Hungarian Immunology

[Therapeutic treatment of rheumatoid arthritis by gene therapy-induced apoptosis]

JAMES M. Woods, VOLIN V. Michael

MAY 10, 2004

Hungarian Immunology - 2004;3(04)

[Gene therapy was initially conceptualized as a treatment for individuals with genetic disorders, where defective genes would be replaced with functional ones. This concept was eventually broadened to include the use of gene therapy as a delivery mechanism for gene products effective in the treatment of diseases. The latter use of gene therapy, essentially as a drug delivery mechanism, was recognized to be particularly useful in the treatment of rheumatoid arthritis because it may have many advantages over traditional therapies. Two groups of target genes that are potentially useful for gene transfer include soluble inflammatory mediators that in theory could suppress the inflammatory process, and apoptotic mediators that may induce cell death, thereby suppressing the accumulation of inflammatory cells in the joint. To date the former group of target genes has received most of the attention, but it is the latter group of apoptosis-inducing targets that will be discussed in this review. We will focus our discussion on target genes that have shown success at inducing apoptosis in animal models of arthritis and will also include discussion of the apoptotic pathways that are altered in the attempts to reduce inflamed synovial tissue.]

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Hungarian Immunology

[Changes of immune system in the elderly]

MEKKEL Gabriella, BARTA Zsolt, BAKÓ Gyula

[”Immunosenescence” means the change of the immune system with ageing. Ageing of the immun system is a physiological process, based on complex immunregulatory alterations, which make the elderly more susceptible for infections, malignant and autoimmun diseases. It’s important to differentiate the primary (physiological) and secondory (caused by diseases) modifications of immunregulatory system. After reviewing the strict Senieur protocoll, which makes a basis for gerontological/geriatry studies, the authors survey in details the changes of the each cell types of the immune system. The impaired functions of the NK (natural killer) and PMN (polymorphonuclear) cells and macrophags (as the parts of innate immunity), the decreased numbers of T lymphocyts, and the less specific antibodies produced by B lymphocyts (as the part of the acquired immunity) together are responsible for the increased susceptibility of the elderly to infections, and for the higher prevalence of malignancies in elderly patients. The imbalance of pro- and anti-inflammatoric cytokines and the TH1- TH2 shift also play role in this process. Appearance of autoantigens and the increased autoreactivity are in the background of the frequency autoimmun diseases in the elderly. The development of malignant diseases is a complex process, caused by on the one hand the changes in innate immunity, on the other the decreased activity of suppressor mechanisms. These changes are not correctly known, but the literature grows increasingly. The good command of the molecular mechanisms provides the facilities to improve remedial interventions in the future.]

Hungarian Immunology

[Investigation of activated T-cells by non-Hodgkin’s lymphoma patients]

VÁRÓCZY László, GERGELY Lajos, ALEKSZA Magdolna, MILTÉNYI Zsófia, ILLÉS Árpád

[BACKGROUND - The immune system has several mechanisms to fight against developing malignant cell clones in the host, one of them is the activated T-cell response. Both CD4+ helper and CD8+ cytotoxic T-cells bear CD69 and HLA-DR molecules as important surface activation markers. AIM - Our aim was to determine, how the ratio of activated T-cells change in the peripheral blood of non-Hodgkin-lymphoma patients during the periods of polychemotherapy. PATIENTS AND METHODS - We used the peripheral blood samples of 43 non-Hodgkin-lymphoma’s patients (20 females, 23 males, mean age 52.4 years). We determined the level of CD3+/HLADR+ and CD3+/CD69+ T-cell subsets before, during and after the periods of polychemotherapy, using the methods of immunofluorescence stain and flow cytometry. RESULTS - We found the ratio of CD3+/HLA-DR+ cells significantly higher in non-Hodgkin-lymphoma’s patients before treatment compared to healthy controls (10.63% vs. 2.97%, p<0.001). During the period of polychemotherapy, this ratio began to increase significantly (16.94% vs. 10.63%, p=0.006). The level of CD3+/CD69+ cells did not change significantly. After treatment, the ratio of activated T-cells decreased, however, we detected significantly higher rate of CD3+/HLA-DR+ lymphocytes in patients who relapsed within one year than in those who stayed in remission (9.55% vs. 20.62%, p<0.001). CONCLUSION - Investigation of CD3+/HLA-DR+ activated T-cells might be a promising method to determine the immune defence and this way the prognostics of lymphoma patients.]

Hungarian Immunology

[History of immunology in Hungary Part V]

KARASSZON Dénes, CSABA Béla

Hungarian Immunology

[Autumn international conferences]

SZEKANECZ Zoltán

Hungarian Immunology

[Immunology of Felty’s syndrome]

BÁLINT Géza, BÁLINT Péter

[Felty’s syndrome can be regarded as “super-rheumatoid” disease. Immungenetically the syndrome is much more homogenous, than rheumatoid arthritis. HLA-DRB1*0401 antigen is present in 83% of the patients. Felty’s syndrome develops usually after a longer course of rheumatoid arthritis, in 1% of rheumatoid patients. Rheumatoid arthritis patients with long lasting unexplained neutropenia can be diagnosed having Felty’s syndrome, even without detectable splenomegaly. On the contrary, rheumatoid arthritis with splenomegaly, but without present or previous neutropenia with unexplained origin cannot be regarded as having Felty’s syndrome. Inspite of the fact, that the arthritis of Felty’s syndrome can be inactive, because of the neutropenia and increased risk of recurrent infections, the patients should be kept under tight supervision, and should be properly treated, if required. Immunologically Felty’s syndrome is characterized by rheumatoid factor positivity in 95-100%, ANA positivity in 50-100%, antihistone positivity in 63-83%. Antibodies against dsDNA rarely, but against ssDNA frequently occur. No anti Sm and interestingly no anti Ro and anti La antibodies can be detected inspite of the high incidence of associated Sjögren’s syndrome. Immunoglobulin levels are higher and complement levels are lower, than in rheumatoid arthritis. Circulating immuncomplex level is usually high. Non-specific antineutrophil anticitoplasmatic antibodies can be found in high percentage. The neutropenia of Felty’s syndrome can be either caused by increased IgG neutrophilic binding activity or by inhibition of the granulocytes colony growing in the bone marrow, by peripheral blood mononuclear cells. Expansion of large granular lymphocytes can be seen in 30-40% of patients with Felty’s syndrome. Large granular lymphocyte syndrome is not rarely associated with rheumatoid arthritis. The neutrophil account is normal or elevated in this syndrome, but splenomegaly occurs. These cases are called as pseudo Felty’s syndrome. The patients with Felty's syndrome suffering from recurrent infections required treatment even if the arthritis is inactive. Methotrexate treatment should be started first, if this treatment fails, other disease modifying drugs or colony stimulating factor can be given. There is no experience with other biological treatments. In treatment of resistant cases splenectomy is indicated. Non-steroid anti-inflammatory drugs should be better avoided.]

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Clinical Neuroscience

[Possibilities of gene therapy with recombinant adenovirus in the cortex and hippocampus]

KOSKA Péter, VALIKOVICS Attila, KISS-TÓTH Éva, SZALAI Adrienn, NAGY Zoltán, FODOR Bertalan

[Background and purpose - Neurodegenerative diseases eg. ischemic stroke causes lifelong disabilities in cognitive functions and movement, furthermore high frequency of death. Antiapoptotic, or growth factor gene targeting to cortical structures could be a useful tool for neuroprotection in ischemic brain diseases. In present study we examined the feasibility of the gene therapy of the cortex and hippocampus via transfecting brain with recombinant adenovirus containing LacZ reporter gene in normal and postischemic condition. Since translation of proteins can be inhibited following ischemia by the phosphorylation of ribosomal subunit eIF2α, phosphor-eIF2α immunohystochemistry were performed. Methods - Our adenovirus vector was introduced via the cisterna magna into control and postischemic gerbil brain. After 48 hours of transfection the brains were examined for X-gal staining. LacZ expressing cells showed blue colour. Five min. transient global ischemia was induced by clipping the vertebral and carotid arteries of gerbil. Phosphor-eIF2α immunohystochemistry were performed following 48 hours of ischemia. Results - Administration of adenoviral vector resulted in transfection of hippocampal CA1, CA2, CA3 cell layers while gyrus dentatus remained untransfected. Cortical pyramidal cell layers were also transfected. In postischemic brain the lack of LacZ gene expression were detected in the CA1 and CA2 layer of hippocampus. Ischemia caused eIF2α phosphorylation in hippocampal CA1, CA2, CA3 and most neuronal layers in the cortex. Conclusion - Introducing adenovirus vector via the cisterna magna may results in effective gene therapy of cortex and hippocampus. To develop effective gene therapy in postischemic hippocampal CA1 and CA2 cell layers needs further investigation. eIF2α phosphorylation probably doesn’t interfere with transgene expression.]

Lege Artis Medicinae

[SECONDARY MALIGNANCIES IN RHEUMATOID ARTHRITIS]

SZEKANECZ Éva, SZŰCS Gabriella, KISS Emese, SZABÓ Zoltán, SZÁNTÓ Sándor, TARR Tünde, SZÁNTÓ János, SZEKANECZ Zoltán

[INTRODUCTION - Survival data for rheumatoid arthritis (RA) have improved during the past years. Due to longer life expectancy, more attention has to be paid to prevention and treatment of long-term sequelae, including secondary malignancies. Incidence of malignant lymphoproliferative diseases and bronchial cancer is higher in a number of rheumatic diseases including RA. Some drugs nowadays very rarely used in RA - primarily cyclophosphamide and azathioprine - may further increase cancer risk. According to several large meta-analyses, biological therapy may also increase the risk of lymphomas, however, as these agents are used for the treatment of active, refractory arthritis, benefit may override such risks. PATIENTS AND METHODS - Altogether 516 RA patients managed at our department were assessed for the incidence and type of secondary malignancies. Although the absolute number of RA patients with a tumor was relatively small, we compared our cohort to the Health for All database and calculated standard incidence ratios (SIR). RESULTS - We identified 13 cases of malignancy (11 females and 2 males) in 516 RA patients (2.5%). In two patients, cancer developed before the onset of RA. RA patients with malignancy had an even higher female predominance (5.5 to 1) than usual. Mean age at onset of RA was 51.4 years, while age at the diagnosis of malignancy was 61.8 years. Mean duration of RA at the time of cancer diagnosis was 11.2 years. Five patients died, 4 due to the underlying malignancy. In the fifth patient, the tumor was considered cured but the patient died of amyloidosis. Among the 8 surviving patients, mean survival is 7.3 years until now, while overall survival of all 13 cancer patients is 4.7 years. Regarding types of malignancies, there were 6 cases of bronchial cancer, 2 cases of follicular thyroid cancer, and one cutaneous B cell lymphoma, one breast cancer, one gall bladder cancer, one colorectal cancer, and one pancreatic cancer. In comparison to the Health for All database, the overall SIR of all malignancies in RA was 1.12 (CI 0,91-1,33), varying between 2.2 and 70.7 among different tumor types. Only one cancer patient received cyclophosphamide therapy and some received methotrexate or anti-TNF agents. CONCLUSION - We identified 13 cases of malignancy among our RA patients. In RA, secondary tumors including bronchial cancer and lymphomas are more common than in the general population. Adequate treatment and monitoring of these patients may help us to lower the risk of malignancies secondary to RA]

Hungarian Immunology

[The role of nerve growth (NGF) factor in the immune and inflammatory events and in autoimmune thyroid diseases]

MOLNÁR Ildikó

[Nerve growth factor (NGF) is a neurotroph cytokine, and beside its effect on the central and peripheral nervous systems NGF plays an important role in the inflammatory and autoimmune processes. There are two types of NGF receptors, the high-affinity (TrkA) and the low-affinity (p75), which activations via signal transduction could lead to the inhibition or induction of apoptosis. Suppression of apoptosis could be induced by cytokines, hormones, antioxidans and increased intracellular Ca2+-levels. In the pathogenesis of many autoimmune diseases (systemic lupus erythematosus, 1-type diabetes mellitus, multiple sclerosis) could detect elevated serum levels of NGF associated with the disease activity. Our study demonstrated increased levels of NGF in autoimmune thyroid diseases (Graves’ disease, Hashimoto’s thyroiditis) in comparison with the controls. Decreased serum levels of NGF were found in Graves’ ophthalmopathy suggesting the role of apoptosis in the development of the eye symptoms. Orbital tissues are characterized with the high expression of TrkA receptors. NGF plays an important role in the pathomechanisms of neuro-immuno-hormonal diseases and its knowledge may be helpful in the diagnosis and therapy.]

Hungarian Radiology

[Rheumatoid arthritis: significance and methodology of cervical spine X-rays in everyday practice]

NÉMETH Ildikó, BUDAY Ilona, MOLNÁR Éva, NYITRAI Márta, SAÁRY Krisztina, TARKOVÁCS Andrea, VARSÁNYI Nóra, FARBAKY Zsófia

[Cervical spine joint destruction in rheumatoid arthritis may lead to progressive vertebral instability. It is a severe risk factor for cord compression, which may even lead to sudden death. Many patients with atlantoaxial subluxation may have no symptoms referable to the neck. True degree of subluxation may occur during anaesthesia when the neck muscles are relaxed and protective spasm is absent. The cervical deformities can be visualised on conventional, transoral and functional lateral view in the flexion and extension positions of the neck. The aim of our study is to demonstrate the usefulness of cervical dynamic X-ray for patients suffering from rheumatoid arthritis. This is the first classical radiological imaging method in the diagnosis and in radiographic follow-up. It is a very important method in the preoperative evaluation to prevent definitive neurologic injury. We describe the method for screening, measuring and grading cervical subluxations and instability in our everyday routine.]

Lege Artis Medicinae

[Crystal deposition in the background of a thyroid nodule]

BÉLY Miklós, PÉTER Ilona, SZŐKE János, GÁTI Tamás, KOLTAI Pál

[The authors present the findings of thyroid surgery in a patient treated for rheumatoid arthritis. An operation was performed due to the rapidly enlarged thyroid. In addition to the complex developmental anomaly, different crystals were found in the surgical material, which had called attention to the possibly affected mineral metabolism. Actually/Currently, the patient is not suffering from a clinically detectable metabolic disease or arthropathia induced by any crystal. The definitive crystal deposition in tissues, however, calls the physicians attention that the patient in addition to the treatment of the underlying disease should be examined in direction of a possibly developing metabolic disease, and, if necessary, an effective therapy should be used in a very early phase. ]