bluuebunny/crossref_metadata_2025 huggingface dataset:
Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability
Authors: Tiphine M. , Letscher‐Bru V. , Herbrecht R.
Published: March 2003

Amphotericin B (amB) remains the gold standard for the treatment of invasive fungal infections. However, the efficacy is limited, with response rates from 10% to 80%. Moreover, amB is toxic, especially for the kidneys. New formulations have been developed in an attempt to improve both efficacy and tolerability. In an attempt to reduce toxicity, a number of investigators have reconstituted amB in a lipid emulsion, but few data are available on efficacy in documented infections. An improvement in immediate and renal tolerance was obtained with equivalent daily dose regimens, but the therapeutic index does not appear to be improved. This approach cannot be recommended at present. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (AmBisome). The efficacy of ABCD on various fungal infections has been assessed in open trials, with a response rate of 49% in aspergillosis, 70% in candidiasis, and 67% in mucormycosis. In two randomized trials comparing ABCD with amB in invasive aspergillosis and in persistent febrile neutropenia, the response rates were equivalent. ABCD was less nephrotoxic. In contrast, immediate reactions to ABCD were as frequent and severe as with amB. These immediate effects are more frequent during the first infusions and lessen as treatment continues. The recommended dose is 3–4 mg/kg/day. ABLC appeared to be effective as rescue therapy in various types of invasive mycoses, with a response rate of 42% in aspergillosis, 67% in candidiasis, and 82% in fusariosis. Efficacy identical to that of amB was demonstrated in a comparative randomized trial involving patients with invasive candidiasis. General and renal tolerability is improved compared with amB. The recommended dose regimen is 5 mg/kg/day. Liposomal amB (AmBisome) is the only truly liposomal formulation. The response rates in preliminary trials were 66% in aspergillosis and 81% in candidiasis. Several comparative studies have confirmed that this formulation has similar or superior efficacy relative to amB in various fungal infections and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. The optimal dosing remains unclear but is generally between 3 and 5 mg/kg/day. A double‐blind trial comparing the tolerance of liposomal amB and ABLC demonstrated that both infusion‐related events and nephrotoxicity were significantly lower for liposomal amB. In sum, the new lipid formulations of amB are effective in various invasive fungal infections. The three formulations exhibit reduced nephrotoxicity compared with conventional amB. Large‐scale comparative clinical trials may clarify issues of relative efficacy in various forms of mycotic infections.Note
Expression of porcine endogenous retrovirus in peripheral blood leukocytes from ten different breeds
Authors: Jin H. , Inoshima Y. , Wu D. , Morooka A. , Sentsui H.
Published: March 2003

The expression of porcine endogenous retroviruses (PERV) was investigated in primary porcine peripheral blood leukocytes (PBL) of ten different pig breeds. The data suggest that PERV exists in all porcine PBL. A new retroviral element, a foamy‐like pol‐related sequence, was also detected in PBL. Three types of PERV were detected in almost every animal. The breeding of PERV‐free pigs is likely to be difficult. Further studies are required to assess the infectious disease risks associated with xenotransplantation.
Safety and efficacy of granulocyte colony‐stimulating factor in kidney and liver transplant recipients
Authors: Turgeon N. , Hovingh G.K. , Fishman J.A. , Basgoz N. , Tolkoff‐Rubin N.E. , Doran M. , Cosimi A.B. , Rubin R.H.
Published: March 2003

Background:Leukopenia is not infrequently encountered following solid organ transplantation, most often in the setting of cytomegalovirus (CMV) disease and/or its treatment with ganciclovir. The present study was undertaken to determine the safety and efficacy of granulocyte colony‐stimulating factor (G‐CSF) in renal and liver transplant recipients with leukopenia.Methods: Between 1 June 1991 and 1 June 1998, patients received G‐CSF for 2 indications: 1) white blood cell count (WBC) <3000/mm3, with a decline from baseline; 2) to shorten the duration of leukopenia associated with chemotherapy. A retrospective review of the outcome of such therapy was undertaken.Results:50 patients were given 100 courses of treatment with G‐CSF; 35 of 168 liver transplant recipients (20.8%), 14 of 391 kidney transplant recipients (3.6%), and 1 of 4 recipients of combined liver–kidney transplants (25.0%) received from 1 to 9 courses of G‐CSF. Presumed causes of leukopenia were identified as ganciclovir in 28 cases (28.0%), CMV in 21 (21.0%), chemotherapy in 12 (12.0%), sepsis in 11 (11.0%), azathioprine in 5 (5.0%), interferon in 3 (3.0%) and other causes in 20 cases (20.0%). The median length of therapy was 10.0 days (range 1–154 days) and the average dose of daily G‐CSF received was 3.9±1.5 μg/kg/day. The average WBC was (2.4±1.3)×103/μl at the beginning of therapy, and (13.8±9.1)×103/μl at the end of therapy. In 7 of 100 treatments (7.0%) a WBC of 5.0×103/μl was not reached during G‐CSF therapy; in 6 of these 7 cases, G‐CSF therapy lasted fewer than 4 days. The mean time needed to reach a WBC count of 5×103/μl was 3.7±3.3 days among 71 patients who had daily WBC counts sent. Eight G‐CSF treatments (8.0%) were followed by episodes of rejection appearing during or within 2 months of treatment; 5 of them were biopsy‐documented. No relation was found between the highest WBC obtained during G‐CSF therapy and the risk of rejection. Eight patients (16.0%) died while receiving G‐CSF, all from infection. Six of these 8 patients were receiving G‐CSF for leukopenia secondary to sepsis. Overall, 25 patients (50.0%) received 49 courses of G‐CSF secondary to CMV and/or ganciclovir therapy. In 40 of 49 courses (81.6%), ganciclovir could be continued at recommended doses. Twenty‐one of 22 patients (95.5%) with symptomatic CMV infection had a clinical response to ganciclovir. Sixteen of 18 patients (88.9%) treated for a CMV infection and followed with serial antigenemia assays attained microbiological cure; both patients who did not were infected with ganciclovir resistant CMV.Conclusion:G‐CSF was well tolerated in solid organ transplant recipients. It was particularly useful in patients with CMV disease, allowing optimal ganciclovir therapy (Note).
Hypogammaglobulinemia after heart transplantation: impact of pre‐emptive use of immunoglobulin replacement (CytoGam®) on infection and rejection outcomes
Authors: Yamani M.H. , Avery R. , Mawhorter S. , Young J.B. , McNeill A. , Cook D.J. , Ratiff N.B. , McCarthy P. , Starling R.C.
Published: March 2003

Hypogammaglobulinemia (HGG) in solid organ transplant (SOT) patients confers an increased risk of opportunistic infections and poorer outcomes. Severe HGG (IgG < 350 mg/dL) after heart transplantation may follow intensification of immunosuppressive therapy and the resultant increased risk of opportunistic infections, particularly cytomegalovirus (CMV) disease. Evaluation of the effects of replacement therapy using intravenous immunoglobulin (CMV‐IGIV, CytoGam®) was conducted in cardiac transplant recipients and the data matched with a historical control group. Patients with severe HGG who received pre‐emptive replacement therapy had significantly fewer opportunistic infections (P < 0.001) and episodes of rejection (grade 3; P = 0.03 and grade 2; P = 0.04) compared with the control group.
Patterns of cytomegalovirus infection in simultaneous kidney–pancreas transplant recipients receiving tacrolimus, mycophenolate mofetil, and prednisone with ganciclovir prophylaxis
Authors: Lo A. , Stratta R.J. , Egidi M.F. , Shokouh‐Amiri M.H. , Grewal H.P. , Kisilisik A.T. , Trofe J. , Alloway R.R. , Gaber L.W. , Gaber A.O.
Published: March 2003

Abstract:Background:The impact of tacrolimus (TAC), mycophenolate mofetil (MMF) and steroid immunosuppression on cytomegalovirus (CMV) infection in combination with ganciclovir prophylaxis in simultaneous kidney–pancreas transplantation (SKPT) has not been well studied.Methods:A retrospective analysis was made of 75 SKPTs performed between 1 January 1996 and 7 January 1999. All patients received ganciclovir for 3 months, but CMV donor (D)+/ recipient (R)− patients received ganciclovir for 6 months.Results:16/74 (22%) were CMV D+/R−, 25 (33%) D+/R+, 16 (22%) D−/R+, and 17 (23%) D−/R− (1 patient with unknown donor serology was excluded). The mean time to CMV infection was 198 days post‐transplant. The incidence of either CMV infection or tissue invasive CMV disease was 16/74 (22%), including 9 (12%) with CMV infection and 7 (10%) CMV disease. The one‐year patient, kidney, and pancreas graft survival rates were 91%, 89%, and 83%, respectively. The mean follow‐up was 29 months (minimum of 12 months). CMV infection was not associated with an increased incidence of graft failure or mortality. The D+/R− group had the highest incidence of CMV infection (44%) compared with the other serologic groups (17%,P=0.02). Concurrent CMV and rejection occurred more frequently in the D+/R− than the other serologic groups (25% vs. 7%,P=0.03). The D−/R− group had the best outcomes, with no CMV infection, improved kidney graft survival at the end of follow‐up (82% vs. 72%,P=0.04) and the highest event‐free survival (no CMV infection, rejection, or graft loss) when compared to the other groups (76% vs. 33%,P<0.01).Conclusions:Compared to previous studies, ganciclovir prophylaxis delayed the onset and reduced the severity of CMV infection in patients receiving TAC, MMF, and steroids. Despite ganciclovir prophylaxis, CMV seronegative patients receiving CMV D+ organs had worse outcomes than seronegative recipients receiving CMV D− organs.
The distribution of porcine pancreatic beta‐cells at ages 5, 12 and 24 weeks
Authors: KA TR Jay , Heald  , Carless NJ , DE Topham  , Downing R.
Published: March 2003

Jay TR, Heald KA, Carless NJ, Topham DE, Downing R. The distribution of porcine pancreatic beta‐cells at ages 5, 12 and 24 weeks. Xenotransplantation 1999; 6: 131‐140. ©Munksgaard, Copenhagen

Islet transplantation is a potential treatment for diabetes mellitus and porcine pancreata may provide a readily available source of islets. The size, number and distribution of islets within the pancreas may influence the choice of age of donor for xenotransplantation. Samples (n = 3 per age group) from the dorsal and ventral pancreas of 5‐, 12‐ and 24‐week‐old hybrid pigs were fixed in formal saline, processed in paraffin wax and stained with an avidin/biotin immunohistochemical kit for insulin, glucagon, somatostatin and pancreatic polypeptide. The arrangement of endocrine cells within the pancreata were studied and mean diameter of β‐cell groups were measured (from insulin stained sections) in 1 mm2 grid areas (n = 10 per section) and collated into groups according to size. Percentage volume density of β‐cells in relation to the whole pancreas was calculated and also the distribution of β‐cell groups, according to their size, within the total β‐cell mass. There were differences in the frequency and arrangement of endocrine cells within islets at the different ages studied. β‐Cell groups < 50 µm in diameter occupied 70 to 80% of the total β‐cell mass at 5 weeks but, as the age of the pig increased, larger cell groups were more abundant. However, the percentage volume density of β‐cells within the total pancreas did not change as the pancreas matured.This study shows that the endocrine porcine pancreas was maturing and its structure changed between the ages of 5 and 24 weeks. The relevance of these findings may have implications on the isolation and function of islets if young pigs are to be used as donors for transplantation as a treatment for diabetes mellitus.
Disordered regulation of coagulation and platelet activation in xenotransplantation
Authors: Robson Simon C. , Cooper David K. C. , D'Apice Anthony J. F.
Published: March 2003

Abstract: Rejection of xenografts is associated with vascular‐based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve into disseminated intravascular coagulation (DIC). Similarly, bone marrow‐derived cellular xenotransplantation procedures are associated with endothelial cell activation and thrombotic microangiopathic injury. These complications generally develop despite the best available measures for depletion of xenoreactive natural antibody, inhibition of complement activation and suppression of T‐ and B‐cell mediated immune responses. The mechanisms underlying the DIC and thrombotic microangiopathy associated with xenotransplantation are unclear. A proposed primary biological dysfunction of xenografts with respect to regulation of clotting could amplify vascular injury, promote immunological responses and independently contribute to graft failure. Disordered thromboregulation could have deleterious effects, comparable to unregulated complement activation, in the pathogenesis of xenograft rejection and may therefore represent a substantive barrier to xenotransplantation.
Anti‐Galα1‐3Gal IgM and IgG antibody levels in sera of humans and old world non‐human primates
Authors: Teranishi Katsuhito , Manez Rafael , Awwad Michel , Cooper David K. C.
Published: March 2003

Organs transplanted from pig to primate are rejected within minutes or hours by an antibody‐dependent, complement‐mediated mechanism [hyperacute rejection (HAR)]. Even after depletion of anti‐Galα1‐3Gal (Gal) antibody (Ab), for example by extracorporeal immunoadsorption, return of natural Ab is believed to be a major factor in the initiation of acute humoral xenograft rejection. Various non‐human primates are used as recipients of pig organs in experimental discordant xenotransplantation (XTx) models. However, anti‐Gal IgM and IgG levels in non‐human primates may differ from those in humans. Serum levels of anti‐Gal IgM and IgG were measured by enzyme‐linked immunosorbent assay (ELISA) in humans (n=14), chimpanzees (n=8), baboons (n=214), cynomolgus monkeys (n=29), rhesus monkeys (n=23) and Japanese monkeys (n=6). The mean level of anti‐Gal IgM was significantly higher in chimpanzees than in other groups, while in rhesus monkeys it was significantly lower than in other groups, except baboons and Japanese monkeys. The mean human anti‐Gal IgG level was higher than in other groups and this difference reached statistical significance except with regard to chimpanzees. The mean anti‐Gal IgG level in baboons was significantly lower than that in humans, chimpanzees and cynomolgus monkeys. The measured differences in anti‐Gal IgM and IgG levels may affect the kinetics of Ab removal and rate of return in different species, and thus may have relevance for translating work in non‐human primate models to the clinical setting.
Analysis of human CD4 T lymphocyte proliferation induced by porcine lymphoblastoid B cell lines
Authors: Bonenfant Christine , Vallée Isabelle , Sun Jishan , Brossay Angélique , Thibault Gilles , Guillaumin Jean Maurice , Lebranchu Yvon , Bardos Pierre , Butler J. E. , Watier Hervé
Published: March 2003

Bonenfant C, Vallée I, Sun J, Brossay A, Thibault G, Guillaumin JM, Lebranchu Y, Bardos P, Butler JE, Watier H. Analysis of human CD4 T lymphocyte proliferation induced by porcine lymphoblastoid B cell lines. Xenotransplantation 2003; 10: 107–119. © Blackwell Munksgaard, 2003

Background: This study was undertaken to characterize the two porcine lymphoblastoid cell lines L23 and L35, derived from a pig inoculated by the retrovirus Tsukuba‐1, and to determine how they induce a strong human lymphocyte proliferation. Methods: Phenotypic characterization was performed by flow cytometry and reverse transcriptase‐polymerase chain reaction analyses. Xenogeneic mixed lymphocyte reactions (XMLR) were performed using unfractionated human peripheral blood mononuclear cells (huPBMC) and purified CD4+ T lymphocytes as responding cells, in the presence of blocking antibodies and fusion proteins. Results: The immunoglobulin genes were demonstrated to be rearranged in L23 and L35 cell lines, in agreement with the expression of a B cell phenotype. Both induced a similar proliferation of huPBMCs and purified human CD4+ lymphocytes from adult or cord blood (naïve cells). Proliferation of CD4+ T lymphocytes was completely blocked by anti‐SLA‐DR plus anti‐SLA‐DQ mAbs, excluding human lymphocyte transformation by porcine viruses. The frequency of proliferative precursors was inconsistent with that induced by a retroviral superantigen but similar to classical direct xenoantigen presentation as observed with other porcine antigen‐presenting cells. Extensive analysis of costimulatory signals led to the identification of the CD28 pathway, in agreement with membrane expression of B7 molecules on L23 and L35 cells, and of the CD2 pathway in L35 cells. Conclusion: These two porcine lymphoblastoid cell lines have been further characterized and clearly identified as belonging to the B cell lineage. By expressing major histocompatibility complex class II antigens and costimulatory molecules, they induce a vigorous proliferative response of human CD4+ lymphocytes through a direct presentation pathway.
Behavioural evidence for ultraviolet vision in a tetraonid species – foraging experiment with black grouse Tetrao tetrix
Authors: Siitari Heli , Viitala Jussi , Hovi Matti
Published: March 2003

In addition to wavelengths visible to humans (400–700 nm), many birds are able to detect near ultraviolet light (320–400 nm). Most studies of ultraviolet (UV) vision in birds have concentrated on the importance of UV vision in intraspecific signalling, especially in passerine birds. However, birds may also use UV vision for other purposes, e.g. foraging. We performed a laboratory experiment to test whether a tetraonid species, black grouse Tetrao tetrix, could detect the difference between UV‐reflecting and non‐UV‐reflecting food items (two colour morphs of bilberry Vaccinium myrtillus). Black grouse preferred UV‐reflecting berries when UV light was used for illumination, but showed no preference in the absence of UV light. This observation establishes a potential UV sensitivity in this species; such a sensitivity should be considered in behavioural experiments with this species.
Individual variation in response to simulated territorial challenge among territory‐holding song sparrows
Authors: Nowicki Stephen , Searcy William A. , Krueger Terry , Hughes Melissa
Published: March 2003

Lack (1946) suggested that male songbirds exhibit consistent individual differences in the vigor or manner in which they defend their territories against intrusion. The causes and consequences of such individual variation have not been incorporated into models of territoriality, however, because of a lack of experimental data confirming Lack's suggestion. In this paper, we test the possibility that male song sparrows Melospiza melodia who are successful territory holders differ consistently in the vigor with which they defend their territory, by conducting repeated song playback trials with the same set of territory‐holding subjects across a breeding season. We found only relatively weak seasonal trends in responsiveness: the amount birds sang in response to playback increased significantly across the breeding season and responsiveness was generally lower when a male's social mate was egg laying. By contrast, we found extensive variation among males in how closely they approached a simulated territorial intrusion. These individual differences remained significantly consistent across four rounds of playback trials that spanned the breeding season as determined by Kendall's coefficient of concordance. Our results confirm that some individual song sparrows are consistently more vigorous than others in territory defense, at least in one conspicuous aspect of their behavior, and suggest that further work is needed to understand the nature and consequences of variation in patterns of defense among successful territory holders.
Why is mimicry in cuckoo eggs sometimes so poor?
Authors: Grim Tomáš
Published: March 2003

I propose that the existence of imperfect adaptations (e.g. egg mimicry) in brood parasites and their hosts (e.g. discrimination abilities) could reflect age‐dependent territory and nest‐site selection patterns of the host. Studies of various passerines indicate that (1) older breeders tend to occupy nest sites of higher quality than do young birds (ideal despotic distribution resulting from interference competition), (2) nest‐site selection affects the risk of parasitism in various habitats, (3) egg recognition in passerines has a strong learning component (therefore naive breeders tend to accept whereas older birds tend to reject parasitic eggs). Because young naive birds, who tend to accept parasitic eggs, usually breed in low‐quality areas where they are frequently parasitised, while old experienced birds, who tend to reject parasitic eggs, breed in high‐quality areas where they are rarely parasitised, the distribution of acceptors and rejecters with respect to the risk of parasitism is non‐random, i.e. populations of some host species may consist of heavily parasitised acceptors and weakly parasitised rejecters. Therefore, the selection pressure exerted by the host on the parasite should be weaker than if brood parasitism was randomly distributed among naive and experienced breeders and affect adaptations such as egg mimicry. This could explain the existence of imperfect adaptations in some brood parasite‐host systems.
Transforming growth factor‐β3 (Tgf‐β3) down‐regulates Tgf‐β receptor type I (Tβr‐I) during rescue of cranial sutures from osseous obliteration
Authors: Opperman LA , Galanis V , Williams AR , Adab K
Published: March 2003

Appropriate biochemical regulation of intramembranous bone growth from sutures is necessary to achieve correct craniofacial morphology. Failure to form sutures (agenesis) or to maintain sutures in their unossified state (craniosynostosis) can result in severe facial dysmorphology. Several factors such as Twist, Msx2, fibroblast growth factors (Fgfs), bone morphogenetic proteins (Bmps) and transforming growth factors‐β (Tgf‐βs) regulate suture patency, likely by interacting with one another. Tgf‐β2 and Tgf‐β3 use the same cell surface receptors, yet have opposite effects on suture patency, cellular proliferation and apoptosis within the suture. One possible mechanism by which Tgf‐β3 rescues sutures from obliteration is by regulating the ability of suture cells to respond to Tgf‐β2. As Tgf‐β3 does not regulate protein levels of Tgf‐β2 in sutures, Tgf‐β3 could regulate tissue responsiveness to Tgf‐β2 by regulating Tgf‐β2 access to receptors. Tgf‐β3 is a more potent competitor than Tgf‐β2 for cell surface receptors, so it is proposed that Tgf‐β3 binds to and down‐regulates Tgf‐β receptor type I (Tβr‐I) expression by suture cells. This down‐regulation would limit the ability of cells to respond to all Tgf‐βs, including Tgf‐β2. To test this hypothesis, an in vitro culture model was used in which fetal rat sutures either remain patent or are induced to fuse when cultured in the presence or absence of dura mater, respectively. Tgf‐β3 was added to cultured calvaria and changes in the number of receptor positive cells within the suture were established. Data were compared with that seen in control sutures and in normal sutures in vivo. It was found that the numbers of cells expressing Tβr‐I within the suture matrix increased over time in sutures remaining patent. Osteoblastic cells lining the bone fronts on either side of sutures were Tβr‐I positive during early morphogenesis, but these numbers declined as sutures fused, both in vivo and in vitro. Addition of Tgf‐β3 to calvaria in culture decreased the number of Tβr‐I expressing cells in both fusing and non‐fusing sutures, with dramatic decreases in the numbers of osteoblasts expressing Tβr‐I.
Epidemiological and genetic study of 121 cases of oral clefts in Kuwait
Authors: Al‐Bustan S A , El‐Zawahri M M , Al‐Adsani A M , Bang R L , Ghunaim I , Maher B S , Weinberg S , Marazita M L
Published: March 2003

Structured Abstract

Authors –
S Al‐Bustan, M El‐Zawahri, A Al‐Adsani, R Bang, I Ghunaim, B Maher, S Weinberg, M Marazita

Aim –
The aim of the study was to ascertain some epidemiological factors such as sex and consanguinity that may be associated with cleft lip with or without cleft palate (CL ± CP) in Kuwait as well as to conduct genetic segregation analysis of these families.

Setting and sample population –
A total of 113 families ascertained through 121 CL ± CP and CP surgical probands in Kuwait. The frequencies of cleft types and the epidemiological variables were calculated using SPSS version 5.0 software. Chi‐square for goodness‐of‐fit test was used to test the significance of the associated epidemiological variables to facial clefts. Genetic segregation analysis was performed on 76 families with extended pedigrees and included only those with non‐syndromic CL ± CP (NS CL ± CP). Major locus segregation analysis was used to fit models to the observed family patterns under Class A regressive models as implemented by REGD routine in S.A.G.E. release 4.0. A test for heterogeneity was also conducted to complete data set in addition to two subsets: Arabs and nomads.

Results –
Of the 121 patients, 34(28.1%) had CP, 30(24.8%) had CL and 57 (47.1%) had CL + CP. The male to female ratio was 0.89 for CP, 1.14 for CL, 1.35 for CL + CP and 1.2 for all the clefts. The percentage of consanguineous families among those with a positive family history (60%) was not significantly different from that of the general population (54.3%), whereas for all the families with clefts the percent consanguineous was significantly lower (38%). No evidence of heterogeneity in the results between the Arab and nomad subsets was observed. The results for the major locus segregation analysis were inconclusive.

Conclusion –
No definite association was observed between consanguinity and the occurrence of facial clefts in Kuwait. General transmission models in the full data set showed no evidence of heterogeneity in the results between the Arab and nomad subsets.
The importance of gd T cells in the resolution of pathogen‐induced inflammatory immune responses
Authors: Carding Simon R. , Egan Paul J.
Published: March 2003

Summary: The aim of our research is to determine the biological function of gd T lymphocytes and in particular the role they play in microbial immunity. Although evidence of gd T‐cell activation and expansion has been obtained from numerous infectious diseases, how they contribute to pathogen‐induced immune responses is still not clear. Based upon extensive studies of gd T‐cell involvement in the immune response to viral and bacterial pathogens in both mice and humans, we have uncovered evidence of their direct involvement in terminating host immune responses to infection and preventing chronic disease. We have identified an interaction between peripheral gd T cells and a population of activated, pro‐inflammatory macrophages elicited by infection that occurs late in the course of infection during or after pathogen clearance. As a result of this interaction, activated gd T cells acquire cytotoxic activity and kill the stimulatory macrophages, leading us to propose a model for gd T‐cell–macrophage interactions that contributes to macrophage homeostasis, the resolution of inflammatory immune responses, and prevention of chronic inflammatory disease.
The roles of surfactant proteins A and D in innate immunity
Authors: Lawson Peter R. , Reid Kenneth B. M.
Published: March 2003

Summary: Research over the last decade on the surfactant proteins SP‐A and SP‐D suggests roles beyond surfactant lipid homeostasis, involving their participation in innate immune defence. SP‐A and SP‐D bind and agglutinate an impressive array of non‐self structures, ranging from bacteria and fungi to allergens and environmental inorganic substrates. Complementing binding, SP‐A and SP‐D initiate and enhance immune cell ingestion and killing of targets. Recently, some exciting developments have extended and clarified their contributions to innate immunity. Knockout mice for SP‐A and SP‐D have been developed. The SP‐A knockout confirms that SP‐A plays a key role in defence against lung pathogens and reveals the underlying defense mechanisms that require SP‐A. These surfactant proteins have also been shown to have important roles in modulating the immune response, instructing, yet quenching, the immune reactions in the lung. The crystal structure of SP‐D plus functional studies with recombinantly altered forms of SP‐A and SP‐D has begun to characterise the structural motifs responsible for mediating their immune functions. Linkage and polymorphism analysis is explaining the role these genes may play in lung diseases and infection.
Structure and biology of complement protein C3, a connecting link between innate and acquired immunity
Authors: Sahu Arvind , Lambris John D.
Published: March 2003

Complement protein C3 is a central molecule in the complement system whose activation is essential for all the important functions performed by this system. After four decades of research it is now well established that C3 functions like a double‐edged sword: on the one hand it promotes phagocytosis, supports local inflammatory responses against pathogens, and instructs the adaptive immune response to select the appropriate antigens for a humoral response; on the other hand its unregulated activation leads to host cell damage. In addition, its interactions with the proteins of foreign pathogens may provide a mechanism by which these microorganisms evade complement attack. Therefore, a clear knowledge of the molecule and its interactions at the molecular level not only may allow the rational design of molecular adjuvants but may also lead to the development of complement inhibitors and new therapeutic agents against infectious diseases.

A.S. is a Wellcome Trust Overseas Senior Research Fellow in Biomedical Science in India. This research was supported by National Institutes of Health grants AI 30040, GM 56698, HL28220, and AI 48487.
Strategies for target cell recognition by natural killer cells
Authors: Diefenbach Andreas , Raulet David H.
Published: March 2003

Summary: Stimulation of natural killer (NK) cells is regulated by a complex balance of inhibitory and stimulatory receptors expressed by NK cells. However, the interaction of stimulatory receptors and their ligands is poorly understood. One stimulatory receptor, NKG2D, is expressed by all NK cells, stimulated CD8+ T cells, γδ T cells and macrophages. Recently, progress has been made in defining cellular ligands for NKG2D. Four different families of ligands have been identified in mice and humans, all of which are distantly related to MHC class I molecules. Some of the ligands are upregulated in transformed and infected cells, provoking an attack by the innate and adaptive immune systems. It appears that these “induced‐self” ligands recognized by the NKG2D receptor may be a precedent for a new strategy of target cell recognition by the immune system.

The authors wish to thank Dennis Wolan for preprints and discussions on the manuscript. AD is a Physician Postdoctoral Fellow of the Howard Hughes Medical Institute.
Tolerance and near‐tolerance strategies in monkeys and their application to human renal transplantation
Authors: Knechtle Stuart J. , Hamawy Majed M. , Hu Huaizhong , Fechner, Jr. John H. , Cho Clifford S.
Published: March 2003

Summary: Studies in non‐human primates to evaluate tolerance strategies in organ transplantation have led to innovation in human transplantation. The two strategies we have studied in detail in non‐human primates are T‐cell depletion by anti‐CD3 immunotoxin and co‐stimulation blockade. Each of these strategies has been extended into early human trials in renal transplantation. The results of these human and non‐human primate studies are summarized. Continued progress in better and safer immunosuppressive methods remains closely linked to research using non‐human primates. However, there has not been a one‐to‐one correspondence between efficacy in the primate and efficacy in humans. Rather, principles can be derived from non‐human primate studies that can be extended into human trials with the knowledge that regimens will likely differ in humans compared to non‐human primates.
Genomic and funtional aspects of the rat MHC, the RT1 complex
Authors: Dressel Ralf , Walter Lutz , Günther Eberhard
Published: March 2003

Summary: The major histocompatibility complex (MHC) plays a central role in controlling immune responsiveness, susceptibility to certain diseases and histo‐incompatibility. A physical map of the complete rat MHC, the RT1 complex, is presented based on a PAC clonal contig (RT1n haplotype). Expression profiling of various tissues of different inbred strains has been carried out for genes of the RT1‐C/E/M region, and different types of variability of expression are shown. As an example of single gene analysis, the RT1‐linked heat shock‐inducible heat shock genes Hsp70‐1 and Hsp70‐2 have been studied. It is demonstrated that their gene products are able to increase lysability of target cells by cytotoxic T lymphocytes.
Experimental autoimmune encephalomyelitis in the rat: lessons in T‐cell immunology and autoreactivity
Authors: Swanborg Robert H.
Published: March 2003

Summary: Experimental autoimmune encephalomyelitis (EAE) in the rat is an acute paralytic disease from which most animals spontaneously recover. The disease can be induced in susceptible inbred Lewis and DA rats with myelin basic protein (MBP), or encephalitogenic MBP peptides administered in complete Freund's adjuvant (CFA). The disease can be adoptively transferred to syngeneic recipients with primed T cells that have been reactivated in vitro with antigen. EAE is mediated by CD4+ Th1 cells that secrete proinflammatory cytokines, and spontaneous remission is associated with CD4+ T cells that secrete transforming growth factor‐beta (TGF‐β). Studies of EAE in susceptible rats have provided many important insights into the interactions of T cells and accessory cells that culminate in the induction of the autoimmune response.
BB rat lyp mutation and Type 1 diabetes
Authors: Ramanathan Sheela , Poussier Philippe
Published: March 2003

Summary: BioBreeding (BB) rats spontaneously develop an autoimmune diabetic syndrome similar to that observed in humans and NOD mice. One of the diabetes susceptibility loci maps to the lyp locus on chromosome 4. In this article we describe the consequences of the BB rat lyp mutation on T‐cell homeostasis, repertoire and function, as well as its role in the pathogenesis of type I diabetes.
Recombinant allergen molecules: tools to study effector cell activation
Authors: Valenta Rudolf , Kraft Dietrich
Published: March 2003

Summary: The IgE antibody‐mediated activation of allergic effector cells is the key pathomechanism underlying the immediate symptoms of Type I allergy, a genetically determined hypersensitivity disease affecting 25% of the population. In recent years important environmental allergens and their epitopes have become available as structurally defined recombinant molecules. In addition, corresponding human monoclonal IgE and IgG antibodies have been isolated. This review summarizes data obtained regarding the three‐dimensional structure of allergens, their IgE epitopes and the recognition of allergens by IgE and IgG antibodies. In particular, we discuss results of recent in vitro and in vivo studies with defined allergen molecules, their epitopes and the corresponding antibodies which support the hypothesis that the density and geometrical arrangement of IgE epitopes on a particular allergen molecule may profoundly affect effector cell activation. If the structural requirements for effector cell activation can be delineated, it may be envisaged that, based on this knowledge, allergens can be converted into hypoallergenic immunogens by reorientation of IgE epitopes. Such allergen derivatives may be used for allergen‐specific immunotherapy with reduced risk of inducing anaphylactic side effects.

The authors would like to thank Dr. Peter Valent, Department of Hematology, Vienna General Hospital, Austria, and Dr. Steven C. Almo, Department of Biochemistry, Albert Einstein College of Medicine, New York, USA, for fruitful collaboration regarding effector cell activation and structural biology, respectively. The skilful editorial assistance of Irmgard Lubelik is acknowledged. This work was supported by grant Y078 GEN of the Austrian Science Fund and by the ICP Program of the Austrian Federal Ministry for Education, Science and Culture.
Elemental signals regulating eosinophil accumulation in the lung
Authors: Foster Paul S. , Mould Arne W. , Yang Ming , Mackenzie Jason , Mattes Joerg , Hogan Simon P. , Mahalingam Surendran , Mckenzie Andrew N. J. , Rothenberg Marc E. , Young Ian G. , Matthaei Klaus I. , Webb Dianne C.
Published: March 2003

Summary: In this review we identify the elemental signals that regulate eosinophil accumulation in the allergic lung. We show that there are two interwoven mechanisms for the accumulation of eosinophils in pulmonary tissues and that these mechanisms are linked to the development of airways hyperreactivity (AHR). Interleukin‐(IL)‐5 plays a critical role in the expansion of eosinophil pools in both the bone marrow and blood in response to allergen provocation of the airways. Secondly, IL‐4 and IL‐13 operate within the allergic lung to control the transmigration of eosinophils across the vascular bed into pulmonary tissues. This process exclusively promotes tissue accumulation of eosinophils. IL‐13 and IL‐4 probably act by activating eosinophil‐specific adhesion pathways and by regulating the production of IL‐5 and eotaxin in the lung compartment. IL‐5 and eotaxin co‐operate locally in pulmonary tissues to selectively and synergistically promote eosinophilia. Thus, IL‐5 acts systemically to induce eosinophilia and within tissues to promote local chemotactic signals. Regulation of IL‐5 and eotaxin levels within the lung by IL‐4 and IL‐13 allows Th2 cells to elegantly co‐ordinate tissue and peripheral eosinophilia. Whilst the inhibition of either the IL‐4/IL‐13 or IL‐5/ eotaxin pathways resulted in the abolition of tissue eosinophils and AHR, only depletion of IL‐5 and eotaxin concurrently results in marked attenuation of pulmonary inflammation. These data highlight the importance of targeting both IL‐5 and CCR3 signalling systems for the resolution of inflammation and AHR associated with asthma.

S.M. is a Postdoctoral Fellow funded by a grant from the Human Frontiers Foundation to P.S.F. and M.E.R. J.M. is supported by the German Research Association (grant MA 2241/1‐1) and S.P.H by a NH&MRC CJ Martin Postdoctoral Fellowship.
Towards patient‐specific tumor antigen selection for vaccination
Authors: Rammensee Hans‐Georg , Weinschenk Toni , Gouttefangeas Cécile , Stevanovi Eq Stefan
Published: March 2003

Summary: In this review, we discuss the possibilities for combining the power of molecular analysis of the antigens expressed in a given individual tumor with the design of a tailored vaccine containing defined antigens. Step 1 is a differential gene expression analysis of tumor and corresponding normal tissue. Step 2 is the analysis of human leukocyte antigen (HLA) ligands on tumor cells. Step 3 is data mining with the aim to select those antigens that might be suitable for tumor attack by the adaptive immune system. Step 4 is the on‐the‐spot clinical grade production of the constituents of the patient tailored vaccine, e.g. peptides. Step 5 is then vaccination and monitoring. Although it will not be possible to cover all relevant antigens expressed in a tumor, the antigens that can be identified with our present technical possibilities might be enough for improved immunotherapy. The scope of the present review is to explore the possibilities and the formidable technical and logistical challenge for such individual patient‐oriented antigen definition to be used for therapeutic immunization.
Variations in immune response genes and their associations with multifactorial immune disorders
Authors: Tsuchiya Naoyuki , Ohashi Jun , Tokunaga Katsushi
Published: March 2003

Summary: There are three genetic methods often used for detecting genes contributing to susceptibility or resistance to multifactorial diseases: nonparametric linkage analysis, case–control association analysis, and transmission disequilibrium test. In this review, we present the theoretical basis that the case–control association study has the highest power of detecting disease genes if there is no population stratification between patients and controls. Taking advantage of the high power, we have carried out extensive case–control association analyses of candidate genes for the search of susceptibility genes to rheumatic diseases in the Japanese as well as in some other populations. Several new associations have been disclosed, including those of TNFR2, FCGR2B, and CD19 gene polymorphisms with systemic lupus erythematosus, in addition to some unexpected findings such as the common occurrence of NKG2‐C null allele in the healthy population. Genome‐wide association studies using single nucleotide polymorphisms (SNPs) or microsatellite polymorphisms have become realistic, and development of new high‐throughput and cost‐effective SNP typing technologies is urgently needed. At the same time, our observations may indicate that the ‘classical’ candidate gene approach will remain a strong alternative, even in the age of ‘post genome‐sequence’.
The influence of the src‐family kinases, Lck and Fyn, on T cell differentiation, survival and activation
Authors: Zamoyska Rose , Basson Albert , Filby Andrew , Legname Giuseppe , Lovatt Matthew , Seddon Benedict
Published: March 2003

The src‐family kinases p56lck (Lck) and p59fyn (Fyn) are expressed in T cells and are among the first signaling molecules to be activated downstream of the T cell receptor (TCR). Evidence is emerging that although closely related, these signaling molecules have discrete functions during development, maintenance and activation of peripheral T cells. For example, during thymopoiesis Lck is uniquely able to provide all the signals required for pre‐TCRβ selection, although Fyn can substitute for a subset of these. Positive selection of CD4 single‐positive (SP) cells is also critically dependent on the expression of Lck but not Fyn, while differentiation of CD8 SP cells proceeds relatively efficiently in the absence of Lck. In naïve peripheral T cells either Lck or Fyn can transmit TCR‐mediated survival signals, and yet only Lck is able to trigger TCR‐mediated expansion signals under conditions of lymphopenia. Stimulation of naïve T cells by antigenic stimuli is also severely compromised in the absence of Lck, but more subtly impaired by the absence of Fyn. We discuss recent experiments addressing how these two src‐kinase family members interface with downstream signaling pathways to regulate these diverse aspects of T cell behavior.
Increased midkine expression in intrahepatic cholangiocarcinoma: immunohistochemical and in situ hybridization analyses
Authors: Kato Masako , Shinozawa Takao , Kato Shinsuke , Endo Kanenori , Terada Tadashi
Published: March 2003

Abstract: Aims/Background: Midkine (MK) is a novel heparin‐binding growth factor whose gene was identified in embryonal carcinoma cells in the early stages of retinoic acid‐induced differentiation. This study investigates the overexpression of MK in intrahepatic cholangiocarcinoma (CC). Methods: Forty‐five primary CC specimens from patients (aged 19–81 years, 24 males and 21 females) were examined. Histologically, 17 cases of CC were classified as the well‐differentiated type, 19 as moderately‐differentiated and 9 as poorly‐differentiated. Immunohistochemical analysis was performed using a rat IgG2a monoclonal antibody against the carboxyl terminal region of human MK. Results: We successfully applied this monoclonal antibody against MK to analyze archival paraffin sections. The cancer tissues showed a positive reaction to this antibody, and there was an intense reaction in their cytoplasm. Approximately 40% of individuals with CC (17/45) had tumor cells that expressed MK, and these were classified into the following types: moderately‐differentiated type (9/19), well‐differentiated type (8/17) and poorly‐differentiated type (0/9). In situ hybridization analysis revealed that signals of MK transcripts were found in the cytoplasm of the cancer cells; the distribution and localization of the MK‐transcript signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. Conclusions: These findings revealed that CC express increased MK at the messenger RNA and protein levels.
De novo acute hepatitis B infection in a previously vaccinated liver transplant recipient due to a strain of HBV with a Met 133 Thr mutation in the “a” determinant
Authors: Yoshida Eric M. , Ramji Alnoor , Erb Siegfried R. , Davis Jennifer E. , Steinbrecher Urs P. , Sherlock Christopher H. , Scudamore Charles H. , Chung Stephen W. , Williams Mark , Gutfreund Klaus S.
Published: March 2003

Abstract: De novo HBV infection post‐liver transplantation (LT) from an anti‐HBc seropositive donor rarely presents as acute failure. We report a 42‐year‐old Caucasian female, HBsAg and anti‐HBc seronegative, with primary biliary cirrhosis who received an allograft from a HBsAg negative, anti‐HBc seropositive donor. The patient, previously vaccinated years pre‐LT, was re‐vaccinated against HBV and 1 year post‐LT had an anti‐HBs titre of 256 IU/l. Two years post‐LT, elevated serum aminotransferases and worsening liver function with an INR of 2.0 developed. The HBsAg became positive, anti‐HBs undetectable and serum HBV‐DNA >2000 pg/ml by hybridisation assay. Liver biopsy revealed significant ballooning degeneration, piecemeal necrosis and positive immunostaining for HBsAg. Progressive liver failure developed followed by sepsis and terminal multi‐organ failure. Subsequent analysis of the predominant HBV strain revealed mutations in the “a” determinant: Met 133 Thr (codon change ATG to ACG) and Asn 131 Thr. Conclusion: Acute de novo HBV infection from an anti‐HBc sero‐positive donor may occur long after LT despite protective anti‐HBs titres post‐vaccination secondary to the emergence of “a” determinant mutated strains of HBV.
HCV and cancer: a case‐control study in a high‐endemic area
Authors: Montella Maurizio , Crispo Anna , De Bellis Giovanna , Izzo Francesco , Frigeri Ferdinando , Ronga Domenico , Spada Orlando , Mettivier Vincenzo , Tamburini M. , Cuomo Oreste
Published: March 2003

Abstract: Background/Aims: HCV is a RNA virus that cannot be integrated with the host genome; it can, however, exert its oncogenic potential indirectly by contributing to the modulatory effects of the host immune system, probably through a capacity to elude the immune system. We have carried out a case‐controlled study on the different oncological pathologies which have, to date, been shown to have a relationship with HCV. Methods: We screened 495 patients with different types of cancer: 114 cases of liver cancer, 41 of multiple myeloma, 111 non‐Hodgkin’s lymphomas, 130 thyroid cancers, 63 cases of Hodgkin’s disease. The controls were 226 patients with no history of cancer. The relationship between each cancer and HCV infection was assessed by means of odds ratios (OR) and corresponding 95% confidence intervals. Results: Risks were greater for liver cancer (OR=32.9 95% CI 16.5–65.4, p<0.0001), multiple myeloma (OR=4.5 95% CI 1.9–10.7, p=0.0004) and B‐cell non‐Hodgkin’s lymphoma (OR=3.7 95% CI 1.9–7.4, p=0.0001). For Hodgkin’s disease there was no significant association (p=0.3). An association between HCV and thyroid cancer was noted (OR=2.8 95% CI 1.2–6.3, p=0.01). Conlusion: Our study is particularly important for public health since the high prevalence of HCV in the South of Italy gives reason to expect increases in not only liver cancer, but also tumors associated with the immune system and thyroid cancer in years to come.