abstract. In the past decades allergic diseases have tremendously increased and hypersensitivity reactions now represent a growing health concern in industrialized countries. Despite various effective therapeutic options for the treatment of allergic diseases, only specific immunotherapy (SIT) has been shown to have effects on the underlying immunological mechanisms, namely functional changes at the level of T helper lymphocytes (Th). It was found that allergen-specific CD4+ Th2 lymphocytes play a key role in the pathophysiology of atopic diseases. During successful SIT, the Th2-dominated immune response is modified towards a Th1 response, leading to a decline in allergen-specific IgE levels in the long term. In order to improve the efficacy and safety of SIT, novel approaches were developed targeting allergen-specific Th2 lymphocytes since specific inactivation or modulation towards Th1 cells could interfere with the disease process. In view of this aspect, this review will basically focus on two new promising approaches to improve SIT: 1) the use of hypoallergenic proteins characterized by reduced IgE-binding capacities but retained T lymphocyte-activating properties and 2) oligodeoxynucleotides containing CpG motifs as an example of adjuvants which foster Th1 immune responses. Both approaches promise to be capable of adjusting the pathological Th2 immune response.
Keywords: type I allergy, specific immunotherapy, T lymphocytes, hypoallergens, oligodeoxynucleotides containing CpG motifs.
- Type I Interferons as Immunoregulatory Molecules; Implications for Therapy in Experimental Autoimmune Uveoretinitis
Junichiro Mizuguchi1, Masaru Takeuchi2 and Masahiko Usui2 (1Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 Japan, 2Department of Ophthalmology, Tokyo Medical University Hospital, 6-7-1 Nishishijuku, Shinjuku-ku, Tokyo, 160-0023 Japan)Abstract. Clinical trials have shown that the type I interferon (IFN)-alpha/beta have some beneficial effects on organ-specific autoimmune disease, such as Behcet’s diseases and multiple sclerosis, although the precise mechanims remain lergaly unresolved T helper cells (Th1)-mediated autoimmune response are involved in the initiation and/or progression of human uveitis, such as Behcet’s disease. The animal model of experimental autoimmune uveoretinitis (EAU), characterized by a monophasic clinical course, has contributed to the understanding of the pathogenesis of human uveitis. Th1 producing IFN-gamma induce EAU development, while Th2 producing IL-4/IL-10 prevent the disease. However, depending on the cytokine milieu, the pro-inflammatory cytokine IFN-gamma may attenuate the autoimmune response and anti-inflammatory cytokine IL-4 exacerbates it. Chemokines also play a crucial role in EAU development, which might be resolved by Th2-mediated immune responses. The administration of IFN-alpha/beta prevents EAU development, accompanied by a dimished production of IFN-gamma/IL-10. Interestingly, however, IFN-alpha/beta also have some beneficial effects on patients with Th2-like phenotype in addition to Th1-like phenotypes. Thus, the immuno-modulatory action of IFN-alpha/beta may be dependent on the context of cytokine combination and/or their concentrations.
Keywords: interferon alpha/beta; autoimmune diseases; T helper cells; human uveitis.
- V Gene Replacement in T and B Lymphocytes: Illicit or Regimented Rearrangement?
Rachel Golub (Unité du Développement des Lymphocytes, Institut Pasteur, 75724 Paris Cedex 15, France)Abstract. Lymphocyte can undergo novel types of secondary genetic rearrangements that alter the specificity of a pre-existing B cell receptor (BCR) or T cell receptor (TCR). V gene replacement is one of them and it replaces an already rearranged V gene segment with an upstream germline V gene segment. This review focuses on the molecular aspect of rearrangement. The role of this mechanism in the immune system is debated.
Keywords: VDJ recombination, immunoglobulin and TCR loci, embedded heptamer, knock-in mice, gene rearrangement, receptor editing.
- The TCR/CD3 Complex: Molecular Interactions in a Changing Structure
Maria José Feito1, Arturo Jiménez-Perianez2, Gloria Ojeda2, Alejandra Sánchez1, Pilar Portolés2 and José M. Rojo1 (1Departmento de Inmunología, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain, 2Centro Nacional de Biología Fundamental, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain)Abstract. The T cell receptor-CD3 (TCR/CD3) complex is a multichain structure in charge of antigen recognition in T cells. Despite many genetic, structural, and functional data obtained in recent years, essential questions concerning the TCR/CD3 complex still remain open, including: 1) the precise number of polypeptides in each TCR/CD3 complex, their interactions and spatial arrangement; 2) the role(s) of each polypeptide in antigen recognition and/or in receptor signal transmission, and 3) the relationship between the TCR/CD3 complex and other membrane or cytoplasmic molecules involved in downstream signaling. In this work we shall review data concerning some of these issues, proposing a model of the overall structure of the TCR/CD3 complex to explain its known features.
Keywords: T cell receptor; CD3; antigen recognition.
- DNA Viruses and Genetic Modification of Dendritic Cells
Lars Jenne and Alexander Steinkasserer (Department of Dermatology, University of Erlangen-Nürnberg, Hartmannstraße 14, D-91052 Erlangen, Germany)Abstract. An alternative approach to the use of tumor-peptide-loaded dendritic cells (DC) in immunotherapy would be the use of genetically modified DC using viral vectors expressing tumor-associated antigens (TAA). However, viruses have developed several immune escape mechanisms and, thus, one has to study the interaction between viruses and DC before these viruses can be used as an alternative strategy. Here we report that vaccinia virus (VV) as well as herpes simplex virus type-1 (HSV-1) are able to potently infect monocyte-derived DC, however, this infection leads to the inhibition of the DC-mediated T cell stimulation in vitro.
Keywords: dendritic cells; viral vectors; gene therapy; vaccinia virus; herpes simplex virus.
- The Emerging Distinct Role of TNF-Receptor 2 (p80) Signaling in Chronic Inflammatory Disorders
Martin H. Holtmann, Marcus Schuchmann, Geraldine Zeller, Peter R. Galle and Markus F. Neurath (Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany)Abstract. Tumor necrosis factor (TNF)-alpha is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF strategies have proven to be clinically effective. Two TNF-specific cell surface receptors, TNF-R1 (p60) and TNF-R2 (p80), have been identified and the function of these receptors and the downstream intracellular signal-transduction pathways have been extensively studied in vitro. For a long time p60 was considered to be the predominant mediator of TNF signaling, whereas p80 was ascribed only an euxilliary function. However, there is increasing clinica and experimental evidence for an important independent role of p80 signaling in chronic inflammatory conditions. The date, most data exist for Crohn’s disease. Upregulation of p80 and increased p80 signaling aggrevates experimental colitis and is likely to contribute to the chronicity of inflammation in vivo. Further studies are required to elucidate critically important steps in TNF signaling that might be dysregulated. This will lead to a better understanding of the pathogenesis of these diseases and poteintially reveal new, more specific therapeutic targets.
Keywords: TNF-alpha, TNF-R2, signal transduction, inflammatory disorders.
Immunochemistry
- The cGMP Synthesis and PKG1 Expression in Murine Lymphoid Organs
Ewa Kurowska1, Marcin Kobiałka1, Ewa Zioło2, Leon Strządała2 and Wojciech A. Gorczyca1, 3 (1Laboratory of Signaling Proteins and 2Laboratory of Cellular Immunology, L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, 3Department of Biogenic Amines, Polish Academy of Sciences, Łódź, Poland)
Abstract. Numerous reports indicate that cyclic 3′,5′ guanosine monophosphate (cGMP) is involved in the regulation of immune processes. However, the mechanisms responsible for the synthesis of this nucleotide and its signaling pathways in immune cells are still not well recognized. The aim of our study was to establish: 1) which form of guanylyl cyclase synthesizes cGMP in murine lymphoid organs and 2) whether the same organs express the isoforms PKG1alpha and/or PKG1beta of protein kinase G, known as a possible target for synthesized cGMP. Cells isolated from thymus, lymph nodes, and spleen were treated with activators (SNP, ANP, CNP, STa) of soluble or particulate cyclases. Sodium nitroprusside (SNP) elevated intracellular cGMP 2-fold in thymic and lymph node cells and about 10-fold in spleen cells. Atrial natriuretic peptide (ANP) caused modest but statistically significant increases of cGMP in cells of all the organs. Additionally, spleen cells elevated their cGMP content about 2-fold in response to C-type natriuretic protein (CNP). In cellular homogenates of all the analyzed organs, the antibody anti-PKG1beta stained the 78 kDa band corresponding to the molecular mass of PKG1. Only homogenates of spleen cells were stained by the antibody recognizing PKG1alpha. Our results indicate that in all the investigated organs, cGMP may be synthesized mainly by soluble guanylyl cyclases in response to nitric oxide. The modest increase of cGMP upon stimulation by ANP suggests that in all these organs either exist only a small subpopulation of cells that express particulate cyclase GC-A or GC-A is expressed at very low level. In spleen cells, however, cyclase GC-B appears to be the more active enzyme. Elevated cGMP concentration may in turn activate PKG1beta in thymus, lymph node, and spleen cells and also PKG1alpha in spleen cells.
Keywords: cyclic nucleotides, guanylyl cyclases, protein kinases, signal transduction, lymphoid organs.