CONTENTS
Review
- Gene Therapy with Herpes Simplex Virus Vectors
DAVID S. LATCHMANAbstract. Gene delivery to the nervous system represents perhaps the ultimate challenge of gene therapy in view of the complexity of this system, the wide variety of intractable neurological diseases and the need to deliver the gene to non?dividing cells. Although a variety of systems for such gene delivery are under development, herpes simplex virus has unique advantages in terms of its large genome size and its ability to enter a latent state in neuronal cells. Considerable progress has been made in the effective disablement of this virus whilst retaining its ability to deliver genes and in producing long term expression of the foreign gene. Although much remains to be achieved in the further disablement of the virus and its testing in rodent and primate models of human diseases, it is likely that these viruses may ultimately be of use in human gene therapy procedures for otherwise intractable neurological diseases.
Keywords: gene therapy; herpes simplex virus; virus vectors.
- Transcriptional Control of MHC Genes and T Cell Development in MHC Class II Deficiency
BARBARA GODTHELP, MARJA C. J. A. VAN EGGERMOND, SAM J. P. GOBIN and PETER J. VAN DEN ELSENAbstract. MHC class II deficiency has proven to be an excellent model to study transcription regulation of MHC genes and T cell development. Cell lines established from MHC class II deficient patients have been of great value for the identification of proteins necessary for MHC expression and their study has resulted in the identification of a common regulatory pathway for MHC class II and class I genes. The lack of MHC class II expression was found to have a profound effect on the development of the CD4+ T cell lineage, in particular on the composition of the T cell receptor repertoire, revealing aberrant thymic selection processes in these patients. Here, we will discuss several aspects of the transcriptional regulation of MHC genes and the impact of deficient MHC class II expression on T cell development.
Keywords: bare lymphocyte syndrome; MHC class II deficiency; MHC gene regulation; T cell development.
- Genomic Catastrophism and the Origin of Vertebrate Immunity
AUSTIN L. HUGHESAbstract. Genomic catastrophism is the belief that unique genetic events, unlike those observed in recent evolutionary history, played a key role in the origin of vertebrate adaptations. Catastrophist hypotheses have been particularly popular is accounting for the origin of vertebrate specific immunity. Two major such hypotheses involve genome duplication by polyploidization and horizontal gene transfer. Recent analyses lead to decisive rejection of the widely cited hypothesis that the vertebrate genome underwent two rounds of genome duplication, and theoretical considerations suggest that genome duplication is unlikely to lead to new adaptive advances. Likewise, the evidence that key elements of the vertebrate immune system arose by horizontal transfer from a bacterium or by incorporation of a transposable element into the vertebrate genome remains relatively weak. Thus, at present, a uniformitarian view of the origin of the vertebrate immune system seems more reasonable, especially given the longer time?frame for vertebrate evolution indicated by molecular data.
Keywords: genome duplication; horizontal gene transfer; immune system evolution; vertebrate evolution.
- Theory and Treatment of the X-Inactivation Chimera in Female-Prevalent Autoimmune Disease
JEFFREY J. STEWARTAbstract. The vast majority of patients with systemic autoimmune diseases such as Sjögren’s syndrome and systemic lupus erythematosus are female. The female prevalence of such autoimmune diseases is poorly understood. In theory, X-chromosome inactivation and resultant tissue chimerism may explain the female predisposition to systemic autoimmunity. For example, autoreactive T cells may fail to be tolerized by self antigens encoded by one of the two X chromosomes (the Kast conjecture). In the periphery, these autoreactive T cells may stimulate B cells expressing the target X-encoded antigen, so the Kast conjecture can be extended to explain how systemic autoimmunity may be induced. Another hypothesis proposes the X-encoded genes cause autoimmunity by affecting B or T cells directly; however, significant evidence has been raised discrediting this hypothesis. An attractive feature of X-inactivation hypotheses is that the discordance rate between monozygotic twins may readily be explained, because otherwise-identical twins may have different X-inactivation patterns. Reviewed here are the immunobiology of X-inactivation chimerism and its roles, both known and postulated, in autoimmune disease. Also discussed are methods appropriate for determining the cellular and molecular targets of autoreactive T cells in female-prevalent autoimmune diseases and methods by which these targets might be used as tolerogens to treat these diseases.
Keywords: X-chromosome inactivation; dendritic cells; systemic autoimmune disease; chimerism; systemic lupus erythematosus; Sjögren’s syndrome.
Clinical Immunology
- Influence of Transplantable Melanomas on the Secretion of Cytokines by Hamster Peritoneal Macrophages
KRYSTYNA KOZŁOWSKA, MIROSŁAWA CICHOREK and MAŁGORZATA ZARZECZNAAbstract. The subject of the study was the influence of two lines of transplantable melanomas on the secretion of cytokines (IL?6, TNF?a, OSM) and total proteins by hamster peritoneal macrophages. The results showed a statistically significant increase of total protein content and decrease of cytokine content in the supernatants of 24 h cultured macrophages from melanoma?bearing animals in comparison with control macrophages. Changes in the secretory function were more marked in the case of macrophages from hamsters bearing amelanotic melanoma. This may suggest that the biological features of melanomas can influence peritoneal macrophages to release the particular cytokines at different levels.
Keywords: interleukin 6; tumor necrosis factor a; Oncostatin M; peritoneal macrophages; transplantable melanomas.
- Chemokine RANTES in Atopic Dermatitis
JOANNA GLÜCK and BARBARA ROGALAAbstract. Chemokines play a key role in inflammatory diseases. The aim of this study was to estimate chemokine RANTES in the sera of patients with atopic dermatitis (AD) and to analyze the correlation between RANTES serum level and the immunological and clinical parameters of the disease. Serum levels of RANTES (ELISA; R&D Systems), total IgE and specific IgE (FEIA; Pharmacia CAP System) were estimated in 24 patients with AD, 28 patients with pollinosis (PL) and 22 healthy nonatopic subjects (HC). The division of the AD group into a pure AD (pAD) subgroup, without a coexisting respiratory allergy, and a subgroup of patients with AD and a respiratory allergy (AD+AO) was done according to Wütrich. Levels of RANTES were higher in the AD group than in the HC group and the PL group. RANTES levels did not differ among subgroups with various clinical scores and between the pAD and AD+AO subgroups. There were no correlations between levels of RANTES and total IgE. Significant positive correlations between serum levels of RANTES and Dermatophagoides farinae and cat dander?specific IgE were found in the AD group. We conclude that the serum level of chemokine RANTES differs patients with AD from patients with PL. The increase of RANTES concentration in the serum of patients with AD depends neither on a clinical picture nor an IgE system.
Keywords: allergic inflammation; atopic dermatitis; chemokine RANTES; IgE.
- Role of Adhesion Molecules in Chronic Allograft Rejection
MARIA NOWACZYK, ANDRZEJ GÓRSKI, MAGDALENA DURLIK, JANUSZ WYZGAŁ3 and AGNIESZKA PERKOWSKA-FRANCKA2Abstract. Endothelial adhesion molecules play an important role in T cell recruitment to an allograft site. Therefore, it could be expected that their blocking may be beneficial for allograft survival. In this report, we show that T cells from patients with chronic rejection have an up-regulated ability to adhere to inflamed endothelium in vitro. Furthermore, this enhanced T cell: endothelial interaction could be blocked by anti-VCAM and anti-E-selectin monoclonal antibodies.
Keywords: anti-VCAM-1; anti-ICAM-1; anti-E-selectin; endothelium; adhesion T cells; chronic rejection.
- Colostrinin®: a Proline?Rich Polypeptide (PRP) Complex Isolated from Ovine Colostrum for Treatment of Alzheimer’s Disease. A Double?Blind, Placebo?Controlled Study
JERZY LESZEK, ANNA D. INGLOT, MARIA JANUSZ, JÓZEF LISOWSKI, KATARZYNA KRUKOWSKA and JERZY A. GEORGIADES
Abstract. A proline?rich polypeptide (PRP) complex, subsequently called Colostrinin®, was isolated from ovine colostrum. The complex showed immunomodulatory properties in mice, rats, and chickens, inducing maturation and differentiation of thymocytes. It was recently found that Colostrinin® is a cytokine?like factor that acts as an inducer of interferon g (IFN?g) and other cytokines in human peripheral blood and cord blood leukocyte cultures and has psycho?immuno?enhancing activity in volunteers. These observations prompted us to study the effect of Colostrinin® on patients with Alzheimer’s disease (AD). Forty six AD patients were divided into 3 groups and randomly assigned to receive orally either Colostrinin® (100 mg per tablet, every second day), commercially available bioorganic selenium (100 mg selenium per tablet, every second day) or placebo tablets. One cycle of the treatment lasted 3 weeks and was separated from the next cycle by a 2 week hiatus. Each patient received 10 cycles of treatment during the year of the clinical trial. Outcomes were assessed by psychiatrists blinded to the treatment assignment. Eight of the 15 AD patients treated with Colostrinin® improved and in the 7 others the disease had stabilized. In contrast, none of the 31 patients from the selenium or placebo groups with similar mild or moderate AD improved. The administration of selenium promoted stabilization in 13 of the 15 patients, whereas in the placebo group only 8 of the 16 patients were stabilized at the 12 month trials end?evaluation. Colostrinin® was found to be a remarkably safe drug. Mild and transient effects were anxiety, stimulation, insomnia, and tiredness. The results obtained showed that oral administration of Colostrinin® improves the outcome of AD patients with mild to moderate dementia. The results are very encouraging and deserve further research.
Keywords: a proline?rich polypeptide (PRP) complex – Colostrinin®; Alzheimer’s disease; therapy.