CONTENTS
Review
- Phage Therapy: Past History and Future Prospects
RICHARD M. CARLTONAbstract. Bacterial viruses (bacteriophages, also called “phages”) can be robust antibacterial agents in vitro. However, their use as therapeutic agents, during a number of trials from the1920s to the 1950s, was greatly handicapped by a number of factors. In part, there were certain limitations inherent in phage physiology (e. g. narrow host range, and rapid clearance from the body); in part there were technological limitations in the era (e. g. lysogeny not yet discovered); but the greatest limitation was the highly inadequate scientific methodologies used by practitioners at the time (e. g., their failure to conduct placebo?controlled studies, to remove endotoxins from the preparations, and to re?confirm phage viability after adding sterilizing agents to the preparations). In recent years, well?controlled animal models have demonstrated that phages can rescue animals from a variety of fatal infections, while non?controlled clinical reports published in Eastern Europe have shown that phages can be effective in treating drug?resistant infections in humans. This encouraging data, combined with the fact that drug?resistant bacteria have become a global crisis, have created a window of opportunity for phage therapy to be tested anew, this time using modern technologies and placebo?controlled designs. If successful, it can be used as a stand?alone therapy when bacteria are fully resistant to antibiotics, and as a valuable adjunct to antibiotics when the bacteria are still susceptible.
Keywords: bacteriophage; phage; bacterial viruses; bacterial infections; multidrug resistance.
- Biochemical and Immunological Characteristics of 4?1BB (CD137) Receptor and Ligand and Potential Applications in Cancer Therapy
GABRIEL SICA and LIEPING CHENAbstract. 4?1BB (CD137) is a member of the tumor necrosis factor receptor (TNFR) superfamily that is expressed primarily on activated T cells. Crosslinking of the 4?1BB receptor activates an intracellular signal cascade that leads to the activation of NF?kB and costimulation of T cell growth. Recent evidence indicates that 4?1BB may preferentially costimulate CD8+ T cell growth and induce cytolytic activity. The cytolytic activity induced by 4?1BB crosslinking is able to eradicate large, well?established, poorly immunogenic tumors and augments allogenic T cell responses in vivo. The 4?1BB/4?1BB ligand costimulatory pathway can provide an alternative T cell costimulatory pathway in the absence of CD28, but may physiologically function as a synergistic or complementary pathway to the CD28 costimulatory pathway. Only some of the basic immunological functions of 4?1BB/4? ?1BB ligand have been elucidated and much study is required to determine its exact role in T cell activation.
Keywords: tumor necrosis factor receptor; tumor; costimulation; T cell activation.
- Cerebral Inflammation in X-Linked Adrenoleukodystrophy
MARTINA C. MCGUINNESS1 and KIRBY D. SMITH2Abstract. X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disease that affects approximately 1 in 25 000 males. It is characterized by elevated levels of saturated very long chain fatty acids (VLCFA), i. e., >C22:0, particularly in ganglioside and cholesterol ester fractions of brain white matter and adrenal cortex. Failure of peroxisomal very long chain fatty acyl?CoA synthetase (VLCS) to activate these VLCFA prevents their degradation by peroxisomal b-oxidation. X-ALD maps to Xq28 and the gene encodes a peroxisomal membrane protein and not the gene for VLCS. The two most common forms of X?ALD are the cerebral (CER) form, with an inflammatory demyelinating reaction that resembles multiple sclerosis (MS), and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. Investigations into the nature of the cerebral inflammatory demyelinating reaction in X-ALD will be the subject of this review.
Keywords: X-linked adrenoleukodystrophy; inflammation; demyelination; cytokines; human leukocyte antigens.
- Retroviruses in Autoimmune Liver Disease: Genetic or Environmental Agents?
ANDREW L. MASON, LIZHE XU, LINSHENG GUO and ROBERT F. GARRYAbstract. Retroviruses have been implicated in the pathogenesis of several human autoimmune conditions including Sjögren’s syndrome, primary biliary cirrhosis, immune mediated diabetes, and multiple sclerosis. The human intracisternal A type particle derived from Sjögren’s syndrome patients’ salivary glands was the first retrovirus to be isolated from a human autoimmune disorder but the agent has yet to be cloned. In primary biliary cirrhosis patients, virus like particles have been observed by electron microscopy in biliary epithelium, endogenous retroviral sequences have been cloned from liver samples, and antibody reactivity to the human intracisternal A type particle has been observed in the majority of patients tested. However, there is no evidence to link the endogenous retroviral sequences in primary biliary cirrhosis patients to the retroviral antibody reactivity or virus like particles. In other patients with liver disease, reactivity to the human intracisternal A type particle was observed in a small but significant proportion of patients with hepatitis C virus infection. If the intracisternal A type particle is an endogenous retrovirus, it is interesting to speculate that hepatitis C virus infection may modulate the endogenous retroviral expression, as chronic hepatitis C has been linked with the development of Sjögren’s syndrome. Furthermore, many patients with chronic hepatitis C virus infection have reactivity to an autoantigen of unknown significance known as GOR that has protein sequence homology with both hepatitis C virus nucleocapsid protein as well as HTLV?1 gag. This may be an another example of an endogenous retroviral protein acting as an autoantigen in liver disease patients. At this time, there is little evidence to suggest that endogenous retroviruses are infectious agents that cause autoimmune disease but they may be implicated as either genetic elements or antigens. Further studies will be required to characterize the role that both exogenous and endogenous retroviruses play in the pathogenesis of autoimmune liver diseases.
Keywords: autoimmune liver disease; hepatitis C virus; human endogenous retroviruses; human intracisterial A?type particle, primary biliary cirrhosis; Sjögren’s syndrome; systemic lupus erythematosus.
- Following Angiogenin during Angiogenesis: a Journey from the Cell Surface to the Nucleolus
ANTONI WIĘDŁOCHAAbstract. Angiogenin is a potent inducer of new blood vessel formation. It binds to high?affinity endothelial cell?surface receptors and, with lower affinity, to extracellular matrix. Angiogenin is the only angiogenic factor known to exhibit ribonucleolytic activity. It belongs to the pancreatic RNase superfamily of proteins. Angiogenin is the only member of the superfamily able to stimulate angiogenesis. Although the catalytic activity of the protein is rather weak, it is critical for its angiogenic properties. Angiogenin is specifically endocytosed by endothelial cells and transported to the nucleus, where it accumulates in the nucleolus. Also, the nuclear location of the angiogenic factor appears to be necessary for its angiogenic activity. The mechanism of action of the protein seems to be unusual, since it does not fit into the current paradigm of how exogenous regulatory polypeptides, including other angiogenic factors, work. Here, the role of transport of angiogenin from the cell?surface into the nucleolus and of its intracellular/nuclear mode of action in stimulation of angiogenesis is discussed.
Keywords: angiogenesis; angiogenin; signaling; nuclear transport; nucleolus.
- Genetic Basis for Rheumatoid Arthritis
DHARAM P. SINGAL, JIANPING LI and YAOHUI ZHUAbstract. Rheumatoid arthritis (RA) is a common disabling disorder of unknown etiology. In the past 2 decades, a number of studies have examined the genetic basis for RA. One major focus of these studies has been to identify genes within the MHC class II (HLA?DR) chromosomal region, which confer susceptibility/resistance to RA. A strong association between HLA?DR4 and adult seropositive RA has been observed in majority of populations. In addition, there is evidence of a positive association between HLA?DR1 and RA. On the basis of prevalence of DR1 (B1*0101) and of subtypes of DR4 (B1*0401, B1*0404 and B1*0405), it has been suggested that a five amino acid sequence motif (QKRAA/QRRAA) from position 70 to 74 in the third hypervariable region of DRb1 molecules is associated with susceptibility to RA. These associations between RA and HLA?DR genes are however incomplete in that about 1/4 of patients do not carry RA?susceptibility DRB1 epitope. Since MHC class III region contains genes that are involved in immune response, we have recently examined the role of a number of microsatellites (D6S273, Bat2, TNFa) and HSP70 promoter region alleles in susceptibility to RA. The results demonstrate that two regions in MHC, class II (DRb1) and class III (D6S273, HSP70, Bat2, TNFa) more completely define the risk for development of RA.
Keywords: rheumatoid arthritis; HLA?DRB1; D6S273; Bat2; TNFa; HSP70.
- CD8+ T Lymphocytes Against Mycobacterium tuberculosis
MICHEL R. KLEIN and KEITH P. W. J. MCADAMAbstract. Tuberculosis (TB) is again a global health problem. Identification and characterization of the correlates of protective immunity against TB is critical for the rationale design of novel TB vaccines. There is accumulating data that CD8+ T lymphocytes are involved in the immune response against mycobacteria. Here the current state of the art is reviewed with respect to phenotype, specificity and effector mechanisms of mycobacteria?specific CD8+ T lympocytes. In addition, the first listing is presented of mycobacteria?derived CD8+ cytotoxic T lympocyte (CTL) epitopes containing sequences published up to the end of 1998.
Keywords: tuberculosis; mycobacterium; CD8; cytotoxic T lympocyte; epitope; vaccine.
Clinical Immunology
- Content of Trace Elements in Serum of Patients with Carcinoma of the Larynx
BEATA ROSTKOWSKA-NADOLSKA, LUCYNA POŚPIECH and MAREK BOCHNIAAbstract. An examination of the content of arsenic, nickel, copper, selenium, zinc, and iron in the serum of 78 patients with carcinoma of the larynx was carried out. The patients were divided into 4 groups: I – patients before treatment, II – patients after surgical treatment, III – patients after radiotherapy, IV – patients after combined treatment (surgery treatment + radiotherapy). The control group was formed of 17 patients operated for deviation of the nasal septum. Higher concentrations of arsenic, nickel and copper were found in the serum of the patients with carcinoma of the larynx before treatment (group I) as compared with the control group, whereas the concentrations of selenium, zinc and iron were lower. In the groups of patients after treatment, the highest concentrations of iron and zinc were found after surgical treatment. The level of selenium in all groups of patients was considerably lower than in the control group.
Keywords: cancer; larynx; trace elements.
- Plasma Cystatin C Concentration in Non-Insulin-Dependent Diabetes Mellitus: Relation with Nephropathy
AGNIESZKA PIWOWAR, MARIA KNAPIK-KORDECKA, HENRYKA BUCZYŃSKA and MARIA WARWAS
Abstract. We determined plasma concentrations of cystatin C, b2-microglobulin – b2-MG (low molecular mass protein markers of glomerular filtration rate – GFR), creatinine (marker of GFR) and urinary N-acetyl-b-D-glucosaminidase (NAG) excretion (marker of glomerular and tubular dysfunction) in 41 non-insulin-dependent diabetic patients. A significant increase of all the measured parameters (p<0. 001, p<0. 05, p<0. 05 and p<0. 001, respectively) in comparison to the control group, was observed. In the patients with microalbuminuria, only plasma cystatin C concentration and urinary NAG excretion increased significantly in comparison to patients with normoalbuminuria. At a cut-off level of 1. 74 mg/l for cystatin C and 1. 81 U/g creatinine for NAG (95% percentile of the normoalbuminuric group), the sensitivity of the tests for detecting microalbuminuria was 82% for cystatin C and 86% for NAG. The specificities were 88 and 92%, respectively. The present study demonstrated that determination of plasma cystatin C might be useful in the detection of incipient diabetic nephropathy and is a potentially better marker than creatinine or b2-MG. No correlation between parameters measured in plasma or urine and glycated hemoglobin was found.
Keywords: cystatin C; b2-microglobulin; N-acetyl-b-D-glucosaminidase; diabetic nephropathy.