bluuebunny/crossref_metadata_2025 huggingface dataset:
Low HLA‐DR expression on peripheral blood monocytes predicts bacterial sepsis after liver transplantation: relation with prednisolone intake
Authors: Haveman J.W. , Van Den Berg A.P. , Van Den Berk J.M.M. , Mesander G. , Slooff M.J.H. , De Leij L.H.F.M. , The T.H.
Published: March 2003

Bacterial sepsis remains a frequent complication after liver transplantation. We previously reported the results of a pilot study that suggested that low expression of HLA‐DR on monocytes is a predictive marker for the occurrence of sepsis. We have studied the value of this marker in an additional cohort of patients, and have analyzed the relation of HLA‐DR expression with the use of immunosuppressive agents. 20 adult liver transplantation patients were prospectively monitored during the first 4 weeks after transplantation. All were treated according to standard protocols. The percentage of monocytes expressing HLA‐DR was measured by flow cytometry. In addition, the effects of incubation of monocytes with prednisolonein vitroon the expression of HLA‐DR was determined in 7 healthy volunteers. Seven patients developed bacterial sepsis after a median 15 (range 10–20) days after transplantation. HLA‐DR expression was significantly lower in these patients on days 7, 14, 21, and 28 after transplantation compared with non‐septic patients. The percentage of HLA‐DR positive monocytes was 30% or less, 3 (1–8) days before onset of sepsis. On day 7 after transplantation, HLA‐DR expression on 50% or less of monocytes had a positive predictive value for sepsis of 71%, whereas the negative predictive value was 85%. Patients who developed sepsis received significantly more prednisolone. Incubation with prednisolonein vitrolowered the expression of HLA‐DR in a dose‐dependent manner. We conclude that low HLA‐DR expression on monocytes is a marker for a high risk of subsequent sepsis in liver transplantation patients. This high risk may be (at least partly) related to the dose of prednisolone.
Prevention of infections in solid organ transplant recipients
Authors: Villacian Jorge S. , Paya Carlos V.
Published: March 2003

Solid organ transplantation has become an important therapeutic option for multiple chronic diseases. With the advent of newer and potent immunosuppressive regimens, graft survival has improved, but at the expense of an increased risk for the development of infections secondary to bacterial, fungal, viral and parasitic pathogens. Prevention of such infectious complications with effective, well tolerated, and cost‐effective anti‐microbials would be ideal to improve the outcome of transplanted patients. However, the emergence of multi‐drug resistant pathogens, medication toxicity and drug‐drug interactions need to be carefully evaluated. This review summarizes the most relevant data pertaining to our current understanding of infection prevention for solid organ transplant recipients. Specific recommendations are given for the prevention of each group of microorganisms and types of solid organ transplant (Note).
Amphotericin B preparations: a maximum tolerated dose in severe invasive fungal infections?
Authors: Ellis M.
Published: March 2003

Availability of lipid formulations of amphotericin B has opened up the possibility of treating invasive fungal infections in immunocompromised patients with high doses of this antifungal agent. Evidence is emerging to suggest that lipid formulations may have heightened efficacy compared to conventional amphotericin B. The issue of optimal dosage has been a neglected area. This article reviews published data accrued from clinical, open‐label, salvage, and other studies, and finds little support that the use of high doses of lipid formulations are more efficacious than lower doses. The response rates for invasive fungal infection from most studies are predictably around 56%, irrespective of the lipid formulation and dose used. Animal models provide evidence that low doses of a lipid formulation are as successful in reducing fungal dissemination and in prolonging survival as higher doses, although concomitant tissue fungal eradication is not as effectively achieved by the lower doses (survival‐mycologic eradication dissociation). Kinetic studies performed in the clinically relevant setting of critically ill patients give further support to the use of low doses, since levels of liposomal amphotericin B at all dosages between 1 and 4 mg/kg/day are similar and above maximum inhibitory concentrations for commonly encountered fungi. There has only been one prospective randomised study designed with the primary end‐point of comparing two dosages of an amphotericin B lipid formulation on clinical response and survival. That European Organization for Research and Treatment of Cancer (EORTC) study concluded that liposomal amphotericin B given at 1 mg was as efficacious as 4 mg/kg/day in treating neutropenic patients with invasive pulmonary aspergillosis. There are a multitude of unanswered questions concerning dosing, and their answers are confounded by difficulties in performing clinical trials and the multiplicity of factors other than antifungal chemotherapy that influence outcome. Maximum tolerated dose studies using existing lipid formulations, or perhaps with the newer formulations such as pegylated immunoliposomal amphotericin B, could be performed to shed light on this difficult area.
Antigen detection in the diagnosis and management of a patient with probable cerebral aspergillosis treated with voriconazole
Authors: Machetti M. , Zotti M. , Veroni L. , Mordini N. , Van Lint M.T. , Bacigalupo A. , Paola D. , Viscoli C.
Published: March 2003

This report describes the diagnosis and management of a 16‐year‐old boy who developed neurological signs and symptoms suggestive of cerebral aspergillosis following a haploidentical bone marrow transplant. A new sandwich enzyme‐linked immunosorbent assay (ELISA) for the detection of Aspergillus galactomannan circulating antigens (Platelia Aspergillus, Sanofi Diagnostic Pasteur, France) was used on serum and cerebrospinal fluid to obtain a presumptive diagnosis and to monitor the course of the disease. Having failed conventional therapy with amphotericin B, the patient received compassionate treatment with voriconazole for a period of 37 days. High levels of voriconazole were observed in both serum and cerebrospinal fluid (CSF), with a trend toward accumulation. After 7 days a marked improvement in the patient’s neurological symptoms was noted, and ELISA data indicated a corresponding decrease in Aspergillus galactomannan levels in both serum and CSF. Voriconazole was well tolerated, with only transient increases in ALT/AST recorded during therapy. Although the patient survived the acute Aspergillus infection, he subsequently died of an unrelated infection.
Human CMV‐IGIV (CytoGam®) neutralizes human cytomegalovirus (HCMV) infectivity and prevents intracellular signal transduction after HCMV exposure
Authors: Andreoni K.A. , Wang X. , Huong S.‐M. , Huang E.‐S.
Published: March 2003

Pretreatment of human cytomegalovirus (HCMV) with human hyperimmune globulin (CytoGam®) in human embryonic lung (HEL) fibroblast culture showed successful inhibition of infectivity, and decreased extracellular viral titers and extracellular viral DNA. CytoGam® prevented HCMV from inducing intracellular activation of NF‐κB, Sp‐1, and PI3‐K signaling pathways and the production of immediate‐early (IE), early (E), and late (L) viral proteins. CytoGam® neutralization of HCMV in this cell culture model prevented the earliest known signal transduction events (NF‐κB, Sp‐1, PI3‐K activation) after viral specific glycoproteins bind to their cognate cell membrane receptors, suggesting that this agent contains highly effective neutralizing antibodies against HCMV.
Infectious complications of lung transplantation
Authors: Alexander B.D. , Tapson Victor F.
Published: March 2003

Abstract: Lung transplantation is associated with a high incidence of infection which directly impacts the morbidity and mortality associated with the procedure. In addition, these infections may also have immunologic consequences that play a role in the evolution of lung injury syndromes, resulting in earlier loss of graft than otherwise would be expected to occur. Although bacteria are responsible for the majority of infections following lung transplantation, fungal infections are associated with the highest mortality. This paper is an overview of the major infectious complications encountered in the lung transplant population. The epidemiology, prophylaxis, and treatment of infections following lung transplantation are critical areas for continued research.
Disseminated microsporidiosis in a renal transplant recipient
Authors: Mohindra A.R. , Lee M.W. , Visvesvara G. , Moura H. , Parasuraman R. , Leitch G.J. , Xiao L. , Yee J. , Del Busto R. , Mohindra A.R. , Lee M.W. , Visvesvara G. , Moura H. , Parasuraman R. , Leitch G.J. , Xiao L. , Yee J. , Del Busto R.
Published: March 2003

Abstract: Disseminated microsporidiosis is diagnosed uncommonly in patients not infected with human immunodeficiency virus (HIV). We present a case of disseminated microsporidiosis in a renal transplant recipient who was seronegative for HIV. Chromotrope‐based stains were positive for microsporidia in urine, stools, sputum, and conjunctival scrapings. Electron microscopy, immunofluorescence, polymerase chain reaction, and cultures of renal tissue identified the organism as Encephalitozoon cuniculi. The patient was treated with oral albendazole and topical fumagillin with clinical improvement. In addition, she underwent a transplant nephrectomy and immunosuppressive therapy was withdrawn. Follow‐up samples were negative for microsporidia. However, the patient developed central nervous system manifestations and died. An autopsy brain tissue specimen demonstrated E. cuniculi by immunofluorescent staining. Disseminated microsporidiosis must be considered in the differential diagnosis of multiorgan involvement in renal allograft recipients.
Hearts from transgenic pigs constructed with CD59/DAF genomic clones demonstrate improved survival in primates
Authors: Chen Raymond H. , Naficy Sephre , Logan John S. , Diamond Lisa E. , Adams David H.
Published: March 2003

We have previously created transgenic pigs bearing the human complement regulatory proteins CD59 and decay‐accelerating factor (DAF) by either the intercellular transfer or the cDNA transgenic method. To achieve more physiologic protein expression, we constructed a new line of transgenic pigs with CD59 and DAF human genomic clones. We transplanted these CD59/DAF transgenic pig hearts into baboons immunosuppressed with cyclosporine, methylprednisone or leflunomide/mofetil mycophenolate. The four wild‐type hearts survived for 20–80 min, whereas the four CD59/DAF hearts functioned for 85–130 h. Immunohistochemical staining showed levels of CD59 and DAF protein expression similar to that in human hearts. Wild‐type and transgenic hearts demonstrate a similar level of IgM deposition, although transgenic hearts suffered less hyperacute rejection and thus less membrane attack complex deposition. The histology of the transgenic grafts after explant was consistent with acute vascular rejection, with a high level of IgG deposit compared with wild‐type control. We conclude that this new line of CD59/DAF transgenic pigs express high levels of the transgene products, which conferred longer survival because of better protection from hyperacute rejection. Similar to previous transgenic pigs, however, these animals suffered from delayed xenograft rejection.
Quantitation and characterization of anti‐Galα1–3Gal antibodies in sera of 200 healthy persons
Authors: Buonomano Roberto , Tinguely Caroline , Rieben Robert , Mohacsi Paul J. , Nydegger Urs E.
Published: March 2003

Buonomano R, Tinguely C, Rieben R, Mohacsi PJ, Nydegger UE. Quantitation and characterization of anti‐Galα1–3Gal antibodies in sera of 200 healthy persons. Xenotransplantation 1999; 6:173‐180. © Munksgaard, Copenhagen

Abstract: The natural occurrence of complement‐activating anti‐Galαl–3Gal antibodies (anti‐Gal) in human serum is considered as a major obstacle to xenotransplantation. In this study we determined anti‐Gal in sera of 200 healthy volunteers (100 male, 100 female) of different age groups using an IgG‐ and IgM‐isotype specific ELISA. In addition, we used a direct hemagglutination test involving rabbit erythrocytes (ER), which are known for abundant surface expression of the Galα1–3Gal antigen. The measured arbitrary ELISA units (U) for anti‐Gal ranged from 5 to 204 U (77 ± 47; mean ± 1 SD) for IgM, and from 1 to 162 U(73 ± 32) for IgG. Anti‐ER hemagglutination titers were between 1: 65536 and 1: 64 (mean 1: 703), with 75% of all serum samples being in the range of 1: 8192–1: 512. Specificity of the tests was determined by immunoabsorption of anti‐Gal on Sepharose‐coupled synthetic Galα1–3Gal antigen, which reduced ELISA as well as agglutination titers by 90% or more. Overall, inter‐individual differences of both anti‐Gal ELISA values and ER agglutination titers exceeded age‐, gender‐, or ABO‐type related changes. A tendency was found to higher anti‐Gal IgM values in women than in men (P < 0.005 by Student’s t‐test), whereas the gender‐difference for anti‐Gal IgG or ER titers was not significant. Application of the anti‐Gal ELISA as well as the ER agglutination assay for pre‐transplant screening of potential pig xenograft recipients is discussed.
Acute vascular rejection is associated with systemic complement activation ina pig‐to‐primate kidney xenograft model
Authors: Loss M. , Vangerow B. , Schmidtko J. , Kunz R. , Jalali A. , Arends H. , Przemeck M. , Rückholt H. , Leuwer M. , Kaup F. J. , Rensing S. , Cozzi E. , White D. J. G. , Klempnauer J. , Winkler M.
Published: March 2003

Abstract: The introduction of h‐DAF transgenic porcine organs into pre‐clinical pig‐to‐primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life‐supporting model of pig‐to‐primate kidney transplantation, unmodified (n = 8) or h‐DAF‐transgenic (n = 9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low‐dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h‐DAF transgenic group. Stable initial graft function with recipient survival > 4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two‐fold increase in C3a levels and a four‐fold increase in sC5b‐9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b‐9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti‐porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short‐term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig‐to‐primate combination.
An investigation of the specificity of induced anti‐pig antibodies in baboons
Authors: Buhler L. , Xu Y. , Li W. , Zhu A. , Cooper D. K. C.
Published: March 2003

Buhler L, Xu Y, Li W, Zhu A, Cooper DKC. An investigation of the specificity of induced anti‐pig antibodies in baboons. Xenotransplantation 2003; 10: 88–93. © Blackwell Munksgaard, 2003

Aim: To provide information on the specificity of induced anti‐pig antibodies (Abs) in baboons after exposure and sensitization to pig antigens. Materials and methods: Baboons (n=7) received either porcine mobilized peripheral blood progenitor cells (n=3), kidney (n=3) or heart (n=1) transplants. After rejection of these cells or organs, pre‐ and post‐rejection sera were analyzed by enzyme‐linked immunosorbent assay (ELISA) and flow cytometry to detect and measure anti‐Galactoseα1,3Galactose (Gal) and anti‐non‐Gal Abs. To study the anti‐non‐Gal carbohydrate response, the sera were incubated with pig red blood cells pretreated with α‐galactosidase (to remove Gal) and three other exoglycosidases to remove other potential oligosaccharide epitopes, and studied by flow cytometry. To study the anti‐swine leukocyte antigen (SLA) response, non‐Gal Abs from two baboons sensitized with kidneys from inbred miniature swine of dd or aa haplotype, respectively, were adsorbed on cells of aa, cc, or dd haplotypes, and binding to aa, cc or dd cells was measured by flow cytometry. Cytotoxicity of anti‐non‐Gal Abs was tested in vitro by a complement‐mediated cytotoxicity assay, using pig cells as targets. Results: In pre‐transplant and pre‐rejection sera, anti‐Gal Abs were detected, but anti‐non‐Gal Abs were either absent or at minimal levels. After exposure to pig antigens, baboons developed induced anti‐Gal and anti‐non‐Gal Abs. No anti‐non‐Gal Abs directed to the tested carbohydrate epitopes could be detected. Anti‐non‐Gal Abs showed minor evidence of specific SLA haplotype reactivity, suggesting that the major Ab response was to pan‐pig determinants. Anti‐non‐Gal Abs showed a low level of complement‐mediated lysis of pig cells in vitro. Conclusions: In this limited study, no Ab response to non‐Gal carbohydrates was observed, and anti‐SLA specificity was minor, indicating that most induced anti‐non‐Gal Ab was directed against non‐specific pig proteins, including SLA‐epitopes.
Xenotransplantation public perceptions: rather cells than organs
Authors: Persson Marie Omnell , Persson Nils H. , Ranstam Jonas , Hermerén Göran
Published: March 2003

Omnell Persson M, Persson NH, Ranstam J, Hermerén G. Xenotransplantation public perceptions, rather cells than organs. Xenotransplantation 2003; 10: 72–79. © Blackwell Munksgaard, 2003

The aim of this study was to describe some of the factors that might play a role in influencing attitude to xenotransplantation: first, the consideration of receiving cells and tissue from xenotransplants in relation to whole xeno‐organs; secondly, the fact that there is greater uncertainty regarding the result and risk of infection associated with xenotransplantation than with allotransplantation. We also describe the attitude to research on xenotransplantation, and the relationship between the attitude to receiving a xenotransplant and an allotransplant. Finally, we describe the attitude to xenotransplantation in relation to treatment for renal failure and waiting‐time for allotransplantation. A questionnaire was sent to randomly selected members of the public aged 18 to 75 (n=1000) and to all patients in the same age range who were waiting for kidney transplants in Sweden in the spring of 1998 (n=460). The response rate was 60% among the public and 87% among the patients. Both study groups were positive to a greater extent in their attitude to receiving cells and tissue than to receiving a whole organ such as a kidney. The response `rather positive' to receiving organs was generally favored by the public, whereas the most generally favored response to receiving cells and tissue was `very positive'. When there was suggested to be a greater uncertainty regarding the outcome with xenotransplantation compared with allotransplantation, the number of negative and uncertain respondents increased, both among the public and the patients. Eighty percent of the public and about 90% of the patients were in favor of continued research on xenotransplantation. Of those members of the public who responded, the attitude to receiving an organ from a human was positive in 86% of cases, with an emphasis on `very positive'. There was a moderate relation between the attitude to receiving an organ from a human and to receiving a xenotransplant. Among the patients, there was no systematic or strong relation between the attitude to xenotransplantation and the kind of dialysis treatment they were on. Neither was there any systematic or strong relation to the waiting‐time. The overall impression is that the attitude to xenotransplantation seems to be most influenced by whether the xenotransplant would involve whole organs or cells and uncertainty regarding the outcome.
Migration orientation behaviour of the red‐billed quelea Quelea quelea
Authors: Dallimer Martin , Jones Peter J.
Published: March 2003

Migration patterns in the red‐billed quelea Quelea quelea have been the focus of intense research as the species is a major crop pest in Africa. The direction and timing of migration are believed to be controlled by the seasonal passage of rainfronts across Africa. In order to assess the validity of hypothesised migration directions in southern Africa, we tested the migration orientation behaviour of wild‐caught red‐billed queleas using Emlen orientation funnels. Queleas tested in Zimbabwe showed mean orientation directions to the west‐north‐west and east‐south‐east. Both directions are in agreement with current hypotheses explaining quelea migration.
Unrealistically high costs of rejecting artificial model eggs in cuckooCuculus canorushosts
Authors: Martín‐Vivaldi Manuel , Soler Manuel , Møller Anders Pape
Published: March 2003

Most studies that have tested the egg‐recognition and egg‐rejection ability of European cuckooCuculus canorushosts have used artificial model eggs that are much harder than real Cuckoo eggs. Here we evaluate whether the use of such models overestimates the costs of egg rejection by hosts. We tested 17 potential cuckoo host species in south‐eastern Spain with both artificial hard cuckoo‐egg models and real eggs taken from a population of house sparrowsPasser domesticusbreeding in captivity. The puncture resistance of sparrow eggs, measured in the laboratory, was more similar to that of real cuckoo eggs than was the resistance of artificial models, although sparrow eggs were less resistant than real cuckoo eggs. Potential host species with a grasp index greater than 200 mm2did not suffer high rejection costs when rejecting hard models, probably because they are grasp ejectors. However, all species with a smaller grasp index suffered high costs when rejecting hard artificial models. For these species the frequency and magnitude of costs were significantly higher when rejecting artificial hard models than when rejecting real eggs. For some species the breakage of real eggs was quite difficult (they needed 97 to more than 4000 pecks in video‐recorded ejections), and sometimes the birds suffered rejection costs. These results show that realistic estimates of the frequency and magnitude of rejection costs for hosts with small bills cannot be obtained by using artificial models, and also that for a variety of medium‐sized puncture ejector species the costs when rejecting real eggs may be low.
Comparison of CT scanograms and cephalometric radiographs in craniofacial imaging
Authors: Chidiac JJ , Shofer FS , Al‐Kutoubi A , Laster LL , Ghafari J
Published: March 2003

Structured Abstract

Objective– To compare measurements from human skulls and their images from cephalometric radiographs (CR) and computed tomography (CT) scanograms, in order to gauge the potential clinical use of the latter.

Design– Based on specific inclusion criteria, including stable centric occlusion, 13 adult skulls were selected from a larger collection. The mandible was taped to the maxilla after securing the occlusion of teeth and condylar seating in the glenoid fossa. Lateral and posteroanterior cephalographs and CT `scout views' were taken of each skull by standardized methods. Landmarks were identified on skulls and images.

Outcome Measures– Linear measurements were made on all three records; angular measurements only on CR and CT images. Intraclass correlation coefficients (r) were calculated to assess similarity among records. Paired t‐tests were used to compare differences between mean measurements.

Results– No statistically significant differences were noted between mean angular values on CR and CT views (P > 0.05). The highest correlations were observed for several vertical midline distances between CT and direct skull measures: 0.82 < r < 0.995–greatest for nasion–menton. For sagittal distances, the highest correlation was between the direct measure of condylion–pogonion and its CR image (r=0.73). Correlations between CR and skull transverse measures were higher (0.46 < r < 0.80) than the corresponding skull vs. CT measures (0.06 < r < 0.38). CT and CR images are 2D slices and projections, respectively, of 3D structures. Vertical CT and skull measures correspond because the CT projection reflects a 1 : 1 ratio in the midsagittal plane; CT projected lateral images are smaller than the skull measures. The CR image reflects a distortion (∼8%) that brings Co–Pg closer to its anatomic distance, inadvertently contributing to better clinical planning, particularly in orthognathic surgery. The pattern of distortion of PA images was in opposite directions for CR and CT views.

Conclusions– Cephalograms and CT scanograms are close in depicting angular relations of structures, but they differ in the accuracy of imaging linear measurements, because the location and size of an object within the imaged 3D structure varies with both records. Logistic and economic considerations favor the use of cephalographs.
Comparison of the expression patterns of two LIM‐homeodomain genes, Lhx6 and L3/Lhx8, in the developing palate
Authors: Zhang Y , Mori T , Takaki H , Takeuchi M , Iseki K , Hagino S , Murakawa M , Yokoya S , Wanaka A
Published: March 2003

Structured Abstract

Authors– Zhang Y, Mori T, Takaki H, Takeuchi M, Iseki K, Hagino S, Murakawa M, Yokoya S, Wanaka A.

Objectives– To compare and contrast the gene expression of two LIM‐homeobox type transcription factors, Lhx6 and L3/Lhx8, in secondary palate formation.

Methods– In situ hybridization histochemistry with digoxygenin (DIG) labelled cRNA probes specific for Lhx6 and L3/Lhx8.

Materials– Serial cryo‐sections of embryonic day (E)13.5, 14.5, and 15.5 mice (C57BL/6).

Outcome Measure– Comparison of the signal intensities of NBT/BCIP precipitate by alkaline phosphatase conjugated anti‐DIG antibody.

Results– From E13.5 to E15.5, Lhx6 and L3/Lhx8 signals are detected in palatal mesenchyme, but the L3/Lhx8 signal is much more intense than the Lhx6 signal. In palatal epithelium, covering the mesenchyme, Lhx6 mRNA is transiently expressed at E14.5, while L3/Lhx8 mRNA expression is never detected throughout the development.

Conclusion– Lhx6 and L3/Lhx8 functions may be partially redundant in the mesenchyme of the secondary palate, but not in the palatal epithelium.
Structural biology of the alternative pathway convertase
Authors: Xu Yuanyuan , Narayana Sthanam V. L. , Volanakis John E.
Published: March 2003

Complement convertases are bimolecular complexes expressing protease activity only against C3 and C5. Their action is necessary for production of the biological activities of the complement system. Formation of these complexes proceeds through sequential protein–protein interactions and proteolytic cleavages of high specificity. Recent structural, mutational and functional data on factors D and B have significantly enhanced our understanding of the assembly, action, and regulation of the alternative pathway convertase. These processes were shown to depend critically on conformational changes, only some of which are reversible. The need for such changes is dictated by the zymogen‐like configurations of the active centers of these unique serine proteases. The structural determinants of some of these changes have been defined from structural and mutational analyses of the two enzymes. Transition of factor D from the zymogen‐like to the catalytically active conformation is completely reversible, while the active conformation of the catalytic center of the Bb fragment of factor B is irreversibly attenuated to a great extent on dissociation of the convertase complex. Both mechanisms contribute to the regulation of the proteolytic activity of these enzymes. Additional studies are necessary for a complete description of the elegant mechanisms mediating these processes.

The original work discussed was supported in part by USPHS grants AR44505 (JEV) and AI39818 (SVLN).
Inhibition of natural killer cell activation signals by killer cell immunoglobulin‐like receptors (CD158)
Authors: Long Eric O. , Barber Domingo F. , Burshtyn Deborah N. , Faure Mathias , Peterson Mary , Rajagopalan Sumati , Renard Valéry , Sandusky Mina , Stebbins Christopher C. , Wagtmann Nicolai , Watzl Carsten
Published: March 2003

Summary: The killer cell immunoglobulin‐like receptor (KIR) family includes receptors that bind to HLA class I molecules on target cells and inhibit natural killer (NK)‐cell cytotoxicity, and receptors such as KIR3DL7 with no known ligand and function. Inhibitory KIR recruit the tyrosine phosphatase SHP‐1 to block signals transduced by any one of a number of activation receptors. Inhibition of overall protein tyrosine phosphorylation by SHP‐1 during binding of KIR to MHC class I on target cells is selective, suggesting that a limited number of substrates are dephosphorylated by SHP‐1. We have chosen to study KIR inhibition as it occurs during binding of KIR to MHC class I on target cells, despite the technical limitations inherent to studies of processes regulated by cell contact. KIR binding to MHC class I on target cells inhibits tyrosine phosphorylation of the activation receptor 2B4 (CD244) and disrupts adhesion of NK cells to target cells. Inhibition of proximal events in NK activation may increase the availability of NK cells by liberating them from non‐productive interactions with resistant target cells. As the receptors and the signaling pathways that induce NK cytotoxicity are not fully characterized, elucidation of the inhibitory mechanism employed by KIR may provide insight into NK activation.

We thank R. Rajalingam and P. Parham for sharing results prior to publication, and Y. Bryceson and Peter Sun for comments on the manuscript.
Control of T‐cell activation by CD4+ CD25+ suppressor T cells
Authors: Shevach Ethan M. , McHugh Rebecca S. , Piccirillo Ciriaco A. , Thornton Angela M.
Published: March 2003

Summary: Depletion of the minor (∼10%) subpopulation of CD4+ T cells that co‐expresses CD25 (interleukin (IL)‐2 receptor α‐chain) by thymectomy of neonates on the third day of life or by treatment of adult CD4+ T cells with anti‐CD25 and complement results in the development of organ‐specific autoimmunity. Autoimmune disease can be prevented by reconstitution of the animals with CD4+ CD25+ cells. CD4+ CD25+‐mediated protection of autoimmune gastritis does not require the suppressor cytokines IL‐4, IL‐10, or transforming growth factor (TGF)‐β. Mice that express a transgenic T‐cell receptor (TCR) derived from a thymectomized newborn that recognizes the gastric parietal cell antigen H/K ATPase all develop severe autoimmune gastritis very early in life. CD4+ CD25+ T cells are also powerful suppressors of the activation of both CD4+ and CD8+ T cells in vitro. Suppression is mediated by a cell contact‐dependent, cytokine‐independent T–T interaction. Activation of CD4+ CD25+ via their TCR generates suppressor effector cells that are capable of non‐specifically suppressing the activation of any CD4+ or CD8+ T cell. Activation of suppressor effector function is independent of co‐stimulation mediated by CD28/CTLA‐4 interactions with CD80/CD86. We propose that CD4+ CD25+ T cells recognize organ‐specific antigens, are recruited to sites of autoimmune damage where they are activated by their target antigen, and then physically interact with autoreactive CD4+ or CD8+ effector cells to suppress the development of autoimmune disease.
Regulatory T‐cell, endogenous antigen and neonatal environment in the prevention and induction of autoimmune disease
Authors: Tung Kenneth S. K. , Agersborg Sally S. , Alard Pascale , Garza Kristine M. , Lou Ya Huan
Published: March 2003

Summary: Recent studies on autoimmune ovarian disease (AOD) induced by thymectomy on d3 (d3tx), and AOD induced by immunization with the ovary‐specific zona pellucida 3 peptide (pZP3), have yielded the following results. First, female tolerance to pZP3 depends on the persistence of endogenous antigen (Ag). Second, following regulatory T‐cell depletion, endogenous Ag in prepubertal d3tx mice triggers AOD and drives disease progression. Third, endogenous ZP3 from ovaries without AOD stimulates a diversified IgG autoantibody (autoAb) response that rapidly follows pZP3 T epitope immunization. Fourth, induction of AOD and autoimmune memory in neonatal female mice by pZP3 in incomplete Freund's adjuvant depends on endogenous Ag stimulation within the neonatal week. Fifth, in a rodent pinworm‐positive environment, neonatal but not adult female mice injected with pZP3 in water develop Th2‐mediated AOD and Th2 memory. Sixth, neonatal T cells transfer AOD to syngeneic athymic recipients, whereas adult T cells are non‐pathogenic and in fact suppress AOD conferred by neonatal T cells. Therefore: 1) the continuous presence of physiologically‐expressed autoAg is critical for both tolerance maintenance and autoimmune disease pathogenesis; the outcome is determined by the integrity of regulatory T cells; and 2) the neonatal mice, deficient in the regulatory T‐cell function, are more responsive than adults to Ag and environmental stimuli that promote autoimmune disease and memory.
Natural CD4+ CD25+ regulatory T cells. Their role in the control of superantigen responses
Authors: Papiernik Martine
Published: March 2003

Summary: CD4 regulatory T cells have a major role in controlling the immune response to self and foreign antigens. Natural CD4+ CD25+ T cells are a major component of the regulatory subset. Their absence is associated with the development of autoimmune and inflammatory diseases and with abnormal peripheral T‐cell homeostasis. Two main characteristics discriminate natural CD4+ CD25+ T cells from their CD4+ CD25− counterparts, namely their cytokine production profile and their behavior during tolerance induction. Natural CD4+ CD25+ T cells produce interleukin (IL)‐10, a cytokine that contributes to their regulatory role. They do not produce IL‐2 and are dependent on exogenous IL‐2 for proliferation in vitro and in vivo. Studies of their response to superantigen administration in vivo show that they are resistant to clonal deletion but can be tolerized by anergy. Their resistance to apoptosis may contribute to their continuous regulatory function, as it allows them to maintain permanent control over effector T cells.
CD8+CD28− T suppressor cells and the induction of antigen‐specific, antigen‐presenting cell‐mediated suppression of Th reactivity
Authors: Cortesini Raffaello , LeMaoult Joël , Ciubotariu Rodica , Cortesini Nicole Suciu Foca
Published: March 2003

Summary: Human CD8+CD28− suppressor T cells (Ts) are a subset of T cells generated in the course of in vitro and in vivo immunizations. Ts recognize MHC class I:peptide complexes and inhibit the reactivity of T helper cells (Th) with cognate antigen specificity. We have demonstrated for the first time that CD8+CD28− Ts represent a unique subset of regulatory cells that induces the differentiation of tolerogenic antigen‐presenting cells, initiating a suppressive loop which results in the induction and spreading of Th unresponsiveness.
The evolution of the MHC‐G gene does not support a functional role for the complete protein
Authors: Arnaiz‐Villena Antonio , Martinez‐Laso Jorge , Castro Maria Jose , Morales Pablo , Moscoso Juan , Varela Pilar , Gomez‐Casado Eduardo , Allende Luis M.
Published: March 2003

Summary: The study of the MHC‐G gene evolution during nearly 40 million years does not support a role for the full molecule. The MHC‐G‐like proteins of New World monkeys are probably classical presenting molecules. Old World Cercopithecinae monkeys do not have a full MHC‐G molecule and human individuals homozygous for the HLA‐G null allele are healthy and do not show birth pathologies.
Differential evolutionary MHC class II strategies in humans and rhesus macaques: relevance for biomedical studies
Authors: Doxiadis Gaby G. M. , Otting Nel , de Groot Natasja G. , Bontrop Ronald E.
Published: March 2003

Summary: The rhesus macaque is an important preclinical model in transplantation research and in investigations of chronic and infectious diseases that need a well‐characterised major histocompatibility complex (MHC‐Mamu). In a large population of pedigreed rhesus macaques, 70 Mamu‐DRB, 18 ‐DQA1, 24 ‐DQB1, and 14 ‐DPB1 alleles were detected. In humans, five HLA‐DRB region configurations are present, displaying diversity with regard to number and combinations of loci. The HLA‐DRB1 gene of each of these configurations is highly polymorphic. For rhesus monkeys, at least 31 Mamu‐DRB region configurations have been determined. In contrast to humans, most Mamu‐DRB region configurations display no or only limited allelic polymorphism. Segregation analyses revealed 28 Mamu‐DQA1/DQB1 pairs, each pair linked to a limited number of Mamu‐DRB region configurations and vice versa. In comparison with humans, the degree of freedom of recombination between Mamu‐DQA1 and ‐DQB1 is extremely low and equivalents of HLA‐DQA2/DQB2 are absent. The Mamu‐DPA1 gene is invariant and ‐DPB1 manifests only moderate allelic variation, whereas the HLA‐DPA1 gene is oligomorphic and HLA‐DPB1 highly polymorphic. Thus, both species used different evolutionary strategies to create polymorphism and diversity at the MHC class II loci in order to cope with pathogens.
Experimental allergic encephalomyelitis in the New World monkey Callithrix jacchus
Authors: Genain Claude P. , Hauser Stephen L.
Published: March 2003

Summary: Models that adequately reflect the complexity of human multiple sclerosis (MS) are needed, especially for preclinical testing of immunomodulatory drugs. Our group has created a unique experimental system in a New World outbred primate, the common marmoset Callithrix jacchus (C. jacchus). Following immunization with myelin, these monkeys develop a chronic, relapsing‐remitting form of experimental allergic encephalomyelitis (EAE), which pathologically recapitulates the hallmark features of lesions of human MS. The MS‐like lesion in C. jacchus results from a complex immune response against myelin antigens and requires both T cells and pathogenic antibodies. Studies of C. jacchus EAE have permitted the identification of a major target for pathogenic autoantibodies in MS, the myelin/oligodendrocyte glycoprotein. Other advantages of the model include a natural bone‐marrow chimerism, which permits T‐cell adoptive transfers between siblings, and the possibility of using different antigens to produce either inflammatory or demyelinating phenotypes of EAE. Despite their small size, sequential in vivo imaging and immunological studies are possible in these monkeys, and have been used to monitor efficacy in preclinical trials. Due to close phylogeny and high homology of immune and nervous system genes with humans, this model should fast‐track the development of novel therapeutics for MS.
The rhesus model of Lyme neuroborreliosis
Authors: Pachner Andrew R.
Published: March 2003

Summary: Similarity of pathology and disease progression make the non‐human primate (NHP) model of Lyme neuroborreliosis appropriate and valuable. In the NHP model of Lyme neuroborreliosis, spirochetal density in the nervous system and other tissues has been measured by polymerase chain reaction and correlated to anti‐Borrelia burgdorferi antibody in the serum and cerebrospinal fluid and to inflammation in tissues. Despite the demonstrable presence of Borrelia burgdorferi, the causative agent of Lyme borreliosis, only minor inflammation of the central nervous system occurs, though inflammation can be demonstrated in other tissues. Infected animals also develop anti‐Borrelia burgdorferi antibody in the serum, although increased amplitude of antibody is not predictive of higher levels of infection. The NHP model continues to provide important insight into the disease process in humans.
Monocytes in the rat: Phenotype and function during acute allograft rejection
Authors: Steiniger Birte , Stehling Oliver , Scriba Andreas , Grau Veronika
Published: March 2003

Summary: Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through post‐capillary venules and further differentiate into organ‐specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non‐vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill‐defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon‐γ they up‐regulate class II MHC molecules, CD161 (NKR‐P1A), CD62L and CD8, while CD4 and CD43 are down‐modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation.
IL‐5‐induced airway eosinophilia – the key to asthma?
Authors: Hamelmann Eckard , Gelfand Erwin W.
Published: March 2003

Summary: Bronchial asthma is a chronic inflammatory airway disease defined by reversible airway obstruction and non‐specific airway hyper‐responsiveness (AHR). Although profound insights have been made into the pathophysiology of asthma, the exact mechanisms inducing and regulating the disease are still not fully understood. Yet, it is generally accepted that the pathological changes in asthma are induced by a chronic inflammatory process which is characterized by infiltration of the bronchial mucosa with lymphocytes and eosinophils, increased mucus production and submucosal edema. There is increasing evidence that an imbalance in the T‐helper (Th) cell response of genetically predisposed individuals to common environmental antigens plays a pivotal role in the pathogenesis of allergic bronchial asthma and other atopic disorders. Following allergic sensitization, T cells from atopic patients tend to produce elevated levels of Th2‐type cytokines, especially interleukin (IL)‐4, IL‐13, IL‐5 and IL‐6, which induce and regulate IgE production and eosinophil airway infiltration. In this review, the role of Th2‐type cytokines, IgE and airway eosinophils in the induction of airway inflammation and AHR is discussed, and animal studies of asthma and AHR, mainly in rodents will be considered. A better understanding of the underlying mechanisms leading to asthma pathology may yield more specific immunological strategies for the treatment of this disease which is increasing worldwide.

I thank the many colleagues in the laboratory of Dr. E. W. Gelfand, National Jewish Research Center, Denver CO, USA, for continuous support and encouragement. E.H. is a fellow of the Deutsche Forschungsgemeinschaft (DFG Ha 2162/1‐1 and 2‐1).
Integrin activation and structural rearrangement
Authors: Takagi Junichi , Springer Timothy A.
Published: March 2003

Summary: Among adhesion receptor families, integrins are particularly important in biological processes that require rapid modulation of adhesion and de‐adhesion. Activation on a timescale of < 1 s of β2 integrins on leukocytes and β3 integrins on platelets enables deposition of these cells at sites of inflammation or vessel wall injury. Recent crystal, nuclear magnetic resonance (NMR), and electron microscope (EM) structures of integrins and their domains lead to a unifying mechanism of activation for both integrins that contain and those that lack an inserted (I) domain. The I domain adopts two alternative conformations, termed open and closed. In striking similarity to signaling G‐proteins, rearrangement of a Mg2+‐binding site is linked to large conformational movements in distant backbone regions. Mutations that stabilize a particular conformation show that the open conformation has high affinity for ligand, whereas the closed conformation has low affinity. Movement of the C‐terminal α‐helix 10 Å down the side of the domain in the open conformation is sufficient to increase affinity at the distal ligand‐binding site 9000‐fold. This C‐terminal “bell‐rope” provides a mechanism for linkage to conformational movements in other domains. Recent structures and functional studies reveal interactions between β‐propeller, I, and I‐like domains in the integrin headpiece, and a critical role for integrin epidermal growth factor (EGF) domains in the stalk region. The headpiece of the integrin faces down towards the membrane in the inactive conformation, and extends upward in a “switchblade”‐like opening upon activation. These long‐range structural rearrangements of the entire integrin molecule involving interdomain contacts appear closely linked to conformational changes within the I and I‐like domains, which result in increased affinity and competence for ligand binding.
Membrane–cytoskeleton interactions during the formation of the immunological synapse and subsequent T‐cell activation
Authors: Das Vincent , Nal Béatrice , Roumier Anne , Meas‐Yedid Vannary , Zimmer Christophe , Olivo‐Marin Jean‐Christophe , Roux Pascal , Ferrier Pierre , Dautry‐Varsat Alice , Alcover Andrés
Published: March 2003

Summary: Upon antigen recognition, T cells undergo substantial membrane and cytoskeletal rearrangements that lead to the formation of the immunological synapse and are necessary for subsequent T‐cell activation. However, little is known about how membrane and cytoskeletal molecules interact during these processes. Here we discuss the involvement of the membrane‐microfilament linker ezrin. We propose that ezrin is a component of the cytoskeleton‐mediated architecture of the immunological synapse that plays a role in T‐cell receptor clustering, protein kinase C θ translocation and intracellular signaling.
Genomics‐based identification of self‐ligands with T cell receptor‐specific biological activity
Authors: Santori Fabio R. , Brown Stuart M. , Vukmanovic Stanislav
Published: March 2003

Summary: Self‐peptide/major histocompatibility complex (MHC) complexes profoundly influence the biology of T lymphocytes. They promote the selection of the T cell receptor (TCR) repertoire in the thymus, maintain the homeostasis of peripheral T cells prior to encounter with antigen, and modify the responsiveness of T cells to foreign antigens. In addition, they can serve as antigens for autoaggressive T cells that induce autoimmune diseases. The complete sequencing of the genomes of human, mouse, and many pathogenic organisms now provides us with a comprehensive list of all possible proteins that may be the source of foreign antigenic and self‐peptides. A computational approach using profile‐based similarity searches on potential self‐MHC‐binding peptides can be used to efficiently predict self‐peptides with biological activities. The common feature of the identified peptides is similarity to antigen. Thus, self‐peptides may form ‘hazy’ images of the universe of antigens that are used as templates to create and maintain the TCR repertoire.