bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective study of toxoplasma reactivation by polymerase chain reaction in allogeneic stem‐cell transplant recipients
Authors: Bretagne S. , Costa J.‐M. , Foulet F. , Jabot‐Lestang L. , Baud‐Camus F. , Cordonnier C.
Published: March 2003

Toxoplasmosis is a rare but life‐threatening complication of allogeneic stem‐cell transplantation. Polymerase chain reaction (PCR) offers the possibility to make the diagnosis earlier than conventional techniques, and is then expected to improve the prognosis. We undertook a prospective screening using a competitive PCR in blood in 32 stem‐cell transplant recipients. The sampling covered the first 150 days post‐transplant, at days 21, 30, 45, 60, 90, 120, and 150. Twenty‐four patients had anti‐toxoplasma antibodies before transplant. Three of them (12.5%) had transient PCR‐positive samples at 21, 45, and 90 days post‐transplant, respectively. The three PCR‐positive patients were febrile but had no funduscopic examination or cerebral computerised tomography (CT) scan abnormalities. The PCR signal disappeared when the patients were given trimethoprim‐sulfamethoxazole, and no full‐blown toxoplasmosis was observed. Toxoplasma reactivation evidenced using PCR is frequent in seropositive patients not receiving trimethoprim‐sulfamethoxazole during the 1–3 months post‐transplant. Toxoplasma PCR should be included in the diagnostic strategy of fever of unexplained origin in allogeneic stem‐cell transplant recipients. Then, prompt specific therapy can be initiated to avoid development of full‐blown toxoplasmosis Note.
Cytomegalovirus in solid organ transplantation
Authors: Rubin R.H.
Published: March 2003

Despite substantial advances made in controlling the effects of cytomegalovirus (CMV) infection, it remains the single most important pathogen in solid organ transplantation (SOT). Because CMV shares some characteristics with other human herpesviruses, it is also an important model system for understanding the actions of herpesviruses 6 and 7, Epstein–Barr virus (EBV) and, potentially, hepatitis C and B. As the lessons learned from HIV influenced our thinking about other viral infections (e.g. importance of viral load), so too what is learned about CMV will be applied to other herpesviruses. The pervasive nature of CMV and the common problems posed by this virus prompted the convening of a panel of experts in the field of SOT to discuss issues associated with CMV in transplant recipients. This supplement reflects the presentations and discussions at this symposium, including the clinical implications of CMV drug resistance, economic impact of CMV on transplant programs, the rationale for CMV hyperimmune globulin (CMV‐IGIV, CytoGam®) in SOT, antibody inhibition of CMV, hypogammaglobulinemia, role of CMV in allograft vasculopathy, and the clinical use of CytoGam therapy in a variety of SOT patients. A number of questions during the general discussion prompted the addition of other material to this Supplement, including the development of CMV‐IGIV for clinical use in SOT recipients and resource utilization associated with CMV‐related hospital readmissions.
Epstein–Barr virus load monitoring: its role in the prevention and management of post‐transplant lymphoproliferative disease
Authors: Rowe D.T. , Webber S. , Schauer E.M. , Reyes J. , Green M.
Published: March 2003

Abstract: The Epstein–Barr virus load in the peripheral blood at the time of diagnosis of post‐transplant lymphoproliferative disease (PTLD) is elevated 1000‐ to 10,000‐fold compared to the level detected in normal latency. With the use of quantitative polymerase chain reaction (PCR), changes in the viral load over time can be measured with a two‐ to fourfold accuracy. This has allowed early detection of first‐time infections and reactivations that may lead to PTLD and has provided an opportunity to intervene before symptomatic disease has occured. Viral load monitoring has also been used to follow patients with PTLD and, along with other parameters, provided an assessment of the effectiveness of therapeutic protocols. Viral load monitoring has led to the discovery that at least two‐thirds of transplant recipients become persistent viral load carriers. While the persistent load appears to be largely carried in latently infected memory B cells, more work is needed to clearly define this type of persistent infection and determine the risks associated with it. New diagnostic tests need to be developed to distinguish the persistent latent viral loads from viral loads that are likely to become symptomatic PTLD.
Recurrent Epstein–Barr virus associated disease in a cardiac transplant patient: evolution from plasmacytic hyperplasia to diffuse large cell lymphoma
Authors: Larratt L.M. , Hamilton M. , Coupland R. , Preiksaitis J.K.
Published: March 2003

Abstract: An Epstein–Barr virus (EBV)‐seronegative 31‐year‐old male underwent cardiac transplantation in 1991 for congenital cardiomyopathy. He presented with a protracted course of waxing and waning lymphadenopathy beginning four years after transplantation with eventual progression to a fulminant EBV‐positive large cell lymphoma eight years after transplantation. Risk factors for the development of post‐transplant lymphoproliferative disease in this patient, the importance of a standardized approach to pathology in assessing therapeutic options, and the management strategies used are discussed.
Pig islet xenograft rejection is markedly delayed in macrophage‐depleted mice: a study in streptozotocin diabetic animals
Authors: Wu Guosheng , Korsgren Olle , Zhang Jianguo , Song Zhenshun , Van Rooijen Nico , Tibell Annika
Published: March 2003

Abstract: The present study aimed to evaluate the effect of depletion of macrophages and/or natural killer (NK) cells on islet xenograft rejection in the pig‐to‐mouse model. Five microliters (4000 to 5000 IEQ, islet equivalents) of adult pig islets were transplanted under the renal capsule of C57BL/6 mice with streptozotocin‐induced diabetes. Macrophages were depleted by injection of liposome‐encapsulated dichloromethylene diphosphonate (Lip‐Cl2MDP) intraperitoneally (i.p.) at a dose of 100 µl/10 g body weight (BW) 2 days before transplantation, and 50 µl/10 g BW weekly thereafter. NK cells were depleted by injection of the monoclonal antibody NK 1.1 (anti‐NK 1.1 mAb) i.p. at a dose of 100 µg/mouse 1 day before transplantation, and then 25 µg per week thereafter. Islet graft survival was monitored by daily measurements of blood glucose. Graft survival was 8 ± 1.2 days in untreated controls, 9 ± 1.0 days with anti‐NK 1.1 mAb alone, 22 ± 4.9 days with Lip‐Cl2MDP alone (P < 0.01 vs. controls), and 26 ± 3.8 days with Lip‐Cl2MDP plus anti‐NK 1.1 mAb (P < 0.01 vs. controls). In the last group, two of six animals were killed with functioning grafts 30 days after transplantation. In untreated controls, rejected xenografts were heavily infiltrated by F4/80+ macrophages and CD3+ T cells. In Lip‐Cl2MDP‐treated groups, the number of F4/80+ macrophages was markedly reduced. On the periphery of xenografts, a small number of CD3+ T cells were observed. In conclusion, our results suggest that strategies targeting macrophages may facilitate islet xenograft survival. A role for NK cells cannot be excluded, but appears to be of minor importance.
Morphometric analysis of miniature swine hearts as potential human xenografts
Authors: Allan James S. , Rose Geoff A. , Choo Joseph K. , Arn J. Scott , Vesga Liana , Mawulawde Kwabena , Slisz Joanna K. , Allison Ken , Madsen Joren C.
Published: March 2003

Abstract: Miniature swine are considered to be potential donors for clinical cardiac transplantation. However, it is unclear how an appropriately sized porcine donor will be selected for a particular human recipient. To address this issue, we performed a morphometric study of the swine heart using transthoracic echocardiography (n = 26) to determine the diameters of the aortic annulus and root, pulmonary artery annulus, and mitral valve annulus. We also obtained direct ex vivo measurements of swine heart weight and linear dimensions (n = 71). Relationships between a swine's height, weight, length, chest circumference and these internal and external cardiac dimensions are described. The strongest correlations were found between a pig's body length and its aortic annulus and root diameters (r‐values = 0.97). These relationships are accurately described by univariate linear regression models. By cross‐relating our morphometric measurements of aortic annulus diameter in the miniature swine with normative human data, we were able to develop a nomogram, relating swine length and human height, which predicts which miniature swine would donate the best size‐matched heart for a particular human recipient.
A soluble chimeric inhibitor of C3 and C5 convertases, complement activation blocker‐2, prolongs graft survival in pig‐to‐rhesus monkey heart transplantation
Authors: Salerno Christopher T. , Kulick David M. , Yeh C. Grace , Guzman‐Paz Manuel , Higgins Paul J. , Benson Barbara A. , Park Soon J. , Shumway Sara J. , Bolman R. Morton , Dalmasso Agustin P.
Published: March 2003

Complement plays a critical role in many pathologic processes and in xenograft rejection. Therefore, effective complement inhibitors are of great interest. In pig‐to‐primate organ transplantation, hyperacute rejection results from antibody deposition and complement activation. Complement activation blocker‐2 (CAB‐2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF) and membrane cofactor protein, inhibits C3 and C5 convertases of both classical and alternative pathways. CAB‐2 reduces complement‐mediated tissue injury of a pig heart perfused ex vivo with human blood. Therefore, we studied the efficacy of CAB‐2 when a pig heart is transplanted heterotopically into rhesus monkeys receiving no immunosuppression. Graft survival in three control monkeys was 1.26 ± 0.2 h; it was markedly prolonged in eight monkeys that received CAB‐2. Of the six monkeys that received a single dose of CAB‐2 (15 mg/kg i.v.), four had graft survivals of 21, 95, 96, and 108 h, and two died at 7 to11 h post‐transplant with a beating graft, as a result of technical complications. The two monkeys given multiple doses of CAB‐2 had graft survivals of 95 and 96 h. CAB‐2 markedly inhibited complement activation, as shown by a strong reduction in generation of C3a and SC5b‐9. At graft rejection, tissue deposition of iC3b, C4 and C9 was similar or slightly reduced from controls, and deposition of IgG, IgM, C1q and fibrin did not change. Thus, complement inhibition with CAB‐2 abrogates hyperacute rejection of pig hearts transplanted into rhesus monkeys, but does not prevent delayed/acute vascular rejection. These studies demonstrate that the beneficial effects of complement inhibition on survival of a pig heart xenograft in rhesus monkeys are similar to those in other primate species and that CAB‐2 may be useful in xenotransplantation and other complement‐mediated conditions.
Porcine cytomegalovirus in pigs being bred for xenograft organs: progress towards control
Authors: Clark Duncan A. , Fryer Jacqueline F. L. , Tucker Alexander W. , McArdle Peter D. , Hughes Allison E. , Emery Vincent C. , Griffiths Paul D.
Published: March 2003

Clark DA, Fryer JFL, Tucker AW, McArdle PD, Hughes AE, Emery VC, Griffiths PD. Porcine cytomegalovirus in pigs being bred for xenograft organs: progress towards control. Xenotransplantation 2003; 10: 142–148. © Blackwell Munksgaard, 2003

In human medicine, human cytomegalovirus (HCMV) is readily transmitted by organ transplant causing end‐organ disease and triggering graft rejection in recipients. Because of a chronic shortage of human organs, pigs transgenic for human complement control proteins are being considered as potential donors. Such xenotransplantation raises concerns about the potential zoonotic transmission of viruses including porcine cytomegalovirus (PCMV), an endemic infection of pigs. Similar to HCMV and PCMV transmission is thought to occur in utero and perinatally. We used quantitative polymerase chain reaction to examine the prevalence, organ distribution and viral load of PCMV in human decay accelerating factor (CD55) transgenic pigs. In animals reared under conventional farm conditions, virus was identified in a wide range of organs including potential xenografts (liver, kidney and heart). The spleen was PCMV DNA positive in all infected pigs. Examination of foetal spleens failed to identify evidence of transplacental infection and prospective monitoring of two litters showed that infection occurred in the postnatal period. This transmission was prevented by hysterotomy derivation and barrier rearing. Our findings demonstrate that PCMV could be eradicated from pig herds being bred for xenotransplantation and argue that the spleen from donor animals should be examined as part of quality control procedures if clinical trials proceed.
Components of productivity in black‐legged kittiwakes Rissa tridactyla: response to supplemental feeding
Authors: Gill Verena A. , Hatch Scott A.
Published: March 2003

In contrast to the high productivity of black‐legged kittiwakes in Britain, kittiwakes at many colonies in Alaska have failed chronically to reproduce since the mid 1970s. To determine if food is limiting productivity and, if so, at what stages of nesting food shortages are most severe, in 1996 and 1997 we supplementally fed kittiwakes nesting on an abandoned building. The effects of feeding were stronger in 1997 than in 1996, possibly because naturally occurring prey were of poorer quality in 1997. Consumption of supplemental herring declined as egg laying approached then increased slowly during incubation and more rapidly after hatching. All of the six components of productivity we studied were improved by supplemental feeding to some degree. Supplemental food did not significantly alter laying success in either year, although fed pairs bred at slightly higher rates than unfed pairs in 1997, the poorer food year. In 1996 and 1997, extra food noticeably increased clutch size and hatching success, but significantly so only in 1997. Fledging success and productivity were substantially augmented by feeding in both years. Fed pairs fledged twice as many chicks per nest as did unfed pairs in 1996 and three times as many in 1997. Fed and unfed pairs lost most of their potential productivity through the inability to hatch eggs, and secondarily because of their poor success at raising chicks. The benefits of supplemental feeding did not carry over from one stage of breeding to another. Pairs cut off from supplemental food after laying or hatching performed similarly to pairs that had not been previously fed. This study provides benchmark values of breeding performance attainable by kittiwakes in Alaska under optimal conditions. These values are comparable to highly productive colonies in Britain and suggest that differences in life‐history characteristics between Pacific and Atlantic breeding populations are primarily controlled by food supply.
Use of sensory cues by fish crows Corvus ossifragus preying on artificial bird nests
Authors: Santisteban Leonard , Sieving Kathryn E. , Avery Michael L.
Published: March 2003

How predators locate avian nests is poorly understood and has been subjected to little experimental inquiry. We examined which sensory stimuli were important in the nest‐finding behavior of fish crows Corvus ossifragus, a common nest predator in the southeastern United States. Using an array of potted trees in a large enclosure, we presented artificial nests to captive crows and quantified responses to visual, auditory, and olfactory nest cues, and nest position. Partial ranks of nest‐treatment preferences were analyzed using log‐linear models. Nest visibility significantly increased the likelihood of predation by fish crows and increasing nest height was a marginally significant influence on nest vulnerability; no responses were apparent to auditory or olfactory stimuli. Our findings demonstrate that fish crows are visually‐oriented nest predators that may preferentially prey on, or more readily encounter, above‐ground nests. Moreover, the experimental design provides a new method for evaluating predator‐prey interactions between nests and their predators. This study also illustrates how sensory capabilities of predators can interact with nest types to determine nest predation patterns.
Local control of the immune response in the liver
Authors: Knolle Percy A. , Gerken Guido
Published: March 2003

Summary: The physiological function of the liver – such as removal of pathogens and antigens from the blood, protein synthesis and metabolism – requires an immune response that is adapted to these tasks and is locally regulated. Pathogenic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the induction of tolerance rather than the induction of immunity. The liver probably not only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal‐venous blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanisms and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, direct interaction of hepatocytes with leukocytes in the blood is unlikely. Sinusoidal endothelial cells, which line the hepatic sinusoids and separate hepatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with passenger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor‐mediated endocytosis. Liver sinusoidal endothelial cells constitutively express all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC class I and class II and CD40) and can function as antigen‐presenting cells for CD4+ and CD8+ T cells. Thus, these cells probably contribute to hepatic immune surveillance by activation of effector T cells. Antigen‐specific T‐cell activation is influenced by the local microenvironment. This microenvironment is characterized by the physiological presence of bacterial constituents such as endotoxin and by the local release of immunosuppressive mediators such as interleukin‐10, prostaglandin E2 and transforming growth factor‐b. Different hepatic cell populations may contribute in different ways to tolerance induction in the liver. In vitro experiments revealed that naive T cells are activated by resident sinusoidal endothelial cells but do not differentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. Besides sinusoidal endothelial cells, other cell populations of the liver, such as dendritic cells, Kupffer cells and perhaps also hepatocytes, may contribute to tolerance induction by deletion of T cells through induction of apoptosis.
Self‐etching vs. traditional bonding systems in orthodontics: an in vitro study
Authors: Velo S , Carano A , Carano A
Published: March 2003

The need for a bonding system that is consistently reliable, biocompatible, and most of all, easy to use and is unaffected by saliva contamination, has led to the development of products that did not require the initial step of etching the enamel surface. In these new systems elements of etching, priming and bonding are all in one component. The aim of this study was to compare the bonding strength of brackets with a traditional technique to the Prompt L‐Pop (monocomponent adhesive) using the same composite resin. The results showed no statistical differences in detachment values of these two groups.
Classification of oral clefts by affection site and laterality: a genotype–phenotype correlation study
Authors: Farina A , Wyszynski D F , Pezzetti F , Scapoli L , Martinelli M , Carinci F , Carls F , Nardelli G B , Tognon M , Carinci P
Published: March 2003

Structured Abstract

Objectives –
The aim of this study was to classify the phenotypes found in a series of patients with non‐syndromic cleft lip (CL) with or without cleft palate (CP) and isolated cleft palate. Additionally, the frequency distribution of cases belonging to families linked to markers on chromosomes 6 and 2 within these phenotypic patterns were estimated.

Design –
A retrospective examination of all the available affected cases collected in Italy.

Setting and Sample Population –
Ninety‐seven affected subjects aged 5–18 years belonging to 38 families were considered. Patterns were identified by variance of the cleft (lip, primary palate, secondary palate) and stratified according to the side of occurrence (right, left, or bilateral). Latent class analysis was used as main statistical tool for carrying out the results.

Results – Three homogenous classes were identified (P < 0.0001) by means of latent class analysis. Individuals were assigned to the most suited class. All three variables (lip, primary and secondary cleft palate) generated a specific class. Optimal findings were reported in cases having `any isolated cleft lip' (class 1); `secondary CP with or without bilateral/right primary cleft palate + bilateral/right cleft lip' (class 2); and `left primary cleft palate + left/bilateral cleft lip with or without secondary CP' (class 3). Correspondence to the evidence of linkage to chromosome 6 showed that 9 of 10 cases presenting with `right primary CP + right CL with secondary cleft palate' (class 2) belonged to a linked family. The same combination, but occurring on the left side (class 3), revealed that only three of nine cases belong to families linked to chromosome 6 (P‐value=0.02). The two patterns (right and left) never occurred in the same family. Three reliable groups were identified based on laterality and the presence of a cleft. A single right sided pattern displayed a statistically different distribution of linkage to chromosome 6 when compared with the homologous left side.

Conclusion –
Non‐syndromic CL with/without CP can be classified according to laterality that can be under genetic control.
In vivo evaluation of a moisture‐activated orthodontic adhesive: a comparative clinical trial
Authors: Karamouzos A , Mavropoulos A , Athanasiou AE , Kolokithas G
Published: March 2003

Structured Abstract

Authors –
Karamouzos A, Mavropoulos A, Athanasiou AE, Kolokithas G.

Objectives –
To evaluate and compare the clinical performance of a water‐activated, ethyl‐cyanoacrylate adhesive to a conventional composite resin. The null hypothesis tested was that there was no difference in bracket survival distribution, over a period of orthodontic treatment, for brackets bonded with either bonding agent.

Design –
Single center randomized controlled clinical study.

Setting and Sample Population – Twenty‐five consecutive patients (15 females and 10 males) were selected and treated with fixed appliances in a university postgraduate orthodontic clinic. All teeth, but the molars, were bonded with twin stainless steel brackets (n=429) using a split‐mouth technique and random allocation of the two adhesives.

Outcome Measure –
Bond failure rates during a period of 9 months were estimated for each adhesive system and the corresponding bracket survival curves were plotted using the Kaplan–Meier product‐limit estimate. Bracket survival distributions with respect to adhesive material, tooth location, investigator, and bond failure interface were then compared by means of a log‐rank test. Bond failure interface was determined using the Adhesive Remnant Index (ARI).

Results – The water‐activated bonding material recorded a significantly higher bond failure (22.4%) than the composite resin (5.1%). There were also statistically significant differences in bracket survival distributions between the two adhesives (log‐rank test: p < 0.001). Premolars exhibited higher bond failure rates than incisors and canines (p < 0001). The predominant mode of failure was within the bonding material.

Conclusion –
Further investigations focused on the improvement of the physical and mechanical properties of the water‐activated bonding system are needed to make it a reliable alternative adhesive for the direct bonding of orthodontic brackets.
The role of complement in inflammation and adaptive immunity
Authors: Barrington Robert , Zhang Ming , Fischer Michael , Carroll Michael C.
Published: March 2003

Major advances in our understanding of the immunobiology of complement were made within the past 5 years primarily due to the development of gene‐targeting technology. New strains of mice bearing specific deficiencies in serum complement proteins or their receptors were developed using this approach. Characterization of these mice has provided new and exciting insights into the biology of the complement system. In this review, we discuss recent results on two important aspects of the complement system, i) host protection and inflammation, and ii) regulation of B lymphocytes of adaptive immunity. While these two roles appear distinct, they are linked. We discuss how natural antibody and classical pathway complement work together in host protection against bacterial infection on the one hand but, on the other, they co‐operate to induce inflammation as observed in reperfusion injury. Significantly, the lymphocytes that produce natural antibody, the B‐1 lymphocytes, are regulated in part by the complement system.

We thank current and past members of the lab who contributed to the work. We especially thank Drs A. Prodeus and R. Reid. The research was supported by grants from the National Institutes of Health to M.C.C. R.B. is supported by a fellowship from the American Arthritis Foundation.
Role of the C5b‐9 complement complex in cell cycle and apoptosis
Authors: Rus Horea G. , Niculescu Florin I. , Shin Moon L.
Published: March 2003

Assembly of C5b‐9 on cell membranes results in transmembrane channels and causes cell death. When the number of C5b‐9 molecules is limited, nucleated cells are able to escape cell death by endocytosis and by shedding of membranes bearing C5b‐9. Sublytic C5b‐9 induces proto‐oncogenes, activates the cell cycle, and enhances cell survival. In addition, C5b‐9 reverses the differentiated phenotype of post‐mitotic cells, such as oligodendrocytes and skeletal muscle cells. The signal transduction pathways responsible for cell cycle activation by C5b‐9 include Gi‐mediated activation of extracellular signal‐regulated kinase 1 and phosphatidylinositol 3‐kinase (PI3‐K). Cell survival enhanced by C5b‐9 is mediated by the PI3‐K/Akt pathway, which inhibits apoptosis through regulation of BAD. These findings indicate that complement activation and membrane assembly of sublytic C5b‐9 play an important role in inflammation by promoting cell proliferation and by rescuing apoptotic cells.

This work was supported by NIH grants NS36231 and NS15662 and by multiple sclerosis pilot award PP‐696.
Ficolins and the lectin complement pathway
Authors: Matsushita Misao , Fujita Teizo
Published: March 2003

Ficolins, found in various tissues, are a group of proteins containing both a collagen‐like and a fibrinogen‐like domain. Recently, it was shown that ficolins present in serum are lectins with a common binding specificity for N‐acetylglucosamine (GlcNAc). The fibrinogen‐like domain is responsible for the carbohydrate binding. Mannose‐binding lectin (MBL) is also a collagenous lectin in serum that is specific for GlcNAc and mannose binding. Its domain organization is similar to that of ficolins, except that MBL has a carbohydrate‐recognition domain instead of a fibrinogen‐like domain. MBL plays a role in innate immunity by acting as an opsonin and activating complement in association with MBL‐associated serine protease (MASP) via the lectin pathway. Investigations of two types of human serum ficolins, ficolin/P35 and Hakata antigen, revealed that they are associated with MASPs and sMAP, a truncated protein of MASP‐2, and that they activate complement. These findings indicate that serum ficolins are structurally and functionally similar to MBL and have the capacity to activate the lectin pathway and thus have a role in innate immunity.

This work was supported by Grants‐in‐Aid for Scientific Research (12470079 and 11670328) from the Ministry of Education, Science, Sports and Culture of Japan.
CR1 and CR1‐like: the primate immune adherence receptors
Authors: Birmingham Daniel J. , Hebert Lee A.
Published: March 2003

Immune adherence describes the phenomenon in which complement‐opsonized substrates, such as immune complexes (IC), viruses, or bacteria, are bound by primate erythrocytes via erythrocyte complement receptors. In vivo studies have shown that this binding allows the erythrocyte to act as an inert shuttle, targeting IC to the monocyte phagocytic system and away from vulnerable tissue. Thus, immune adherence appears to play an integral role in the primate in promoting the safe clearance of circulating IC and preventing IC‐mediated pathologies. The complement receptors that mediate immune adherence comprise two unique but closely related gene products, either the type one complement receptor (CR1) in humans or CR1‐like in non‐human primates. This review focuses on the structure, function, and physiological role of the primate immune adherence receptors.
Activating and inhibitory nature of the murine paired immunoglobulin‐like receptor family
Authors: Takai Toshiyuki , Ono Masao
Published: March 2003

Summary: Clones for murine paired immunoglobulin‐like receptors (PIR) were first isolated as those coding for type I transmembrane glycoproteins with six immunoglobulin‐like domains homologous to human FcαR, bovine Fcγ2R, and other related receptors. However, they turned out to bind neither IgA nor other immunoglobulins in the case of the ectopic expression on COS‐1 fibroblastic cells. PIR‐A and B are expressed on a wide variety of cells in the murine immune system, such as in B cells, mast cells, macrophages, and dendritic cells, mostly in a pairwise fashion. PIR‐A requires homodimeric Fc receptor common γ chain, which harbors an immunoreceptor tyrosine‐based activation motif, for its efficient cell surface expression and for the delivery of activation signaling. In contrast, PIR‐B contains immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) in its cytoplasmic portion and inhibits receptor‐mediated activation signaling in vitro upon engagement with other activating‐type receptors such as the antigen receptor on B cells and the high affinity Fc receptor for IgE on mast cells. ITIMs of PIR‐B on macrophages and B cells have been shown to be constitutively phosphorylated in their tyrosine residues. Although the ligand for PIR still remains unknown, the transgenics and the gene‐targeted mice will provide us with valuable information on their physiological roles in the immune regulation.

We thank Hiromi Kubagawa for discussion. This work is supported by CREST Program of JST, Virtual Research Institute of Aging funded by Boehringer Ingelheim, and by research grants from the Ministry of Education, Science, Sports and Culture of Japan to T. Takai.
Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance
Authors: Sakaguchi Shimon , Sakaguchi Noriko , Shimizu Jun , Yamazaki Sayuri , Sakihama Toshiko , Itoh Misako , Kuniyasu Yuhshi , Nomura Takashi , Toda Masaaki , Takahashi Takeshi
Published: March 2003

Summary: There is accumulating evidence that T‐cell‐mediated dominant control of self‐reactive T‐cells contributes to the maintenance of immunologic self‐tolerance and its alteration can cause autoimmune disease. Efforts to delineate such a regulatory T‐cell population have revealed that CD25+ cells in the CD4+ population in normal naive animals bear the ability to prevent autoimmune disease in vivo and, upon antigenic stimulation, suppress the activation/proliferation of other T cells in vitro. The CD25+ CD4+ regulatory T cells, which are naturally anergic and suppressive, appear to be produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling tumor immunity and transplantation tolerance.
Variable expression of activation‐linked surface antigens on human mast cells in health and disease
Authors: Valent P. , Schernthaner G.‐H. , Sperr W. R. , Fritsch G. , Agis H. , Willheim M. , Bühring H.‐J. , Orfao A. , Escribano L.
Published: March 2003

Summary: Mast cells (MC) are multipotent effector cells of the immune system. They contain an array of biologically active mediator substances in their granules. MC also express a number of functionally important cell surface antigens, including stem cell factor receptor (SCFR=kit=CD117), high affinity IgER (FcεRI), or C5aR (CD88). Respective ligands can induce or promote degranulation, migration, or cytokine production. Other integral surface molecules can mediate adhesion or cell aggregation. Recent data suggest that a number of critical molecules are variably expressed on the surface of human MC. In fact, depending on the environment (organ), stage of cell maturation, type of disease, and other factors, MC express variable amounts of activation‐linked antigens (CD25, CD63, CD69, CD88), cell recognition molecules (CD2, CD11, CD18, CD50, CD54), or cytokine receptors. At present, however, little is known about the mechanisms and regulation of expression of such antigens. The present article gives an overview of MC phenotypes in health and disease, and attempts to provide explanations for the phenotypic variability of MC.

This study was supported by Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich – FWF grants # P12517 and # P14031, Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS 98/1345), and Fundación Oftalmológica J. Cortés.
Role of human FcεRI+ cells in HIV‐1 infection
Authors: Marone Gianni , Florio Giovanni , Petraroli Angelica , Triggiani Massimo , De Paulis Amato
Published: March 2003

Summary: Enhanced serum IgE levels in adults and children with HIV‐1 infection could be a marker of poor prognosis. HIV‐1 infection is believed to involve a switch toward a “TH2‐like” cytokine pattern. HIV‐1 gp120 from different clades is a potent stimulus for histamine release from human basophils and mast cells. Gp120 also induces IL‐4 and IL‐13 synthesis from basophils. It functions as a viral superantigen by interacting with the VH3 region of IgE to induce mediator release from human FcεRI+ cells. The chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES, is expressed by basophils and lung mast cells. By interacting with the CCR3 receptor on FcεRI+ cells, HIV‐1 Tat protein is a potent chemoattractant for basophils and lung mast cells. Tat protein also induces IL‐4 and IL‐13 release from basophils. Incubation of basophils with Tat protein upregulates the surface expression of the CCR3 receptor, a co‐receptor of HIV‐1 infection. Extracellular Tat affects the directional migration of human FcεRI+ cells, CCR3 expression and TH2 cytokines release. We have shown that HIV‐1 proteins gp120 and Tat trigger the release of cytokines critical for TH2 polarization from FcεRI+ cells through two distinct mechanisms. In addition, Tat upregulates the β‐chemokine receptor CCR3, making FcεRI+ cells more susceptible to infection with CCR3 tropic HIV‐1 isolates.

This paper is dedicated to Rita Levi‐Montalcini who first suggested an involvement of FcεRI+ cells in HIV‐1 infection. This work was supported by a grant from the Istituto Superiore Sanità (AIDS project 40B.64 and 40A.67), CNR (Target project Biotechnology No. 99.00216.PF31 and No. 99.00401. PF49) and MURST (Rome, Italy).
The discovery of thymus function and of thymus‐derived lymphocytes
Authors: Miller J. F. A. P.
Published: March 2003

Summary: For centuries the thymus remained an enigmatic organ with unknown functions. The first demonstration of its crucial role in establishing the development of a normal immune system was provided in 1961, when it was shown that mice thymectomized immediately after birth had poorly developed lymphoid tissues, impaired immune responses and inordinate susceptibility to intercurrent infections. Although thymus lymphocytes were believed to be immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating and giving rise to a progeny of cells that could not produce antibody, but enabled other lymphocytes, derived from bone marrow, to differentiate to antibody‐forming cells. This was the first unequivocal demonstration, in mammalian species, of the existence of two major interacting subsets of lymphocytes, T and B cells. It required a re‐evaluation of many immunological phenomena, such as tolerance, memory and autoimmunity, and it was followed by an avalanche of work elucidating many of the mysteries of the immune system.
Human histocompatibility proteins
Authors: Strominger Jack L.
Published: March 2003

Summary: Transplantation antigens (later called histocompatibility proteins) were named by Peter Gorer in the 1930s. After 4 decades of immunological work emphasizing their importance in immunobiology, structural work on these proteins began about 1970. During the first decade, HLA proteins were isolated and then separated into two groups. Biochemical studies established the close structural relationships of these groups (now called class I and class II MHC proteins). These structures both contained four domains, although the domains were linked differently. Two of these domains were immunoglobulin‐like. They were the first proteins (aside from immunoglobulins) identified as members of the immunoglobulin superfamily of proteins. The crystallization of these proteins in the second decade led to elucidation of the structures of class I and class II MHC proteins, which has changed the way we think about immunology. These molecules each present peptides (8–9mers in the case of class I and 13–14mers in the case of class II) to initiate the immune response.
Mechanisms contributing to the activity of integrins on leukocytes
Authors: Hogg Nancy , Henderson Robert , Leitinger Birgit , McDowall Alison , Porter Joanna , Stanley Paula
Published: March 2003

Summary: Understanding how the integrins on leukocytes operate is important because these receptors control the activity of leukocytes in all phases of their lives. Thus integrins control leukocyte development and maturation in bone marrow, the circulation of naive cells in secondary lymphoid tissue, e.g. the lymph nodes, and leukocyte responses to inflammatory signals emanating from injured tissues. Using as an example LFA‐1, which is expressed by all leukocytes, we outline how the activity of this integrin is modified to meet the challenges posed by these leukocyte activities. Briefly, we discuss three means by which LFA‐1 is adapted to bind more efficiently to its chief ligand, ICAM‐1. LFA‐1 can undergo changes in conformation leading to increased affinity, can be clustered on the membrane and, finally, when activated can move into the lipid raft compartment of the membrane. The study of humans with the β2 deficiency syndrome termed leukocyte adhesion deficiency (LAD)‐1 and analysis of LFA‐1 null mice has given further insight into integrin activation mechanisms and the in vivo roles of LFA‐1 and other leukocyte integrins.
Integrin‐dependent regulation of gene expression in leukocytes
Authors: Rossetti Grazisa , Collinge Mark , Molteni Raffaela , Bender Jeffrey R. , Pardi Ruggero
Published: March 2003

Summary: In addition to their role in strengthening intercellular adhesion, leukocyte integrins transduce signals which affect genetic programs, consequently defining cell phenotype and function. These signals can be independently sufficient, or can cooperate with other environmental stimuli to affect gene expression regulation. In the past several years, there has been an emergence of mechanistic data which contribute to our understanding of these critical integrin roles. In this review, we describe anchorage‐dependent T lymphocyte proliferation and, in particular, how leukocyte integrin engagement overcomes the G1 to S cell cycle restriction point in antigen‐activated T cells. The related role of αLβ2 integrin (LFA‐1) as a T cell co‐stimulatory molecule is discussed. This includes defining mechanisms whereby LFA‐1 engagement enhances transcriptional activation of numerous genes by regulating its association with transcription modulators such as JAB‐1, and through interaction with other gene‐activating signaling complexes such as JAK‐STATs. Evidence is presented to support that leukocyte integrin engagement provides potent signals which stabilize otherwise labile activation mRNA transcripts, including those encoding cytokine and extracellular matrix degrading proteins. These integrin‐dependent mechanisms, all described recently, play important roles in T cell differentiation and proliferation, immune surveillance and inflammatory responses.
A developing picture of lymphopoiesis in bone marrow
Authors: Hirose Jun , Kouro Taku , Igarashi Hideya , Yokota Takafumi , Sakaguchi Nobuo , Kincade Paul W.
Published: March 2003

Summary: The earliest progenitors of lymphocytes are extremely rare and typically present among very complex populations of hematopoietic cells. Additionally, it is difficult to know how cells with any given set of characteristics are developmentally related to stem cells and maturing lymphoid precursors. However, it is now possible to divide bone marrow into progressively smaller fractions and exploit well‐defined culture systems to determine which ones contain cells that can turn into lymphocytes. Analysis of steroid hormone sensitive cells and use of two‐step cultures is providing additional information about the most likely differentiation pathways for B and natural killer cell lineage lymphocytes. A newly identified category of early lymphoid progenitors can now be sorted to high purity from RAG1/GFP knock in mice. Furthermore, the same experimental model makes it possible to image lymphoid progenitors in fetal and adult hematopoietic tissues.
Clustering of MHC–peptide complexes prior to their engagement in the immunological synapse: lipid raft and tetraspan microdomains
Authors: Vogt Anne B. , Spindeldreher Sebastian , Kropshofer Harald
Published: March 2003

Summary: Protein reorganization at the interface of a T cell and an antigen‐presenting cell (APC) plays an important role in T cell activation. Imaging techniques reveal that reorganization of particular receptor–ligand pairs gives rise to an intercellular junction, termed the immunological synapse. In this synapse antigenic peptides associated with major histocompatibility complex (MHC) molecules form multimolecular arrays on the APC side, engaging an equivalent number of clustered T cell receptors (TCRs) on the T cell. The accumulation of MHC molecules carrying cognate peptide in the APC–T cell interface was thought to depend on the specificity and presence of TCRs. Recent evidence, however, suggests that the APC is equipped to preorganize MHC–peptide complexes in the absence of T cells. To this end, MHC molecules become incorporated into two types of membrane microdomains: (i) cholesterol‐ and glycosphingolipid‐enriched domains, denoted lipid rafts, that preconcentrate MHC class II molecules; and (ii) microdomains made up of tetraspan proteins, such as CD9, CD63, CD81 or CD82, that mediate enrichment of MHC class II molecules loaded with a select set of peptides. It follows that the integrity, composition and dynamics of these microdomains are candidate determinants favoring activation or silencing of T cells.
Genetics and genomics of asthma and allergic diseases
Authors: Cookson William
Published: March 2003

Summary: Asthma and eczema (atopic dermatitis) are characterized by a number of unexplained phenomena: the familial aggregation of disease, the initiation of disease by apparently trivial exposure to allergens, the preferential transmission of disease from affected mothers and the large increase in prevalence of disease in Westernized societies in the last century. A number of genes and chromosomal regions have been identified that consistently show linkage to asthma and its related phenotypes. Known loci modify the strength of the atopic response, nonspecific inflammation, the ability to respond to particular allergens and nonspecific airway reactivity. Eczema has been shown to be due to a different set of genetic loci that are shared with other skin diseases such as psoriasis and leprosy. Genetic and genomic studies both provide evidence that epithelial surfaces are active in the induction of allergic disease.
Iron enhances hepatitis C virus replication in cultured human hepatocytes
Authors: Kakizaki Satoru , Takagi Hitoshi , Horiguchi Norio , Toyoda Mitsuo , Takayama Hisashi , Nagamine Takeaki , Mori Masatomo , Kato Nobuyuki
Published: March 2003

Abstract: Background: Iron overload in the presence of increasing concentrations of iron is one of the indicators of poor response to interferon therapy in chronic hepatitis C. In order to analyze the effect of iron on hepatitis C virus (HCV) replication, we measured replication in an HCV‐infected cell line. Methods and Results: Cells from a non‐neoplastic HCV‐infected human hepatocyte line (PH5CH8) susceptible to HCV infection and supportive of HCV replication were used in this study. The replication of HCV RNA was measured by reverse transcription‐nested polymerase chain reaction (RT‐nested PCR). PH5CH8 cell viability was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assay. PH5CH8 cells were incubated with 0, 1, 10, 50, and 100 μM of FeSO4 at 37°C with 5% CO2. Forty‐eight hours after iron supplementation, the quantity of HCV RNA in the cells incubated in 50 and 100 μM of FeSO4 was approximately ten times that of the cells with no iron supplementation. Similar changes were observed beginning at 12 h from supplementation with FeSO4 and continued for at least 72 h after supplementation. MTT assay indicated that iron did not have cytotoxic effects on the PH5CH8 cells. Conclusion: Iron enhances HCV replication in a hepatocyte cell line. The results suggest that iron deposition in hepatocytes could facilitate HCV infection in the liver.