CONTENTS
Review
- Mechanisms of Immune Regulation in Alzheimer’s Disease: a Viewpoint
FLORENTINE MARX, IMRICH BLASKO and BEATRIX GRUBECK-LOEBENSTEINAbstract. The immune system may play an important role in the neurodegenerative process in Alzheimer’s disease (AD). Complement components, eicosanoids and cytokines are found in cerebral amyloid plaques. These inflammatory proteins may stimulate the amyloid b (Ab) production, support its aggregation and increase its cytotoxicity, thus aggrevating the pathology of AD. Ab may trigger their release from activated microglia and astrocytes which are the main sources of these proteins. However, there are also indications for a protective role of the immune system against the development of AD. Microglial cells have been shown to degrade Ab and recent evidence suggests a role of autoreactive Ab?specific T cells in the elimination of the peptide. This mechanism seems to be impaired in the majority of patients with AD. An Ab?specific immune reaction may thus represent a natural defence mechanism directed against the accumulation of dangerous amyloidogenic substances. Impairment of the immune system and the failure to eliminate a toxic metabolite can be the basis for a chronic non?specific inflammatory process in the brain, as described above. AD is a good example how an immune response may lead to tissue destruction and neuronal loss instead of maintaining the integrity of the body.
Keywords: Alzheimer’s disease; Alzheimer amyloid precursor protein; amyloid b; cytokines; T lymphocytes; autoreactivity; inflammation.
- Mechanistic and Clinical Aspects of b?Lactam Antibiotics and b?Lactamases
LAKSHMI P. KOTRA and SHAHRIAR MOBASHERYAbstract. Bacterial infections have been a major cause of concern in the recent years due to the emergence of drug resistance strains and inability of the current therapeutic regimens to treat these infections in certain cases. b?Lactam antibiotics have been drugs of choice since the introduction of penicillin. These drugs inhibit bacterial cell?wall?synthesizing enzymes, the so?called penicillin?binding proteins (PBPs) selectively, thus providing an effective strategy for treatment of the bacterial infections. Significantly, bacteria have developed resistance mechanisms to neutralize the antibiotic action of b?lactam drugs. b?Lactamases are enzymes that hydrolyze the b?lactam moiety of these drugs, rendering them inactive. This is the primary mechanism of resistance to this class of antibiotics. There are 255 known b?lactamases to date and the continued use of b?lactams may select for newer variants yet. A discussion of the roles of these enzymes in the manifestation of the drug?resistant phenotype and their implications for pathogenecity of clinical strains of bacteria is presented.
Keywords: b-lactams; b-lactamases; antibiotic; drug resistance; bacterial infection.
- Expression and Function of CD30 on T Lymphocytes
MACIEJ TARKOWSKIAbstract. T cell receptor, accessory molecules, cytokines are important regulatory factors that determine the development and function of T lymphocytes. Among them are also molecules belonging to superfamily of tumor necrosis factor receptor (TNFR) which beside CD30 include CD27, CD40, TNFR?I and ?II, Fas (CD95), OX40, 4?1BB (CDw137), nerve growth factor receptor, lymphotoxin?b receptor, Apo3/DR3/Ws1?1/lymphocyte associated receptor of death, DR4, DR5/TNF?related apoptosis?inducing ligand, osteoprotegerin, and TNFR?related 2. CD30 recognized originally on Reed?Sternberg cells of Hodgkin’s lymphoma became of interest in studies of Th1 and Th2 cell differentiation. This paper shows recent findings regarding CD30 expression and its pleiotropic role in T cell function. It provides information about controversial role of CD30 as Th2 cell differentiation marker and gives concise insight into the function of this receptor as a signal transducing molecule.
Keywords: CD30; T cells; cytokines.
- Immunotherapy with Recombinant Human Interleukin 2 in Patients with Hematological Malignancies after Bone Marrow or Peripheral Blood Stem Cell Transplantation
IRENA FRYDECKA, AGATA KOSMACZEWSKA, DOROTA BOĆKO, LIDIA CISZAK2 and PAWEŁ KACZMAREK1Abstract. High-dose chemotherapy in conjunction with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) is increasingly being used for treatment of patients with hematological malignancies. Residual tumor cells, resistant to high?dose chemoradiotherapy, are responsible for reccurence of the disease. Interleukin 2 (IL?2), a pleiotropic cytokine which plays a central role in immune response, has been introduced in several clinical trials in patients with hematological malignancies after BMT or PBSCT to increase immunocompetence of these patients and eradicate residual malignant cells. At present there is no general agreement on the optimum dosage or route of administration and clinical trials also gave conflicting results. Establishment of optimum dosage schedules and methods of administration should enable a better assessment of the place of IL?2 in the treatment of these patients.
Keywords: interleukin 2; bone marrow transplantation; peripheral blood stem cell transplantation.
Clinical Immunology
- Serum Haptoglobin, CA 125 and Interleukin 6 Levels in Malignant and Non?Malignant Tumors of the Ovary
WANDA DOBRYSZYCKA, IWONA KĄTNIK?PRASTOWSKA, JERZY GERBER, KRYSTYNA LEMAŃSKA, KRYSTYNA UTKO2 and KRZYSZTOF ROZDOLSKI3Abstract. In sera of women with malignant and non?malignant ovarian tumors, concentrations of the following proteins were determined: haptoglobin, measured by the reactions either with hemoglobin (Hp?Hb) or with concanavalin A (Hp?Con A), CA 125 antigen and interleukin 6 (IL?6). Besides preoperative data, obtained from all the patients and the group of healthy women, in the patients with ovarian cancer (III/IV FIGO stages) effects of administration of cytostatics were measured by monitoring changes in the levels of the examined parameters through the course of the therapy. All the results were submitted to statistical evaluation which showed differences and correlations among definite groups (normal/non?malignant, normal/cancers, non?malignant/cancers). Similar results were obtained for Hp?Hb and CA 125 determination. Moreover, a correlation between haptoglobin level and age was found. Patterns of monitoring revealed a surprising absence of Hp?Con A interaction in some cases.
Keywords: haptoglobin?hemoglobin; haptoglobin?concanavalin A; interleukin 6; CA 125; ovarian cancer.
- Development and Disappearance of Tolerance to Induction of Interferon and Tumor Necrosis Factor Response in Athletes Treated with Natural Immunostimulant
ANNA D. INGLOT, KRZYSZTOF A. SOBIECH, JANINA ZIELIŃSKA?JENCZYLIK, ALICJA SYPUŁA, JACEK MAJDA3 and MARIA LORENC1Abstract. The effect of nonspecific immunostimulation was examined in 15 basketball players subjected to extensive physical effort. The Tołpa* Torf Preparation (TTP*), a natural immunostimulating drug, was applied orally, one 5 mg tablet daily, in two 21?day cycles, separated by 2?week hiatus. Blood samples were collected 4 times, after each of two TTP* cycles and after the first and second hiatus. Whole blood assay was used to determine the spontaneous and induced production of interferon (IFN) and tumor necrosis factor (TNF). The levels of the cytokines were measured by microbioassays. TTP* stimulated synthesis of IFN and TNF in the whole blood cultures. However, after the oral administraton of TTP* for 3 weeks the leukocytes of the athletes developed hyporeactivity to IFN induction by TTP* and to a lesser extent to another “superinducer” – a mixture of phytohemagglutinin and bacterial lipopolysaccharide. The hyporeactivity state disappeared spontaneously within 2 weeks. In contrast, the tolerance to TNF induction did not develop during the TTP* administration. The increase of immunoglobulins, mainly of IgM and IgG classes and an acute phase protein – a1?antitrypsin, was observed at the late phase of the treatment. We suggest that the cytokine levels may be early markers for immunoprophylaxis. Furthermore, high production of IFN and TNF may be associated with extensive physical effort.
Keywords: nonspecific immunostimulation; basketball players; interferon; tumor necrosis factor; whole blood assay.
- Heparin Modulates Migration of Human Peripheral Blood Mononuclear Cells and Neutrophils
TERESA ŻAK-NEJMARK, MARYLA KRASNOWSKA, RENATA JANKOWSKA2 and MAREK JUTEL1Abstract. Evidence has now accumulated that heparin can significantly affect immune response including allergic inflammation. Cell motility is supposed to be very crucial in this process. Thus the aim of our study was to investigate whether heparin is a chemoattractant for some inflammatory cells and is also capable of influencing chemotaxis induced by typical chemoattractants. Peripheral blood mononuclear cells (PBMCs) and neutrophils from 10 healthy subjects were obtained by gradient centrifugation. Chemotaxis assays towards either heparin (molecular weight 16 kDa) or low molecular weight heparin – fraxiparine (molecular weight 5 kDa) were performed in Boyden chambers. We found that both heparin molecules are chemoattractants for both PBMCs and neutrophils in the wide concentration range (0.1–2000 mg/ml). However, maximal chemotaxis was observed at concentrations 50–100 mg/ml (fraxiparine) and 1–50 mg/ml (heparin). We also found that fraxiparine was able to significantly increase chemokinesis and decrease chemotaxis in the gradient of both fMLP and IL?8. These results indicate that heparin is a potent regulator of cell migration.
Keywords: peripheral blood mononuclear cells; neutrophils; migration; heparin influence.
- Soluble CD23 in Allergic Diseases
BARBARA ROGALA and BARBARA RYMARCZYKAbstract. CD23, a differentiation marker of B cells is identified with the low?affinity receptor for IgE – FceRII. The CD23 molecule is continuously cleaved by autoproteolysis into soluble fragments called sCD23, considered as a multifunctional cytokine. sCD23 is supposed to play an important role in IgE synthesis. IgE is a hallmark of atopy and its overproduction is a characteristic feature of allergic diseases. The aim of this study was to determine sCD23 (25 kDA) serum levels in patients with inhalant allergy and hymenoptera venom?induced allergy with relevance to IgE system. The trial consisted of 18 patients with pollinosis, 25 with house dust mite allergy and 12 with hymenoptera venom?induced allergy. Eighteen healthy volunteers without signs of atopy served as a control group. Serum levels of sCD23 (25 kDa), total IgE and allergen specific IgE were measured as well. The results were presented as median value, 25–75% range and a total value range. Nonparametric tests (the U Mann?Whitney test, Kruskal and Wallis test and Spearman’s correlation rang test) were used. In patients with allergic disorders serum levels of sCD23 were significantly higher than in the control group (p<<0. 05). No correlation between IgE levels and sCD23 was detected in all the investigated groups. sCD23 does not appear to be a hallmark of allergic diseases, however serum level of that molecule is significantly elevated in patients suffering from allergic disorders. No correlation between sCD23 and IgE has been observed. sCD23 serum level has no relevance to the types of allergic diseases.
Keywords: soluble CD23; allergy.
- Regulatory Effects of Lactoferrin and Lipopolysaccharide on LFA?1 Expression on Human Peripheral Blood Mononuclear Cells
MICHAŁ ZIMECKI, RYSZARD MIĘDZYBRODZKI, JOEL MAZURIER and GENEVIĚVE SPIK
Abstract. The aim of this study was to investigate effects of human lactoferrin (hLF) with regard to LFA?1 expression on unstimulated and lipopolysaccharide (LPS) ?activated human peripheral blood mononuclear cells (PBMC). The investigations were carried out on 30 healthy volunteers, males and females, 24–58 years old. We found that hLF, at an optimal dose of 5 mg/ml/106 cells in 24?hour culture, exerted regulatory effects on LFA?1 expression, depending on distribution of this molecule on cells in control cultures and on the effects of LPS. First, we revealed several patterns of LFA?1 distribution and density of this marker among studied individuals. The effects of LPS and hLF on LFA?1 expression patterns were differential. LFA?1 expression was stimulated by individual actions of LPS or hLF, additive or synergistic effects of both factors, it could be also inhibited by hLF alone or in combination with LPS. In about one third of cases no significant effects of LPS or hLF on LFA?1 expression were seen. Removal of monocytes from the PBMC population diminished LFA?1 expression in control cultures and abolished LPS? or hLF?elicited changes. The regulatory effects of hLF were also blocked by treatment of PBMC cultures with anti?tumor necrosis factor alpha (TNF?a) antibodies. Taken together, the data showed that hLF and LPS had immunoregulatory properties with respect to LFA?1 expression on human PBMC and that these actions were mediated by monocytes and TNF?a.
Keywords: lactoferrin; lipopolysaccharide; LFA?1 (CD11a); peripheral blood mononuclear cells; regulation.