bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of cytomegalovirus in cardiac allograft vasculopathy
Authors: Weill D.
Published: March 2003

Cardiac allograft vasculopathy is the most common cause of death and retransplantation following heart transplantation, and about 10% of patients per year have evidence of accelerated vascular disease; 50% at 5 years. Cytomegalovirus (CMV) infection has been associated with accelerated cardiac vasculopathy and decreased 5‐year survival. Prophylactic therapy using ganciclovir has reduced the incidence of CMV disease, but not in the group at highest risk, namely the seronegative recipient of an allograft from a seropositive donor (D+/R–). Combination prophylaxis consisting of CMV hyperimmune globulin (CMV‐IGIV) plus ganciclovir is associated with decreased intimal thickening, reduced coronary artery disease and obliterative bronchiolitis, and improved survival.
Major carbohydrate epitopes in tissues of domestic and African wild animals of potential interest for xenotransplantation research
Authors: Oriol R. , Candelier J‐J. , Taniguchi S. , Balanzino L. , Peters L. , Niekrasz M. , Hammer C. , Cooper D. K. C.
Published: March 2003

Oriol R, Candelier J‐J, Taniguchi S, Balanzino L, Peters L, Niekrasz M, Hammer C, Cooper DKC. Major carbohydrate epitopes in tissues of domestic and African wild animals of potential interest for xenotransplantation research. Xenotransplantation 1999; 6: 79‐89. ©Munksgaard, Copenhagen.

Abstract:we investigated the main glycotopes expressed on the tissues of 44 animal species, including primates, nonprimate mammals, marsupials, birds, and a reptile. Paraffin‐embedded tissue sections of kidney, heart, liver, pancreas, lung, brain and intestine of 24 domestic animal species were stained with seven fluorescent‐labeled lectins. Testis sections of 20 African wild animal species were tested with the same lectins. Overall, three main immunofluorescence patterns were found in the vascular compartment. First, humans and Old World monkeys express genetically polymorphic ABH antigens and do not express αGal. Second, New World monkeys, other mammals, and marsupials do not express ABH antigens, but have large amounts of a genetically monomorphic αGal. Third, birds and reptiles do not express either ABH or αGal, but have monomorphic βGal, probably different from the lactosamine precursor of ABH and αGal. Epithelial cells producing exocrine secretions also expressed carbohydrate epitopes. The fluorescence patterns of the cells of the exocrine compartment are similar, but not identical, to those expressed in the vascular compartment. All the animals tested have some ABH and βGal in exocrine tissues, but New World monkeys and lower mammals are the only ones expressing αGal in exocrine tissues.
IgG, but not IgM, mediates hyperacute rejection in hepatic xenografting
Authors: Schraa E. O. , Stockmann H. B. A. C. , Broekhuizen A. J. , Scheringa M. , Schuurman H. J. , Marquet R. L. , IJzermans J. N. M.
Published: March 2003

We reported previously that no classical features of hyperacute rejection (HAR) could be found in liver grafts in the guinea‐pig (GP)‐to‐rat model and that recipients died shortly after transplantation of non‐immunologic causes. Thus, the GP‐to‐rat model is not suitable for studying the mechanisms of discordant liver xenograft rejection. In the hamster to rat model, long‐term survival of a liver graft is possible, but extremely low levels of xenoreactive natural antibodies are present. To mimic a discordant situation with pre‐formed IgM and IgG antibodies, we sensitized rats 1 or 5 weeks before grafting. Specific anti‐hamster IgM antibodies were found in recipients sensitized at week –1 but not week –5. Anti‐hamster IgG was present in all recipients, albeit considerably higher in animals sensitized 5 weeks before grafting. In these two models, we examined the mechanism of HAR of liver grafts and compared this with heart xenografts. Control heart and liver grafts were rejected 4 and 7 days after transplantation respectively. Liver grafts in recipients sensitized at week –5 showed venous congestion and bleeding after reperfusion, indicating HAR, however this was not observed after sensitization at week –1. This surprising finding was confirmed by histology. Massive extravasation, edema, and acute liver cell degradation were noticed in grafts subjected to HAR. Liver grafts of recipients sensitized at week –1 showed only minimal changes. Heart grafts were rejected hyperacutely in both sensitization models. IgG antibodies could be detected on liver grafts in the group sensitized at week –5 but not in the group sensitized at week –1. Minimal IgM depositions were found on liver grafts of animals sensitized 1 week before grafting. Rejected heart grafts from similar sensitization groups showed identical antibody depositions; only IgM depositions were massive. Complement depositions were found in all groups. These results indicate that IgG, but not IgM, mediates HAR in hepatic xenografting. Such a predominance of IgG over IgM does not exist for heart grafts.
Lack of antibody production against Hanganutziu‐Deicher (H‐D) antigens with N‐glycolylneuraminic acid in patients with porcine exposure history
Authors: Kobayashi Takaaki , Yokoyama Itsuo , Suzuki Akemi , Abe Mikiko , Hayashi Shuji , Matsuda Haruo , Morozumi Kunio , Breimer Michael E. , Rydberg Lennart , Groth Carl G. , Tibell Annika , Korsgren Olle , Takagi Hiroshi , Nakao Akimasa
Published: March 2003

Abstract: The significance of non‐αgalactosyl antigens remains unclear in pig‐to‐primate xenotransplantation. Hanganutziu‐Deicher (H‐D) antigens with terminal N‐glycolylneuraminic acid (NeuGc) are widely expressed on endothelial cells of mammalian species, with the exception of humans. As baboons and monkeys also express H‐D antigens, a pig‐to‐non‐human primate experimental model cannot resolve the question of whether H‐D antigens can elicit a potent humoral response in human recipients. The purpose of this study was to elucidate the clinical significance of H‐D antigens by examining the sera from patients who have been previously exposed to porcine tissue.

After the digestion of porcine aortic endothelial cells (PAEC) by neuraminidase, NeuGc and N‐acetylneuraminic acid (NeuAc) were quantitated by HPLC. IgG and IgM antibody levels against H‐D antigens were measured by NeuGc‐GM3‐coated ELISA plates in the sera of patients who had undergone ex vivo kidney perfusion 1 to 3 weeks and 2 years previously (n = 2) or had been injected with fetal porcine islets 2 months previously (n = 10).

HPLC determined that 9.7×107 NeuAc and 6.3×107 NeuGc residues per cell were released from PAEC by neuraminidase, while 25.7×107 NeuAc and an undetectable level of NeuGc were released from human aortic endothelial cells (HAEC). No significant elevation of IgG or IgM antibody levels against NeuGc‐GM3 was observed in sera from patients with a history of porcine exposure.

Considering the active production of antibody against the foreign galactosyl antigens after pig‐to‐human xenotransplantation, some production of antibodies against the equally foreign H‐D antigens would be expected, because large amounts of NeuGc terminated saccharides are present in the pig endothelial cell surface. However, no production of antibodies directed to H‐D antigens could be found in patients exposed to porcine tissue. Further studies are warranted to explain why H‐D antigens do not elicit a significant antibody production.
Plasma perfusion by apheresis through a Gal immunoaffinity column successfully depletes anti‐Gal antibody: experience with 320 aphereses in baboons
Authors: Watts A. , Foley A. , Awwad M. , Treter S. , Oravec G. , Buhler L. , Alwayn I. P. J. , Kozlowski T. , Lambrigts D. , Gojo S. , Basker M. , White‐Scharf M. E. , Andrews D. , Sachs D. H. , Cooper D. K. C.
Published: March 2003

Abstract: Background: Anti‐Galα1–3Gal (Gal) antibodies (Gal Ab) contribute to the rejection of porcine organs transplanted into primates. Extracorporeal immunoadsorption (EIA) has been developed to eliminate Gal Ab from the circulation.

Methods: Between 1995 and 1999 we performed 320 EIAs in baboons using a COBE‐Spectra apheresis unit incorporating a synthetic Gal immunoaffinity column. Three plasma volumes were immunoadsorbed on each occasion. The 221 consecutive EIAs performed in 41 immuno‐suppressed baboons between January 1997 and April 1999 form the basis of this review. Of these 41 baboons, 29 underwent a series of three or four EIAs at daily intervals, seven had multiple series of three EIAs, and the remainder underwent single or double EIAs. Serum Gal Ab levels were monitored by ELISA before and at intervals after the course of EIA.

Results: There were two fatal complications, one from a respiratory mishap (unrelated to the EIA) and one from persistent hypotension unresponsive to therapeutic interventions. Seven procedures (3%) were terminated early owing to technical difficulties and/or persistent hypo‐tension. Mean pre‐EIA Gal Ab levels in naïve baboons were 33.1 µg/ml (IgM) and 14.5 µg/ml (IgG). Immediately after three consecutive EIAs, IgM was depleted by a mean of 97.3% and IgG by 99.4%. By 18 to 24 h later, Gal Ab was returning but depletion remained at 80.1% (IgM) and 84.7% (IgG). The subsequent rate of return of Gal Ab depended on the immunomodulatory protocol used.

Conclusions: (1) With appropriate monitoring, EIA is an acceptably safe procedure, even in small (< 10 kg) baboons. (2) Three consecutive EIAs are effective in removing > 97% of Gal Ab. (3) In the majority of cases, return of Gal Ab begins within 24 h, irrespective of the immuno‐modulatory protocol.
Production of human monoclonal antibodies against Galα(1–3)Gal
Authors: Wittig Olga , Taylor Peter , Montaño Ramón , Alonso José , Romano Egidio
Published: March 2003

The hyperacute rejection observed in models of pig‐to‐human xenotransplantation is mainly because of the presence of natural antibodies in human blood with specificity for the Galα(1–3)Gal (Gal) carbohydrate moiety present on the surface of porcine endothelial cells. Human monoclonal anti‐Gal antibodies could be of use both in the study of the basic mechanisms of hyperacute rejection as well as in its clinical prevention. In the present study we prepared 42 heterohybridomas (human–mouse) secreting antibodies with specificity for the Gal epitope. All of the antibodies produced were of the IgM isotype, according to a dot‐blot assay. Twenty‐seven antibodies were further characterized, and shown to be specific for Gal by different methods, including an enzyme‐linked immunosorbent assay, in which the plates were sensitized with mouse laminin as a source of Gal. Specificity was also confirmed using purified Gal carbohydrate in a hemagglutination inhibition assay. The antibodies were shown to mediate lysis of Gal‐expressing rabbit erythrocytes in the presence of complement. However, the heterohybridomas themselves were shown to express Gal, a result of the mouse P3x63Ag8.653 hybridoma cells used during hybridoma generation. The presence of this epitope on the surface of anti‐Gal‐producing cells, and on the antibody itself, represents a limitation to the production of high affinity anti‐Gal antibodies.
Pig peripheral blood mononuclear cells are directly associated with the thrombotic microangiopathy that complicates the induction of chimerism in pig‐to‐baboon xenotransplantation
Authors: Benatuil Lorenzo , Fernandez Ana Zita , Apitz‐Castro Rafael , Romano Egidio
Published: March 2003

The infusion of large numbers of porcine cells into primates in order to induce specific immunologic tolerance by mixed hematopoietic chimerism, results in thrombotic microangiopathy that can be fatal. For this reason, it is important to study in vitro the interaction of primate endothelial cells with pig cells. We show that pig peripheral blood mononuclear cells (p‐PBMC) activate human endothelial cells (hECs) through direct contact. Thus, when endothelial cells are cultured in the presence of p‐PBMC, overexpression of VCAM‐1 and E‐selectin adhesion molecules occurs within 3 h of culture and continues for at least 9 h. The co‐culture of p‐PBMC and hECs also results in an important adhesion of human platelets to both types of cell. Thus, viewed with the microscope, platelets aggregate above the endothelial cells and also around the pig cells. We present data that suggest that the presence of p‐PBMC may be more important with regard to the increase of platelet adhesion to the endothelial cells than the activation alone of the cells. Our results also show that p‐PBMC, and not the activated endothelia or the culture supernatant of activated hECs, are able to activate the coagulation cascade because they are able to generate thrombin when added to defibrinated human plasma. Overall, these findings suggest that p‐PBMC are of primary importance for the development of the thrombotic disorders that occur in primates transplanted with pig progenitor cells.
Results of crossmatch between chimpanzee lymphocytes and sera of highly sensitized potential renal transplant recipients
Authors: Rabkin David G. , Nowygrod Roman , Hardy Mark A. , Reemtsma Keith
Published: March 2003

Background: We tested the hypothesis that patients with a high frequency of lymphocytotoxic antibodies against human cells are not highly sensitized to major histocompatibility complexes expressed by chimpanzee cells. Methods: Sera from six “hopelessly” sensitized patients (percentage reactive antibodies (PRA)  > 99%) on the renal transplant waiting list were crossmatched with peripheral blood lymphocytes from 10 chimpanzees. Lymphocytotoxic antibodies reacting with chimpanzee peripheral blood lymphocytes were identified. Results: Three of the six patients with a high frequency of lymphocytotoxic antibodies against human cells had no xenospecific antibodies. Conclusion: Patients with a high frequency of lymphocytotoxic antibodies against human cells are not all panel‐reactive to chimpanzees. Unilateral donor nephrectomy in non‐human primates may offer an opportunity for safe expansion of the donor organ pool for these patients.
Xenogeneic milieu markedly remodels endocrine cell populations after transplantation of fish islets into streptozotocin‐diabetic nude mice
Authors: Morrison Carol M. , Yang Hua , Al‐Jazaeri Ayman , Tam Janet , Plisetskaya Erika M. , Wright James R.
Published: March 2003

Morrison CM, Yang H, Al‐Jazaeri A, Tam J, Plisetskaya EM, Wright JR Jr. Xenogeneic milieu markedly remodels endocrine cell populations after transplantation of fish islets into streptozotocin‐diabetic nude mice. Xenotransplantation 2003; 10: 60–65. © Blackwell Munksgaard, 2003

It is unknown whether irrelevant foreign endocrine products secreted by xenografts would be biologically active and potentially harmful to recipients; even if entirely inert, continuous production might result in harmful circulating antigen–antibody complexes. We examined the fate of such a product using a fish (tilapia)‐to‐mouse islet xenograft model. Teleost fish islets, like mammalian islets, are composed primarily of cells producing insulin, glucagon or somatostatin; however, teleost fish have two different populations of somatostatin (SST) producing delta cells, one producing SST‐14, a 14 amino acid SST identical to mammalian SST, which is derived from the pre‐proSST‐I gene which is present in all vertebrates, and the other a “large” (i.e. 22 to 28 amino acid) SST derived from a pre‐proSST‐II gene, which is not found in mammals. In contrast to `large' SST, which has no mammalian homolog, teleost fish insulins, glucagons and SST‐14 exhibit significant biological activity in mammals. Tilapia islets were transplanted under the kidney capsules of streptozotocin‐diabetic nude mice, and mice with functioning grafts were killed at various times after transplantation. Serial sections of graft‐bearing kidneys were stained by immunoperoxidase for insulin, SST‐14, SST‐25 and glucagon positive cells, and the areas of each cell type in the graft were measured using image analysis. Sections of untransplanted tilapia islets (both in situ and after harvest/culture) were also immunostained and measured as controls. Xenotransplantation of fish islets into diabetic nude mice resulted in the rapid degeneration and near total loss of SST‐25+ cells, as well as a marked redistribution of the proportions of the remaining endocrine cell types. The proportions of cell types in the grafts gradually changed from a piscine pattern to that of mammalian islets.
Ecological barriers shaping fuel stores in barn swallows Hirundo rustica following the central and western Mediterranean flyways
Authors: Rubolini Diego , Gardiazabal Pastor Andrea , Pilastro Andrea , Spina Fernando
Published: March 2003

The crossing of ecological barriers is among the most energy‐demanding and risky phases of migration. Scanty field data exist on the relationships between ecological barriers and pre‐migratory fuel storing in songbirds. The aim of this study was to analyse whether the distance to be covered across ecological barriers can be considered as a factor affecting pre‐migratory fuel stores in barn swallows Hirundo rustica following the two main western European flyways, funnelling through Iberia and Italy. Data refer to 13029 swallows and were collected during July–October in 1997–1998 at 19 roost sites, scattered over Spain and Italy (south of 43°N). During the post‐breeding phase (PB, July–August) energy stores did not differ significantly between the two geographical areas, whereas during the pre‐migratory phase (PM, September–October) swallows in Italy carried larger energy stores than those in Spain. Assuming that swallows leave for migration from the fuelling site, we found a significant positive correlation between the width of ecological barriers and an average index of energy stores for each roost site during the PM phase. The width of ecological barriers (along a N‐S migration route) was expressed as (1) the distance between the roost site and the coast of North Africa (representing the Mediterranean Sea), and (2) the distance between the roost site and the southern margin of the Sahara desert (the total width of ecological barriers). The weaker correlations obtained when considering only the Mediterranean as a barrier suggest that swallows may cross the desert without substantial refuelling in North Africa. Hence, we showed that fuel stores have a degree of population‐specific variability among Italian and Iberian barn swallows and that the extension of ecological barriers may play a role in determining the amount of stores needed for the migratory flight.
Territorial status and survival in red grouse Lagopus lagopus scoticus: hope for the doomed surplus?
Authors: Park Kirsty J. , Hurley Martha M. , Hudson Peter J.
Published: March 2003

A previous study of survival in territorial and non‐territorial red grouse Lagopus lagopus scoticus conducted between 1957 and 1967 found that territorial status in the autumn pre‐determined over‐winter survival. A very high proportion of territorial birds survived and virtually all non‐territorial birds died or emigrated. We tested the hypothesis that over‐winter survival was dependent on territorial status within four grouse populations in Scotland between 1986 and 1993. In contrast to the previous study, 66% of non‐territorial birds survived over winter compared to approximately 70% of territorial birds. There was no significant effect of territorial status on the survival estimates. Moreover, some of the birds considered to be non‐territorial during autumn went on to successfully raise a brood. We suggest that on our study sites, territory ownership in autumn did not greatly influence over‐winter survival, and territorial behaviour did not determine breeding density as previously supposed. We postulate differences with other studies may reflect variations in scale and predation pressure.
Male‐biased sex ratios in broods of the cooperatively breeding bell miner Manorina melanophrys
Authors: Clarke Michael F. , Jones David A. , Ewen John G. , Robertson Raleigh J. , Griffiths Richard , Painter Jodie , Boag Peter T. , Crozier Ross
Published: March 2003

We examined the sex ratios of adults and nestlings in the cooperatively breeding bell miner Manorina melanophrys. Males were over‐represented among helpers (mean of 6.8 male helpers per nest compared to 0.3 female helpers). 58% of nestlings sampled were identified as male using a molecular genetic marker. This was a significant departure from parity, yet the magnitude of the bias varied between years. The beneficial and male‐biased nature of helping behaviour in this species and the similar size of male and female nestlings suggest the net cost of raising males is lower than the cost of raising females. Consequently, the male‐biased sex ratio of nestlings we observed is consistent with the predictions of the repayment hypothesis that females may bias the production of their young towards the more helpful sex. Difficulties of generating quantitative predictions from repayment models that can be tested in the field are discussed.
Harlequin duckHistrionicus histrionicuspopulation structure in eastern Nearctic
Authors: Brodeur Serge , Savard Jean‐Pierre L. , Robert Michel , Laporte Pierre , Lamothe Pierre , Titman Rodger D. , Marchand Stéphane , Gilliland Scott , Fitzgerald Guy
Published: March 2003

During May 1996 and April 1997, eight harlequin duck males were captured and fitted with satellite transmitters while migrating along the shores of Forillon National Park, Québec, Canada. Another 17 males were equipped with satellite transmitters in river systems of eastern Hudson Bay, Ungava Bay and northern Labrador in June 1997 and 1998. Our objectives were to determine relationships between breeding, moulting and wintering areas, and to determine whether distinct population segments existed among harlequin ducks in eastern North America. All birds tracked from Forillon migrated to Labrador. Moulting areas were identified for six birds. Forillon males were followed to the eastern North American major wintering site in Maine. Males captured in northern Québec and Labrador migrated to moult and winter in south‐western Greenland. Our data suggest the presence of two demographically distinct population segments in eastern North America, perhaps originating from the Pleistocene glacial refuge in western Greenland and south of the Laurentide ice sheet in eastern Canada or United States.
The genetic effects of forest fragmentation on five species of Amazonian birds
Authors: Bates John M.
Published: March 2003

Restriction fragment length polymorphisms of mtDNA were used to assess genetic structure at two geographic scales for five species of Neotropical forest‐understory birds. At the local scale (in northeastern Bolivia), I studied populations of each species from six sites within 200 km of one another. At this scale, I studied the effects of forest fragmentation on mtDNA genetic structure: three sites were in natural forest fragments separated by cerrado (savanna), and three sites were in continuous forest. Genetic variation did not appear to have been lost in the forest fragment populations of any species. However, for three antbirds (Thamnophilidae), patterns of haplotype distributions suggest fragmentation affected genetic structure in an unusual way. For these species, numerically dominant haplotypes in forest fragments did not occur in continuous forest, whereas predominant haplotypes in continuous forest are widespread (occurring in fragments and continuous forest). These results suggest that forest fragmentation on a local geographic scale can affect genetic differentiation even in birds, a group that is considered to disperse well. The two other taxa studied were a woodcreeper (Dendrocolaptidae) and a tyrant‐flycatcher (Tyrannidae). These two taxa did not show genetic effects of forest fragmentation, but they possessed notably different numbers of haplotypes per total individuals surveyed. The woodcreeper had few haplotypes (5 in 58 individuals), whereas the flycatcher had many (31 in 34 individuals). The numbers of haplotypes per individuals surveyed for the three antbirds were intermediate. Such variable levels of polymorphism can greatly influence analyses of genetic structure. At the regional geographic scale (across southwestern Amazonia), the flycatcher exhibited lower levels of differentiation than the other taxa. Levels of estimated sequence divergence within the other four taxa are similar to levels of differentiation between species from other avian studies, suggesting that genetic diversity is underestimated by current species‐level taxonomy in these birds.
Carboxypeptidase R is an inactivator of complement‐derived inflammatory peptides and an inhibitor of fibrinolysis
Authors: Campbell William , Okada Noriko , Okada Hidechika
Published: March 2003

Carboxypeptidase R (CPR) exists in precursor form (proCPR) in plasma in contrast to carboxypeptidase N (CPN), which is present in the active state. CPR plays two important roles, one of which appears to be the control of the inflammatory response by inactivation of anaphylatoxins such as complement‐derived C3a and C5a. Therefore, an increase in CPR activity may facilitate rapid inactivation of these inflammatory mediators generated at the site of bacterial infection. Upregulation of proCPR expression during the inflammatory response initiated for instance by endotoxin (lipopolysaccharide) should play a role in suppressing hyper‐reactivity as seen in septic shock. CPR also functions as an inhibitor of fibrinolysis, where its ability to prevent binding of plasminogen to lysine residues on fibrin clots significantly lengthens tissue plasminogen activator (tPA)‐induced fibrinolysis time. Therefore, upregulation of proCPR production during the inflammatory response may exacerbate thrombosis contributing to the development of disseminated intravascular coagulation as well as other conditions involving thrombosis. Co‐administration of tPA and a specific inhibitor of CPR, such as potato carboxypeptidase inhibitor, which does not affect CPN, may be useful in thrombolytic therapy.

This work was supported by a research grant form the Organization for Pharmaceutical Safety and Research.
An integrative model of regulation centered on recognition of TCR peptide/MHC complexes
Authors: Kumar Vipin , Sercarz Eli
Published: March 2003

Summary: We have described a T‐cell receptor (TCR)‐centered model of immune regulation, in which MHC/TCR peptide complexes provide for the activation of regulatory T cells and likewise act as their target structures. In this model, the disease‐causing effectors are TCR Vβ8.2+ and each of the required CD4 and CD8 regulatory T‐cell populations are specific for different conserved regions of the Vβ8.2 chain, in the appropriate MHC context. We have characterized the dominance, the dynamics as well as the TCR usage of both effector and regulatory T cells. We have begun to characterize the essential elements of the regulatory program, including the mechanism of interaction among effector and regulatory T‐cell populations. Principles learned in this model have important implications for immune regulation in general.
Immunobiology of dendritic cells in the rat
Authors: Turnbull Emma , MacPherson Gordon
Published: March 2003

Summary: Dendritic cells (DC) are crucial orchestrators of the adaptive immune response. They are highly effective antigen samplers and have a unique ability amongst antigen presenting cells to activate naïve T lymphocytes and subsequently direct the quality of the immune response. Understanding how DC initiate and regulate immune responses requires in‐depth knowledge of DC function at cellular and molecular levels. Research on the biology of DC has predominantly used in vitro‐generated and ex vivo‐isolated DC from mice and humans. It is, however, often difficult to relate such DC to those that actually exist in vivo. The model we have developed in the rat permits analysis of DC in a near‐physiological setting, and provides a description of DC biology that other systems must take into account. In this review we focus on our own research on DC in the gastro‐intestinal tract, covering a variety of concepts in DC biology, and relate our findings to the work of others, to provide an overall picture of what is known regarding the nature of this complex cell type in the rat.
Heme oxygenase‐1, a protective gene that prevents the rejection of transplanted organs
Authors: Soares Miguel P. , Brouard Sophie , Smith R. Neal , Bach Fritz H.
Published: March 2003

Summary: Endothelial cells (EC) play a pivotal role in regulating inflammatory reactions such as those involved in the rejection of transplanted organs. This occurs through the expression of a series of pro‐ and anti‐inflammatory genes that are associated with the activation of these cells. Presumably, the expression of pro‐inflammatory genes promotes events that lead to graft rejection, while expression of anti‐inflammatory (protective) genes suppresses those events and thus contributes in sustaining graft survival. Understanding how the expression of these genes is regulated and their mechanism of action are important issues for the development of new therapeutic strategies to suppress graft rejection. We have studied this phenomenon using experimental models of transplantation in rats. We discuss here data that supports the concept that grafts can express anti‐inflammatory (protective) genes that mitigate inflammatory reactions leading to graft rejection. The data reviewed focus on the role of one of such genes, the stress responsive gene heme oxygenase‐1, and of its byproduct carbon monoxide, which can suppress graft rejection and lead to long‐term graft survival.
The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs
Authors: Cohn Melvin
Published: March 2003

Summary: Living systems operate under interactive selective pressures. Populations have the ability to anticipate the future by generating a repertoire of elements that cope with new selective pressures. If the repertoire of such elements were transcendental, natural selection could not operate because any one of them would be too rare. This is the problem that vertebrates faced in order to deal with a vast number of pathogens. The solution was to invent an immune system that underwent somatic evolution. This required a random repertoire that was generated somatically and divided the antigenic universe into combinatorials of determinants. As a result, it became virtually impossible for pathogens to escape recognition but the functioning of such a repertoire required two new regulatory mechanisms: 1) a somatic discriminator between Not‐To‐Be‐Ridded (‘Self’) and To‐Be‐Ridded (‘Non‐self’) antigens, and 2) a way to optimize the magnitude and choice of the class of the effector response. The principles governing this dual regulation are analyzed in the light of natural selection.

Abstract

A. ‘...doth protest too much’

E. Two classes of pathogen must be faced

II. The NTBR–TBR discrimination

A. The three laws of the NTBR‐TBR discrimination

B. The mechanism of the NTBR‐TBR discrimination

C. Facing the “chicken and egg” problem

III. The regulation of effector class

IV. The somatically selected immune repertoire

A. The Protecton is the unit of function

B. The humoral immune system

C. The cell‐mediated immune system

D. The meaning of specificity

V. Why understand when you can cure without it?

VI. Coda: Extracting the postulates used to explain immune behavior

O.K. José! What would it take to change your mind?

Mechkonik
A novel adhesion pathway that regulates dendritic cell trafficking and T cell interactions
Authors: Van Kooyk Yvette , Geijtenbeek Teunis B. H.
Published: March 2003

Summary: Dendritic cells (DC) are present in essentially every tissue, where they operate at the interface of innate and acquired immunity by recognizing pathogens and presenting pathogen‐derived peptides to T cells. Cell–cell interactions between DC, T cells and endothelial cells are crucial to all immunological processes. Recently, several C‐type lectin receptors have been characterized that are abundantly expressed on the surface of DC. It is now becoming clear that these lectin receptors serve not only as antigen‐receptors recognizing pathogens, but they may also function as adhesion receptors and/or signaling molecules. In particular the DC specific C‐type lectin DC‐SIGN (CD209) regulates adhesion processes, such as DC trafficking by interacting with ICAM‐2 and T cell synapse formation, upon binding of ICAM‐3. C‐type lectins such as DC‐SIGN contain a lectin domain that recognizes in a Ca2+‐dependent manner carbohydrates such as mannose‐containing structures presented on the glycoproteins ICAM‐2 and ICAM‐3. Although the integrin LFA‐1 is a counter‐receptor for both ICAM‐2 and ICAM‐3, on DC, DC‐SIGN is the high affinity adhesion receptor for ICAM‐2/‐3. Here we discuss how the heterogeneity of mannose‐residues exposed on cellular proteins and pathogens regulates specific binding of a repertoire of DC‐expressed C‐type lectins that contribute to the diversity of immune responses created by DC.
Imaging immune surveillance by T cells and NK cells
Authors: McCann Fiona E. , Suhling Klaus , Carlin Leo M. , Eleme Konstantina , Taner Sabrina B. , Yanagi Kumiko , Vanherberghen Bruno , French Paul M. W. , Davis Daniel M.
Published: March 2003

Summary: As T cells and natural killer (NK) cells survey the surface of other cells, cognate receptors and ligands are commonly organized into distinct micrometer‐scale domains at the intercellular contact, creating an immune or immunological synapse (IS). We aim to address the still unanswered questions of how this organization of proteins aids immune surveillance and how these domains are biophysically constructed. Molecular mechanisms for the formation of the IS include a role for the cytoskeleton, segregation of proteins according to the size of their extracellular domains, and association of proteins with lipid rafts. Towards understanding the function of the IS, it is instructive to compare and contrast the supramolecular organization of proteins at the inhibitory and activating NK cell IS with that at the activating T cell IS. Finally, it is essential to develop new technologies for probing molecular recognition at cell surfaces. Imaging parameters other than fluorescence intensity, such as the lifetime of the fluorophore's excited state, could be used to report on protein environments.
Natural selection and the diversification of vertebrate immune effectors
Authors: Hughes Austin L.
Published: March 2003

Summary: The molecules of the vertebrate immune system provide some of the best documented examples of natural selection acting at the molecular level. The major histocompatibility complex (MHC) molecules are a family of highly polymorphic loci whose products present peptides to T cells. Four distinct lines of evidence support the hypothesis that the natural selection acts to maintain MHC polymorphism: (1) evidence from the unusual allelic frequency distribution seen at MHC loci; (2) evidence from the pattern of nucleotide substitution at MHC loci, which shows an enhanced rate of nonsynonymous (amino acid‐altering) substitution in the codons encoding the peptide‐binding region of the molecules; (3) the existence of long‐lasting polymorphisms at certain MHC loci; and (4) the fact that introns at MHC loci are homogenized by recombination and subsequent genetic drift. Certain other immune system gene families provide evidence that natural selection has acted to create diversity among family members. Examples include molecules of the specific immune system (such as immunoglobulin V region genes) and molecules of the innate immune system (such as defensins).
On the role of self‐recognition in T cell responses to foreign antigen
Authors: Štefanov́a Irena , Dorfman Jeffrey R. , Tsukamoto Makoto , Germain Ronald N.
Published: March 2003

The key role of the thymus in shaping the peripheral T cell receptor (TCR) repertoire has been appreciated for nearly a quarter of a century. For most of that time, a single model has dominated thinking about the physiological role of the positive selection process mediated by TCR recognition of self‐peptides and major histocompatibility complex (MHC) molecules. This developmental filter was believed to populate secondary lymphoid tissues with T cells bearing receptors best able to recognize unknown foreign peptides associated with the particular allelic forms of the MHC molecules present in an individual. More recently, self‐recognition has been suggested to regulate the viability of naïve T cells. Here we focus on new results indicating that a critical contribution of positive selection to host defense is insuring that each peripheral T cell can use self‐recognition to (i) enhance TCR signaling sensitivity upon foreign antigen recognition and (ii) augment the clonal expansion that accompanies limiting foreign antigen display at early points in an infectious process. We also detail new insights into the intracellular signaling circuitry that underlies the effective discrimination between low‐ and high‐quality ligands of the TCR and speculate on how this design might facilitate an additional contribution of self‐recognition to T cell activation in the presence of foreign stimuli.
Hepatitis C virus core protein promotes cell proliferation through the upregulation of cyclin E expression levels
Authors: Cho Jae‐We , Baek Won‐Ki , Suh Seong‐Il , Yang Se‐Hwan , Chang Jun , Sung Young Chul , Suh Min‐Ho
Published: March 2003

Abstract: Aims/Background: The hepatitis C virus (HCV) core protein is known to play an important role in hepatocarcinogenesis. Recent studies have suggested that the increased proliferation rate of hepatocytes is a major risk factor for the development of hepatocellular carcinoma. In this study, we investigated whether the HCV core protein promotes the cell growth rate through the modulation of cyclin E expression levels. Methods/Results: HCV core stable transfectant Rat‐1 cell lines showed a markedly increased proliferation rate compared to mock cells. Cyclin E expression and its associated kinase activities were remarkably increased in HCV core stable transfectants. Cyclin E mRNA levels were also upregulated in these cell lines. Conclusions: Our data suggest that the HCV core protein promotes cell proliferation through upregulation of the cyclin E expression levels, implying this property of HCV core protein plays an important role in hepatocarcinogenesis.
Chinese medicinal herbs for chronic hepatitis B: a systematic review
Authors: Liu Jianping , McIntosh Heather , Lin Hui
Published: March 2003

Abstract: Aims/Background: Chronic hepatitis B is a serious health problem worldwide. Chinese medicinal herbs are widely used for treatment of chronic hepatitis B in China and many clinical trials have been conducted. This systematic review is to assess the efficacy and safety of Chinese medicinal herbs for chronic hepatitis B. Methods: Randomised clinical trials comparing Chinese medicinal herbs versus placebo, no intervention, nonspecific treatment, or interferon treatment for chronic hepatitis B with ≥3 months follow‐up were included. No language and blinding limitations were applied. The electronic databases were searched, combined with handsearches on Chinese literature. Data were extracted independently by two reviewers. The methodological quality of trials was assessed by the Jadad‐scale plus allocation concealment. Results: Nine randomised trials (n=936) were included, with only one being of high quality. There was a funnel plot asymmetry (intercept 3.37, p=0.047). Compared to nonspecific treatment or placebo, the herbal compound Fuzheng Jiedu Tang showed an effect on clearance of serum HBsAg (relative risk 5.19, 95% CI 1.24–21.79), HBeAg (10.85, 3.56–33.06), and HBV DNA (8.50, 1.23–58.85). Polyporus umbellatus polysaccharide showed an effect on serum HBeAg (3.06, 1.13–8.29) and HBV DNA (4.14, 1.0–17.19); Phyllanthus amarus showed an effect on serum HBeAg (3.35, 1.49–7.56). Phyllanthus compound and kurorinone showed no significant difference on clearance of serum HBeAg and HBV DNA and on alanine aminotransferase normalisation compared to interferon. No serious adverse event was observed. Conclusions: Chinese medicinal herbs are not recommended for chronic hepatitis B because of the publication bias and low quality of the trials. Rigorously designed, randomised, double‐blind, placebo‐controlled trials are needed.
Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells
Authors: Svegliati‐Baroni Gianluca , Saccomanno Stefania , Van Goor Harry , Jansen Peter , Benedetti Antonio , Moshage Han
Published: March 2003

Abstract:Background /Aims:Reactive oxygen species (ROS) induce HSCs activation, proliferation and collagen gene expressionin vitro. Nitric oxide (NO) represents a reactive molecule that reacts with ROS, yielding peroxynitrite. We thus verified the effect of NO on ROS‐induced HSCs proliferationin vitroand correlated iNOS expression and ROS formation to HSCs activation in the early phase of liver injury leading to hepatic fibrosisin vivo.Methods/Results: HSCs were incubated with iron ascorbate (FeAsc)in vitro, which induced ROS production, ERK1/2 phosphorylation and increased cell proliferation. This effect was significantly reduced by the presence of the NO donor S‐nitroso‐N‐acetylpenicillamine. Liver injury was inducedin vivoin rats by dimethylnitrosamine administration. HSCs activation started 6 h after DMN administration and peaked at 1 week. ROS generation and neutrophil infiltration were evident for at least 48 h after DMN treatment, showing an identical distribution pattern. Only a few inflammatory cells expressed iNOS 6 h after DMN administration.Conclusions:we have shown that NO acts as a ROS scavengerin vitro, thus inhibiting HSCs proliferation. ROS production by infiltrating neutrophils occurs in the early phase of liver fibrosis and can represent a stimulus to HSCs activationin vivo. The reduced iNOS expression may account for the low NO levels and the inability to prevent the ROS‐induced HSC activationin vivo.
Large‐needle biopsy versus thin‐needle biopsy in diagnostic pathology of liver diseases
Authors: Röcken C. , Meier H. , Klauck S. , Wolff S. , Malfertheiner P. , Roessner A.
Published: March 2003

Abstract: Background/Aims: A study was carried out to determine whether thin‐needle biopsy (TNB) yields enough material to study diffuse liver diseases. Methods: Using TNB (20G and 21G) and a conventional Menghini‐type large‐needle biopsy (LNB; 17G), the amounts of tissue obtained and the histopathological diagnoses were compared. The biopsies were obtained by surgeons with a several‐stroke method (17GS) and by physicians with a single‐strike method (17GP , 20GP , 21GP). A total of 343 biopsy specimens from 258 patients were included in the study. Results. A comparison of the mean values for the length of the core biopsy, as well as the mean numbers of portal tracts and terminal hepatic veins among the four groups showed significant differences (p<0.001): the mean number of portal tracts obtained with 17GS was 13.8±6.5, with 17GP it was 9.7±5.9, with 20GP it was 6.7±4.4, and with 21GP it was 4.0±3.1. A comparison of the histopathological diagnoses showed no major differences between 17GP and 20GP; the diversity and frequencies of the diagnoses were similar. Conclusion: We suggest that the use of TNB, particularly 20G‐size needles, could be extended to the investigation of diffuse liver diseases in which LNB carries a high risk of complications or is contraindicated, and when the diagnosis is the primary reason for the biopsy rather than grading or staging of a known diffuse disease.
Involvement of platelet‐activating factor in hepatic apoptosis and necrosis in chronic ethanol‐fed rats given endotoxin
Authors: Murohisa Gou , Kobayashi Yoshimasa , Kawasaki Tsunehisa , Nakamura Satoshi , Nakamura Hirotoshi
Published: March 2003

Abstract: Background/Aims: Platelet‐activating factor (PAF)—a potent activator of neutrophils—plays an important role in the pathogenesis of endotoxin‐induced tissue injury. However, the role of PAF in hepatic damage during alcoholic hepatitis remains unclear. The aims of the present study were to test whether PAF contributes to hepatic injury in an animal model of alcoholic hepatitis and to investigate the involvement of the Fas‐receptor/Fas‐ligand system in this process. Methods: Male Sprague–Dawley rats were pair‐fed with Lieber–DeCarli ethanol liquid diet or isocaloric control diet for 6 weeks. Liver injury was induced by the intravenous (i.v.) injection of lipopolysaccharide (LPS) (1 mg/kg). Rats were pretreated with a specific PAF receptor antagonist (TCV‐309; 100 mg/kg i.v.) or vehicle 1 h before LPS treatment. Results: Chronic ethanol administration remarkably sensitized the rats to the effects of LPS, with resultant severe hepatocellular injury, accompanied by significant increases in serum levels of alanine aminotransferase (ALT), tumour necrosis factor (TNF)‐α and interleukin (IL)‐8 (CINC/gro). Histological examination of the damaged livers showed hepatocyte apoptosis and necrosis with extensive infiltration by neutrophils, whereas immunohistochemical studies revealed enhanced Fas‐receptor expression on hepatocytes and hepatic accumulation of neutrophils expressing Fas‐ligand. Pretreatment with the PAF receptor antagonist protected against hepatic injury, suppressing hepatocyte apoptosis and necrosis, infiltration of neutrophils, expression of Fas‐receptor and Fas‐ligand, and serum TNF‐α levels. Conclusions: Our study suggests that PAF is an important mediator of hepatic injury in the ethanol/endotoxin model of alcoholic hepatitis.
Characterization of CD4+ T helper cell fine specificity to the envelope glycoproteins of simian immunodeficiency virus
Authors: Sarkar S. , Kalia V. , Murphey‐Corb M. , Montelaro R.C.
Published: March 2003

Abstract: Virus‐specific CD4+ T cells (Th) play a crucial role in the control of lentiviral replication. To better understand the epitope‐specificity of CD4+ Th repertoire to the envelope glycoprotein (Env) of simian immunodeficiency virus (SIV), we analyzed Th responses to 20‐mer overlapping Env peptides in eight genetically heterogeneous macaques chronically infected with live attenuated SIV. A set of 19 ‘broadly reactive’ Th peptide‐epitopes was defined from the distinct sets of responder peptides for individual macaques. The majority of broadly reactive peptide‐epitopes (14 of 19) were uniformly distributed on the transmembrane (TM) domain of Env. Only five broadly reactive responder peptides localized to the surface domain (SU) of Env, and they were all confined to two non‐glycosylated regions towards its carboxyl‐terminus. This first comprehensive report of Env peptide‐specific Th responses associated with attenuated SIV vaccine immunity indicates a profound influence of glycosylation on the development of Th responses and has important implications for acquired immunodeficiency syndrome (AIDS) vaccine development.
Long life for high amperage cells
Authors: Øye Harald A.
Published: March 2003

All aluminium smelters try to raise their productivity either by increasing their amperage on existing design or designing high‐amperage cells. This will usually mean modification of the materials used in the cell that may influence cell life. This paper discusses the advantages and problems with raising cell amperage.