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Introduction Les inhibiteurs de point de controle immunitaire (ICIs) ont considerablement change ces dernieres annees le pronostic de nombreuses neoplasies. Ces traitements peuvent induire des toxicites graves, comme la myocardite, la myasthenie et la myosite. Ces dernieres sont d’ailleurs souvent intriquees. Au cours de ces toxicites, les anticorps anti-recepteurs de acethyl-choline (anti-RAch), hautement specifiques des myasthenies hors ICIs, peuvent etre positifs. Leur signification clinique ou pronostique, n’est pas claire. L’objectif de cette etude etait de decrire le profil clinique et biologique des patients presentant une myosite induite par ICIs avec anti-RAch positifs et de les comparer avec ceux testes anti-RAch negatifs. Patients et methodes Etude monocentrique retrospective menee entre 2018 et 2021. Tous les patients anti-RAch positifs etant des hommes, il etait decide de n’inclure que les patients masculins anti-RAch negatifs de notre cohorte. Le diagnostic de myosite etait retenu d’apres les donnees histologiques musculaires (10/12 cas) ou devant l’association myalgies + augmentation CPK + EMG et imagerie musculaire positifs. Comme signes clinique evocateurs de myasthenie on retenait la presence d’au moins un signe parmi dysphonie, dysphagie, diplopie et/ou ptosis. Une myocardite etait definie et classee en certaine, probable ou possible, selon des criteres cliniques, biologiques et morphologiques en vigueur (Bonaca MP, 2019). Les anti-RAch et les anti-Musk etaient systematiquement recherches par methode ELISA. Resultats 12 hommes etaient inclus. L’âge au moment du diagnostic etait de 73 ans (50-87). Les traitements par ICIs instaures etaient : Nivolumab seul (n = 4), Nivolumab +Ipilimumab (n = 3), Pembrolizumab (n = 3), Cemiplimab (n = 1) et Avelumab (n = 1), pour melanome (n = 9), carcinome epidermoide cutane (n = 1), carcinome renal (n = 1) et carcinome de Merkel (n = 1). Le nombre median de cure a la constatation de la toxicite etait de 1 cure (1-3) avec un delai median 3 semaines (2-6). Les anti-RAch etaient positifs chez 5/12 patients, les anti-Musk toujours negatifs. Groupe anti-RAch positifs : d’apres nos criteres, 3/5 patients presentaient des signes cliniques evocateurs de myasthenie. Aucune fatigabilite n’etait notifiee, un decrement n’etait retrouve a l’electromyogramme que dans 1/5 cas. A noter que les anti-RAch etaient presents dans le serum de 2/2 patients testes avant l’instauration du traitement par ICIs. Comparaison des groupes anti-RAch positifs vs anti-RAch negatifs : aucune difference significative n’etait retrouvee en terme de severite de l’atteinte musculaire (testing MRC median 4 (3-5) vs 5 (3-5)), d’atteinte axiale ou diaphragmatique (2 cas vs 2), d’augmentation des CPK (7 N vs 8 N, p = 0,87). Les signes evocateurs de myasthenie etaient en frequence similaire : dysphonie (2 cas vs 2), dysphagie (2 cas vs 3), diplopie (2 cas vs 1) ou ptosis (0 cas vs 3). Bien que plus frequente dans le groupe anti-RAch positifs (3 cas vs 1) la survenue d’une myocardite probable ou certaine etait similaire (p = 0,22). De meme, le recours a une unite de soins intensif etait plus frequente dans le groupe anti-RAch positifs (4 cas vs 1), sans que l’effectif ne permette de conclure (p = 0,07). La prise en charge therapeutique etait similaire dans les deux groupes. Les ICI ont ete arretes ou suspendus chez tous les patients. Selon la gravite initiale, les patients recevaient tous des corticoides, en bolus intra-veineux (n = 5) meme lorsque les anti-RAch revenait positifs a posteriori (n = 3). 2 patients avec anti-RAch positifs recevaient initialement l’adjonction d’un immunomodulateur (Abatacept ou IVIg), comme un patient avec anti-RAch negatifs (IVIg). La duree de traitement par corticoides (suivi median 255 jours, 60-800) etait similaire dans les deux groupes : 3 mois vs 3 (2-7). Deux patients recemment pris en charge etaient en remission partielle a 1 mois, alors que la corticotherapie orale etait en deroissance. Conclusion La positivite des anti-Rach n’est pas rare au cours des myosites induites par les ICIs, ce qui doit inciter a les rechercher systematiquement. Ils ne semblent pas associes a un profil clinico-biologique ou pronostique particulier, notamment en terme de signes cliniques evocateurs de myasthenie. Toutefois d’autres etudes comparatives sont necessaires afin de mieux cerner le profil clinique de ces patients, notamment en terme de severite globale, et d’assurer une prise en charge et un suivi cible. La recherche des autres anticorps rencontres au cours des myasthenies, notamment ceux qui ne sont pas recherches en routine comme les anti-LRP4 meriterait d’etre systematique a des fins nosologiques rigoureuses. Certaines donnees de la litterature (Mammen AL, 2019) et le fait que les anti-RAch etaient positifs dans le serum de 2/2 patients testes avant le traitement par ICIs, suggerent la possibilite d’un role de ces anticorps dans la genese de ces myosites induites par les ICIs.

Introduction et but de l’etude Le LADA (Latent Autoimmune Diabetes of Adult onset) est defini comme un diabete survenant apres 30 ans avec presence de marqueurs d’auto-immunite specifiques du diabete de type 1 (GAD, IA2 ou ZnT8) mais n’ayant pas necessite d’insulinotherapie pendant au moins 6 mois suivant le diagnostic. Il a ete montre que la prevalence du LADA en Europe est d’environ 5 a 12 % dans des cohortes de patients adultes diagnostiques diabetiques de type 2 (DT2) [1] . La chirurgie bariatrique est de plus en plus utilisee comme traitement du DT2. En France, 10 a 15 % des patients operes de chirurgie de l’obesite sont diabetiques [2] . La remission du diabete est observee a court terme chez une grande majorite des patients operes de chirurgie (75 %) mais elle diminue avec le temps (10–40 % a 5 ans). Une serie de cas de “diabetes refractaires a la chirurgie” publiee dans Diabetes Care avait montre qu’un des patients resistants traite par insulinotherapie presentait une forte positivite des antiGAD en faveur d’un LADA [3] . Finalement la prevalence du LADA n’a jamais ete a notre connaissance recherchee chez ces patients obeses diabetiques candidats a une chirurgie bariatrique. Materiel et methodes Deux cent six patients consecutifs obeses severes, diabetiques et candidats a une chirurgie bariatrique ont ete inclus. Des donnees biocliniques, le type de chirurgie envisagee et le dosage des anticorps anti GAD et IA2 ont ete collectes de facon systematique et prospective. Les patients presentant un diabete de type 1 candidats a la chirurgie bariatrique ont ete exclus de cette cohorte. Resultats et analyse statistique Nous avons retrouve une prevalence des autoanticorps anti GAD et/ou IA2 chez 10 % des 206 patients obeses severes et diabetiques de type 2 soit un taux equivalent a la prevalence classiquement rapportee du LADA dans le DT2. Les patients presentant une auto-immunite sont significativement plus jeunes que les patients sans marqueurs d’auto-immunite (46 ans versus 52 ans, p Conclusion Nos donnees confirment que la prevalence d’une autoimmunite specifique de la cellule beta-pancreatique est importante chez des patients diabetiques de type 2 obeses severes candidats a une chirurgie bariatrique. L’obesite severe de ces patients aurait pu laisser penser une moindre prevalence, le LADA etant classiquement associe a un IMC plus bas et un âge jeune dans le DT2. Le devenir de ces DT2 avec presence d’antiGAD et/ou IA2 apres chirurgie bariatrique est pour le moment inconnu mais il nous parait important de rechercher ces marqueurs d’autoimmunite de facon systematique en preoperatoire pour pouvoir a l’avenir identifier leur valeur predictive notamment sur la duree de la remission du diabete.

After a steady increase between the 1950s and the 1970s, laryngeal cancer mortality has been levelling off since the early 1980s in men from most western and southern European countries and since the early 1990s in central and eastern Europe. To update trends in laryngeal cancer mortality, we analyzed data provided by the World Health Organization over the last two decades for 34 European countries and the European Union (EU) as a whole. For major European countries, we also identified significant changes in trends between 1980 and 2012 using joinpoint regression analysis. Male mortality in the EU was approximately constant between 1980 and 1991 (annual percent change, APC=-0.5%) and declined by 3.3% per year in 1991-2012. EU age-standardized (world population) rates were 4.7/100,000 in 1990-91 and 2.5/100,000 in 2010-2011. Rates declined in most European countries, particularly over the last two decades. In 2010-11, the highest male rates were in Hungary, the Republic of Moldova, and Romania (over 6/100,000), and the lowest ones in Finland, Norway, Sweden, and Switzerland (below 1/100,000). In EU women, mortality was stable around 0.29/100,000 between 1980 and 1994 and slightly decreased thereafter (APC=-1.3%; 0.23/100,000 in 2000-01). We also considered male incidence trends for nine European countries or cancer registration areas. In most of them, declines were observed over recent decades. Laryngeal cancer mortality thus showed favourable trends over the last few decades in most Europe, following favourable changes in tobacco and, mostly for Mediterranean countries, alcohol consumption. What's new? The study quantifies the favourable trends of laryngeal cancer mortality in most European countries over the last few decades, following reduction in tobacco and, for Mediterranean countries, alcohol consumption.

Summary Insulin-dependent (type 1) diabetes is a prototypic organ-specific autoimmune disease resulting from the selective destruction of insulin-secreting β cells within pancreatic islets of Langerhans by an immune-mediated inflammation involving autoreactive CD4+ and CD8+ T lymphocytes which infiltrate pancreatic islets. Current treatment is substitutive, i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycaemia) and lack of effectiveness over the long term in preventing severe degenerative complications. Finding a cure for autoimmune diabetes by establishing effective immune-based therapies is a real medical health challenge, as the disease incidence increases steadily in industrialized countries. As the disease affects mainly children and young adults, any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity. Thus, inducing or restoring immune tolerance to target autoantigens, controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens, appears to be the ideal approach. Our objective is to review the major progress accomplished over the last 20 years towards that aim. In addition, we would like to present another interesting possibility to access new preventive strategies based on the ‘hygiene hypothesis’, which proposes a causal link between the increasing incidence of autoimmune diseases, including diabetes, and the decrease of the infectious burden. The underlying rationale is to identify microbial-derived compounds mediating the protective activity of infections which could be developed therapeutically.

Opportunism and specialization appear to be widespread in apoid wasps, although the factors affecting the diet preference (and thus explaining the degree of specialization) are still largely unknown. Four hypotheses that stressed the importance of the size, sex, habitat, and taxonomic identity of prey of the beetle-hunting digger wasp, Cerceris rubida, were formulated and tested. The wasp population hunted for phytophagous beetles belonging to abundant families around the wasp nesting site. In practice, the prey appeared to be hunted only in two cultivated fields, thus habitat accounted for a majority of the observed diet. The size of wasps was furthermore correlated with the size of their prey, and thus this also accounted for the frequencies of hunted prey and the strong individual specialization for both taxa and size. However, in the exploited habitat, some species were significantly over-hunted than expected and some other significantly avoided by the wasps, causing an unexpected major role of prey taxon on the probability of being hunted, over the other explanatory variables (body size, body shape, sex, availability). This contrasts to that found in other wasp species, which appear to select prey basing essentially on their ecology and size or their relative abundance (opportunism). The results obtained in the present study show that even an apparent 'generalist' predator may turn out to be taxonomically specialized. Together with a re-evaluation of previous studies, our results further suggest that the effect of size constraints and the developmental plan of prey (holometaboulous versus hemimetabolous) may have promoted either taxonomic opportunism or specialization in different lineages of apoid wasps. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 99, 544-558. ADDITIONAL KEYWORDS: biological traits - individual selection - provisioning - resource use.

Resume Introduction La chimiokine CXCL10 induite par l’interferon γ serait impliquee dans la physiopathologie de la pneumopathie interstitielle diffuse (PID) de la sclerodermie systemique (ScS). L’objectif de cette etude etait d’evaluer les taux seriques de CXCL10 chez des patients ayant une ScS. Methodes CXCL10 a ete dosee par methode Elisa dans le serum de 23 volontaires sains (mediane : 60,0 ans ; 58,0–67,3) et 29 patients atteints de ScS (63,1 ans ; 60,1–69,4). Ces derniers ont egalement eu des explorations fonctionnelles respiratoires, un examen tomodensitometrique du thorax et une echographie cardiaque. Les taux de CXCL10 (mediane et interquartile 25–75 %) ont ete compares entre patients et volontaires sains, et entre patients avec et sans PID. Resultats Les patients avaient un taux serique median de CXCL10 plus eleve que les volontaires sains (110,0 pg/ml ; 60,8–223,8 pg/ml contre 52,0 pg/ml ; 41,3–65,8 ; p Conclusion Ces resultats montrent l’implication de CXCL10 dans la physiopathologie de la ScS et suggerent plus particulierement une relation a la PID rencontree au cours de cette maladie.

Although therapeutic advancements have made Hodgkin's lymphoma (HL) a largely curable disease, trends in HL mortality have been variable across countries. To provide updated information on HL mortality in the Americas, overall and 20-44 years age-standardized (world population) mortality rates from HL were derived for the 12 Latin American countries providing valid data to the World Health Organization database and with more than two million of inhabitants. For comparative purpose, data for the United States and Canada were also presented. Trends in mortality over the 1997 to 2008 period are based on joinpoint regression analysis. Declines in HL mortality were registered in all Latin American countries except in Venezuela. In most recent years, HL mortality had fallen to about 0.3/100,000 men and 0.2/100,000 women in Argentina, Brazil, Chile, Colombia, Ecuador and Guatemala, that is, to values similar to North America. Despite some declines, rates remained high in Cuba (1/100,000 men and 0.7/100,000 women), Costa Rica and Mexico as well as in Venezuela (between 0.5 and 0.6/100,000 men and between 0.3 and 0.5/100,000 women). In young adults, trends were more favorable in all Latin American countries except Cuba, whose rates remained exceedingly high (0.8/100,000 men and 0.6/100,000 women). Thus, appreciable declines in HL mortality were observed in most Latin America over the last decade, and several major countries reached values comparable to North America. Substantial excess mortality was still observed in Cuba, Costa Rica, Mexico and Venezuela, calling for urgent interventions to improve HL management in these countries. What's new? Mortality from Hodgkin's lymphoma differs between developed and less-developed regions of the world, with mortality rates having declined markedly in the former but less so in the latter. In this study of Hodgkin's lymphoma mortality in 12 Latin American countries, selected based on population size and completeness of mortality data, appreciable declines were registered for the period 1997-2008 in most of the countries assessed, with rates reaching those observed in North America. However, substantial excesses remained in Cuba, Mexico, and Venezuela, calling for urgent intervention in these middle-income countries. Copyright

Cytokines play a role in alopecia areata. We used immunohistochemical and in situ hybridization studies to demonstrate the persistence of pro-inflammatory as well as apoptotic mechanisms in skin biopsies from patients with chronic alopecia areata. In situ hybridization allows the visualization of the distribution of immunocompetent cells in vivo. We studied skin biopsies from 11 untreated alopecia areata patients and two normal controls. In situ hybridization was performed on frozen sections using 35S-radio-labeled riboprobes, specific for IL-1beta, IL-2, IL-6, INFgamma, and granzyme B mRNA. Immunohistochemistry was carried out using an anti-IL-1beta monoclonal antibody, and a monoclonal antibody directed against the human Fas protein. We demonstrated the presence of cells labeled with IL-1beta, IL-6, INFgamma, and granzyme B antisense probes. Similarly, cells labeled with anti-IL-1beta were found in 10 of 11 cases. The labeled cells were located in the mononuclear peri- and intrafollicular infiltrate. Cells expressing granzyme B were found in close contact with the follicle. Fas positivity was demonstrated in four of four cases at the level of the cytoplasmic membrane of the hair follicle keratinocytes. These results, based on visualizing the labeled cells, demonstrate that pro-inflammatory cytokines are produced by the mononuclear cell infiltrate in close contact with follicles in alopecia areata. Furthermore, they demonstrate for the first time that apoptotic mechanisms involving granzyme B and Fas-Fas ligand pathways may play a major role in the persistence of chronic alopecia areata.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

The objective of this study was to assess the association between alcohol drinking before and during pregnancy and the risk of spontaneous abortion using data from a case-control study conducted in Milan, Italy. A total of 462 women (median age 30 years) were admitted for spontaneous abortion (within the 12th week of gestation) to a network of obstetrics departments in the greater Milan area. Of these, 148 (32%) were between the fourth and the eighth week of gestation and 314 (68%) between the ninth and the 12th week. A control group was made up of 814 women (median age 29 years) who gave birth at term (> 37 weeks gestation) to healthy infants (Apgar 5th minute > or = 8, weight > or = 3000 g) on randomly selected days at the same hospitals where cases had been identified. A total of 212 cases (46%) and 355 controls (47%) reported alcohol drinking before conception. Considering non-drinkers as the reference category, the relative risks (RR) of spontaneous abortion were 1.2 [95% confidence interval (CI), 0.9-1.6] and 0.8 (95% CI, 0.6-1.1), respectively, in drinkers of one to seven and more than seven drinks per week before conception. No association emerged between the duration of alcohol drinking and the risk of spontaneous abortion. A total of 166 cases (35.9%) and 263 (32.3%) controls reported any alcohol drinking during the first trimester of pregnancy. The corresponding relative risk was 1.1 (95% CI, 0.9-1.4) and no relationship emerged between the number of drinks per week and the risk of abortion.(ABSTRACT TRUNCATED AT 250 WORDS)

CD3-specific monoclonal antibodies were the first rodent monoclonals introduced in clinical practice in the mid 1980s as approved immunosuppressants to prevent and treat organ allograft rejection. Since then compelling evidence has been accumulated to suggest that in addition to their immunosuppressive properties, CD3-specific antibodies can also afford inducing immune tolerance especially in the context of ongoing immune responses. Thus, they are highly effective at restoring self-tolerance in overt autoimmunity, a capacity first demonstrated in the experimental setting, which was recently transferred to the clinic with success.

CD3-specific monoclonal antibodies were the first rodent monoclonals introduced in clinical practice in the mid 1980s as approved immunosuppressants to prevent and treat organ allograft rejection. Since then compelling evidence has been accumulated to suggest that in addition to their immunosuppressive properties, CD3-specific antibodies can also afford inducing immune tolerance especially in the context of ongoing immune responses. Thus, they are highly effective at restoring self-tolerance in overt autoimmunity, a capacity first demonstrated in the experimental setting, which was recently transferred to the clinic with success.

Regulation of the immune response to self-antigens is a complex process that depends on maintaining self-tolerance while retaining the capacity to mount a robust immune response to foreign antigens. Autoreactive T cells specific for these autoantigens are present in most normal individuals but are kept under control by multiple diverse peripheral tolerance mechanisms. In the last few years, there has been a re-emergence of suppressor cells as among the most central of these regulatory mechanisms. These cells, which express CD4, CD25, and CD62L, develop in the thymus and survive in a CD28-dependent manner in the periphery to maintain the homeostatic equilibrium of immunity and tolerance. In this review, we will summarize studies of these regulatory cells as they relate to autoimmune diseases and more specifically to type 1 diabetes and attempt to address some of the many outstanding questions. Finally, evidence is provided to support the ability of anti-CD3 mAbs to stimulate the regulatory T cells and reset the rheostat of immune tolerance in an animal model of autoimmune diabetes, the NOD mouse.

Asthma is a major public health problem, with variable trends in several countries. We analysed mortality trends from asthma in Italy and Spain between 1980 and 1996. Overall asthma-related mortality at all ages increased between 1980 and 1987 in both sexes in Italy, from 16.6 in 1980-1981 to 29.0 in 1986-1987 per million males, and from 8.0 in 1980-1981 to 13.8 in 1986-1987 per million females, but decreased thereafter to reach 14.6 per million in males and 8.7 in females in 1996. The downward trends after 1987 were consistent in middle age and elderly population, but asthma mortality tended to rise in children and young adults over the last few years. In Spain, overall age-standardized mortality rates from asthma declined in men from 37.8 in 1980-1981 to 10.1 in 1996, and from 19.5 in 1980-1981 to 13.2 per million females in 1996. In women, the fall in mortality rates was smaller, and overall mortality was higher than in males since early 1990s. Trends of asthma mortality in Italy and Spain were favourable over the last decade.

Several studies reported data on the increased risk of erectile dysfunction (ED) in populations of diabetic men, but few presented data separately for Type 1 and Type 2 subjects. No comparison data for these diabetic subgroups are available with regard to risk factors for ED.Eligible for the study were men aged 20-69 years with a diagnosis of insulin-dependent (Type 1) or non-insulin-dependent (Type 2) diabetes who were observed on randomly selected days in 178 diabetes centres in Italy. Erectile dysfunction was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance.The study population consisted of 1383 Type 1 and 8373 Type 2 men. The prevalence of ED increased with age for both groups. After taking into account the effect of age Type 2 men (37/100 men) tend to report ED less frequently than Type 1 men (51/100 men). A significant positive relationship was reported between ED and poor metabolic control and smoking for both Type 1 and Type 2 men, whereas high body mass index (BMI) increased only the risk of ED in Type 1 cases.The study offers a quantitative estimate of the prevalence of ED and its main risk factors in Type 1 and Type 2 diabetic subgroups.

Objective: To investigate the relation between wine drinking and intake of selected indicator foods, which may vary in various populations. Design: Cross-sectional analysis of the comparison group of a case- control study. Setting: A network of teaching and general hospitals from six Italian areas. Subjects: 5642 control subjects (3261 females and 2381 males) aged 20‐74 y (median age 58 y), admitted for acute, non-neoplastic conditions unrelated to alcohol consumption. Participation rate was over 95%. Intervention: Trained interviewers collected information using a structured and validated questionnaire. The average intakes of selected food items were computed, together with the multivariate odds ratios (OR) of eating above the median of each food. Results: No appreciable difference in either sex for any food indicator considered (fruit, raw vegetables, cooked vegetables, salad and fish) was observed between abstainers, wine, and other alcoholic beverage drinkers. If anything, female wine drinkers reported less frequently high consumption of salad (ORa 0.8) and raw vegetables (ORa 0.8), both estimates being of borderline significance. Conclusions: In no instance did wine drinkers or mixed drinkers (who include a large proportion of wine drinkers, too) show an association with indicators of healthy diet. Sponsorship: Italian Association for Cancer Research, Milan, Italy. Descriptors: drinking patterns; wine intake; dietary habits; alcoholic beverages; alcohol intake; cross-sectional study; diet European Journal of Clinical Nutrition (2000) 54, 177‐179

The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts.We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes.None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection.These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.

The first administration of CD3 monoclonal antibodies, such as anti-human CD3 (OKT3), induces a massive release of several cytokines, including tumor necrosis factor alpha (TNF-alpha), interferon (IFN)-gamma, interleukin (IL)-2, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor.Cytokine levels in patient's sera were measured by specific ELISA. In vitro cultures were performed using OKT3-stimulated peripheral blood mononuclear cells and/or whole blood from patients and normal controls.Here we describe that OKT3 administration to human renal allograft recipients also leads to a significant release of IL-10. Contrasting with most OKT3-induced cytokines, such as TNF-alpha whose release is transient, IL-10 levels show a more progressive increase, they peak only by 4-8 hr after the first OKT3 injection and persist longer. Thus, significant IL-10 levels are still detectable at the time of the second and the third OKT3 injection. Administration of corticosteroids, 1 hr before the first OKT3 injection, significantly reduced both TNF-alpha and IL-10 release. Experiments were performed to evaluate the source(s) of IL-10 and its (their) influence on the initial T-cell activation. When stimulated in culture with soluble OKT3, the production of IL-10 was dependent on the cooperation between T lymphocytes and monocytes. It is important that, as assessed through the use of a specific neutralizing antibody, the endogenous IL-10 produced in the co-culture system exerted a negative feed-back on the release of the other pro-inflammatory CD3-induced cytokines, which was reproducible.These results are supportive of a major role of IL-10 in the down-modulation of the OKT3-triggered T-cell activation cascade.

A hospital-based case-control study was conducted in the Heilongjiang Province of northeast China between May 1993 and May 1995, A total of 129 histologically confirmed brain cancer cases (73 gliomas and 56 meningiomas) and 258 matched controls were interviewed in 6 major hospitals to examine the influence of dietary factors in developing brain cancer, Information was obtained about frequency of consumption of 57 food items. Odds ratios (ORs) were obtained from conditional logistic regression, including allowance for socio-demographic factors, alcohol, tobacco and total energy intake. Consumption of fresh vegetables (OR = 0.29 for the highest quartile compared with the lowest one), and specifically of Chinese cabbage and onion, fruit (OR = 0.15), fresh fish (OR = 0.38) and poultry (OR = 0.16) was inversely related to the risk of developing brain cancer. A protective effect was also seen for vitamin E intake, calcium and, although non-significantly, beta-carotene and vitamin C. Risk of brain cancer increased with consumption of salted vegetables (OR = 2.54) and salted fish. (C) 1999 Wiley-Liss, Inc.

Pathogenic autoreactive T lymphocytes are mediators of spontaneous insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is demonstrated by their capacity to transfer diabetes into syngeneic immunoincompetent recipients. In addition, especially in prediabetic NOD mice, peripheral CD4+ T lymphocytes were identified that are highly effective, in conventional mixing cotransfer experiments, at preventing disease transfer. The present data demonstrate that mature heat-stable Ag-TCR alpha beta+CD8-thymocytes from prediabetic NOD mice also express this inhibitory capacity. Selection using an L-selectin (CD62L)-specific Ab showed that TCR alpha/beta+CD4+CD62L+ thymocytes, emerging from the mainstream differentiation pathway, concentrate this ability to regulate autoreactive effectors. Compared with mature TCR alpha beta+CD8- thymocytes, significantly lower numbers of TCR alpha beta+CD4+CD62L+ were sufficient to achieve an efficient inhibition of disease transfer into NOD-scid recipients. This protective ability was potentiated following in vitro culture in the presence of IL-7. In contrast, TCR alpha beta+CD62L- thymocytes, highly enriched in class I-restricted NK T cells, were unable to influence diabetes transfer. Identical results were obtained using thymocytes that have been cultured in vitro for 4 days in the presence of IL-7. These results support the active role in NOD mice of a thymus-derived CD4+ subset that controls peripheral pathogenic autoimmune effectors.

Considerable progress has been made in the knowledge of the epidemiology of gestational trophoblastic disease (GTD) in the last few years. There are two main and widely known points related to this disease: its geographical distribution and the different frequency in the various classes of age. GTD is more frequent in South-East Asia, India and Africa, and is rare in European and North American populations. For example, in the United States, the frequency of GTD was 108 per 100,000 pregnancies in the 1970's. In Europe, particularly in Italy, frequencies are lower. In northern Italy, the frequency of hydatidiform mole, in the period 1979-1982, was equal to 62 per 100,000 pregnancies, but in Indonesia and in China, the reported rates were 993 and 667 per 100,000 pregnancies respectively. GTD disease is more frequent in the extreme classes of age (under 20 and over 40 years) and the risk may be more than 100 times greater over 50 years. Besides these risk factors, the possible role of both genetic (familiarity, blood groups) and environmental factors (diet, cigarette smoking, etc.) has been investigated on the onset of GTD. This paper reviews the epidemiologic knowledge on GTD.

The relationship between frequency of consumption of whole grain food and risk of selected neoplasms has been analysed using data from an integrated series of case-control studies conducted in northern Italy between 1983 and 1996. The overall dataset included the following incident, histologically confirmed neoplasms: oral cavity and pharynx 181, oesophagus 316, stomach 745, colon 828, rectum 498, liver 428, gallbladder 60, pancreas 362, larynx 242, breast 3,412, endometrium 750, ovary 971, prostate 127, bladder 431, kidney 190, thyroid 208, Hodgkin's disease 80, non-Hodgkin's lymphomas 200, multiple myelomas 120. Controls were 7,990 patients admitted to hospital for acute, non-neoplastic conditions, unrelated to long-term modifications in diet and neat likely to have been caused by tobacco or alcohol use. Odds ratios (OR) for subsequent scores (never/occasional/ frequent) of whole grain food consumption were derived after allowance for age, sex, education, smoking, alcohol intake and body mass index. High intake of whole grain foods consistently reduced risk of neoplasm at:all sites, except thyroid. The ORs for the highest category of consumption were 0.2-0.3 for upper digestive and respiratory tract neoplasms, 0.5 for stomach, colon and gallbladder, 0.7 for rectum, 0.6 for liver, 0.8 for pancreas and prostate, 0.9 for breast and endometrium, 0.6 for ovary, 0.4 for bladder and kidney, 1.3 for thyroid and around 0.5 for lymphomas and myeloma. The rests for trend in risks were significant for all neoplasms, except pancreas, endometrium, Hodgkin's disease and multiple myeloma. No significant heterogeneity was found across strata of age at diagnosis, sex, education, smoking habit, alcohol intake and body mass index. Thus, even in the absence of a univocal and satisfactory biological interpretation, the consistency of the patterns observed indicate that, in this population, higher frequency of whole grain food intake is an indicator of reduced risk of several neoplasms, (C) 1998 Wiley-Liss, Inc.

We conducted a randomized, double-blind, placebo-controlled, rising single-dose study to investigate the effects of recombinant human (rh) interleukin (IL) 10 in renal transplant patients who received OKT3 as induction therapy.Patients received 0.1 (n=6), 1 (n=6), or 10 microg/kg (n=3) rhIL-10 or placebo (n=6) intravenously 30 min before the first injection of 5 mg of OKT3. We monitored IL-10 serum levels, the effect of rhIL-10 on OKT3-induced cytokine production, clinical toxicity, and the incidence of immunization against OKT3.Serum IL-10 levels in the three experimental groups reached 0.8+/-0.2, 7.9+/-1.3, and 118.6+/-7.3 ng/ml (mean+/-SEM), respectively, 30 min after rhIL-10 injection. Peak plasma levels of tumor necrosis factor-alpha (TNF-alpha) were reduced from 2953+/-1599 pg/ml in patients injected with OKT3 and placebo to 447+/-155, 703+/-246, and 459+/-246 pg/ml in patients injected with 0.1, 1, and 10 microg/kg rhIL-10, respectively. Values for 24-hr TNF-alpha area under the curve decreased from 8988+/-3551 pg x hr/ml in control patients to 2284+/-494, 3950+/-955, and 2420+/-931 pg x hr/ml for the 0.1, 1, and 10 microg/kg rhIL-10 dose groups, respectively (P=0.045). There was also a trend toward reduced plasma levels of IL-2, IL-8, and interferon-gamma in rhIL-10-pretreated patients. Although none of the patients who received placebo or 0.1 or 1 microg/kg rhIL-10 developed an IgM antibody response directed against OKT3 during the first 10 days, this occurred in all three patients who received the highest rhIL-10 dose. In two of these patients, neutralization of OKT3 was associated with a reversible acute rejection episode.Pretreatment with doses of up to 1 microg/kg rhIL-10 is safe and reduces the release of TNF-alpha induced by OKT3. However, higher doses might promote early sensitization to OKT3.

Clusters of spontaneous abortion among video display terminal (VDT) users in North America and Canada in the late 1970s aroused suspicion about the potential risk of an association between VDT. exposure and pregnancy outcome. This case-control study considered the association between VDT use and the risk of miscarriage. Cases were 508 women admitted for spontaneous abortion to the Clinica Luigi Mangiagalli and a network of obstetric departments in the Milan area. Controls were 1,148 women who gave birth at term to healthy infants on randomly selected days at the same hospitals where cases were identified. No association emerged between VDT exposure and spontaneous abortion, the estimated odds ratio being 1.0 (95% CI: 0.8-1.2). This evidence agrees with studies conducted in different countries by various authors.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

We analysed the relationship between coffee and alcohol intake, smoking and risk of multiple pregnancies using data from a case-control study on risk factors for multiple births conducted in Italy. Cases were 133 women who delivered multiple births not related to treatment for infertility (33 monozygotic and 100 dizygotic twins). Controls were 395 women admitted for normal delivery at the same clinic where cases had been identified. The odds ratios (OR) of multiple pregnancy were 1.5[95% confidence interval (CI) 0.8-2.8] and 2.0 (95% CI 1.0-3.7) for women drinking respectively one to two or three or more cups of coffee per day in comparison with non-coffee drinkers. Considering separately dizygotic and monozygotic pregnancies, the estimated OR were respectively for women drinking three or more cups of coffee, 1.7 and 3.1 for dizygotic and monozygotic pregnancies. The risk of multiple pregnancy tended to be higher in women drinkingor= 15 alcohol drinks per week: in comparison with tea-totallers the estimated OR for drinkor = 15 glasses per week were 2.3 and 2.6 respectively for dizygotic and monozygotic pregnancies. Heavy smokers (or = 10 cigarettes per day) were at increased risk of multiple pregnancy: in comparison with never smokers, the estimated OR for multiple pregnancy was 1.6 (95% CI 0.9-2.7). Considering separately the two groups of multiple pregnancy, the OR of dizygotic and monozygotic pregnancy were 1.4 (95% CI 0.8-2.5) and 2.4 (95% CI 0.9-6.1) for women smokingor = 10 cigarettes/day, but the trend in risk with number of cigarettes smoked per day and duration of the habit was not significant.

Recent knowledge into the pathophysiological mechanisms mediating the immune abnormalities characteristic of end-stage renal disease (ESRD) has focused on the dual activation versus deficiency state of immunocompetent cells. Despite major advances in renal replacement therapy, notably hemodialysis, no significant improvement in the immune status of uremic patients has been achieved. After a brief review of the role of T cells and B cells in the normal immune response, the functional and phenotypic T and B cell abnormalities observed in uremic patients are presented. Special emphasis is placed on our recent findings indicating that these abnormalities are observed at an early stage in the course of chronic renal failure, worsen with the progression of uremia, and are exacerbated by the dialysis procedure. The previous hypotheses that could reconcile the so-called Janus-faced behavior of T cells in uremia are updated in light of the recent findings obtained in the search of therapeutic strategies that could counteract the impaired responsiveness of patients with ESRD to vaccination against hepatitis B virus. Perspectives of research aimed at elucidating the respective role of T helper cell subpopulations (Th1 and Th2) could contribute to understanding of the mechanisms of the multifaceted process of uremia-related immune dysregulation and of the rationale for possible immunointervention strategies.

We recently described a case of anaphylaxis occurring at the time of retreatment with OKT3 of a renal allograft recipient in whom, for the first time, high anti-OKT3 IgE levels were documented. This led us to examine a large series of sera from 181 OKT3-treated patients to better define the frequency of IgE sensitization, its fine specificity (anti-isotypic and/or anti-idiotypic) and its relation to the appearance of IgG anti-OKT3 antibodies (Abs). Six patients out of the 181 assayed have developed anti-OKT3 IgE Abs as detected by ELISA. The earliest time of appearance of IgE anti-OKT3 Abs was 10 days after starting OKT3 (range, 10-25). The IgE response peaked by day 18 (range, 11-35) and had usually disappeared at 3 months after treatment. A more careful dissection of the fine specificity of the IgE response revealed that three of the four patients tested had developed an exclusive anti-idiotypic response. In the last patient, an anti-isotypic component was present since anti-OKT3 IgE Abs also reacted with control IgG2a, IgG2b, and IgG3 monoclonal antibodies. Importantly, anti-OKT3 IgE Abs were only detected in heavily sensitized patients also showing high titers of IgG specific Abs by ELISA (or = 1/1000) as well as "blocking" anti-OKT3 antibodies, as assessed by immunofluorescence. We conclude that (1) exposure to OKT3 may lead to specific IgE sensitization that, however, only appears in about 38% of the patients; (2) IgE Abs mostly appear in patients also showing high levels of conventional IgG anti-OKT3 Abs including the presence of "blocking" anti-idiotypic Abs, and (3) IgE Abs may be directed to both idiotypic and isotypic determinants of the monoclonal antibody.

In the present study, we demonstrate that unresponsive spleen T cells from mice injected with a low dose of anti-CD3 mAb (single 10 micrograms i.v. injection) significantly inhibit Con A-induced proliferation of normal spleen cells. The induction of this phenomenon requires in vivo activation since spleen cells from mice injected with the F(ab')2 fragment of anti-CD3 mAb fail to promote it. Suppression of normal T cell proliferation is concomitant with increased expression of IL-2 receptor on spleen cells from anti-CD3-treated mice. It disappears within 3 days when IL-2R has returned to background levels. A normal proliferative response to Con A can be restored when high concentrations of IL-2 are added together with the "suppressor" cells. Taken together, these data support the notion that activated spleen cells from anti-CD3-injected mice exert their inhibitory effect by competing for the IL-2 generated during culture.

Hepatitis B virus (HBV) DNA sequences have been detected in leucocytes from HBV-infected individuals. The aim of this study was to assess the specificity of HBV for a special leucocyte subset in nine healthy chronic HBV carriers, nine HBs antigen-positive patients with chronic active hepatitis, 16 HBs antigen-negative haemophiliacs with HBc and/or HBs antibodies, and 10 patients with HBV-related systemic necrotizing vasculitis. HBV-DNA sequences were found by Southern blot hybridization in the leucocytes of 15 out of the 44 (34%) patients. The prevalence was not significantly different between the four groups. HBV-DNA was found in the CD4+ cells (9/11) as well as in the CD8+ cells (4/11), B cells (4/12) and monocytes (2/12). In conclusion, leucocytes, and particularly CD4+ lymphocytes, are frequently infected by HBV in patients with HBV serum markers.

The monoclonal antibody OKT3 is a potent immunosuppressant inducing both T-cell depletion and antigenic modulation of the CD3/T-cell receptor complex. CD3 + lymphocytes are cleared from the circulation within 1 hour of intravenous administration of OKT3. Periodic monitoring of remaining or reappearing CD3 + lymphocytes gauges the adequacy of OKT3 dosing and OKT3 consumption by anti-OKT3 antibodies. The maximum acceptable concentration of CD3 + lymphocytes for maintaining the effectiveness of OKT3 therapy remains controversial due to variable sensitivity of the methods used. Intravenously administered OKT3 has a half-life of approximately 18 hours and results in trough serum levels ranging from 500 to 1000 ng/ml in 3 to 4 days. The antibody response to OKT3 is oligoclonal, and both IgM and IgG antibodies to OKT3 may develop, showing restricted specificity; anti-isotypic and/or anti-idiotypic antibodies can be detected. The IgG anti-idiotypic antibodies are the ones that neutralize the therapeutic activity of OKT3, and their specific detection involves the use of an immunofluorescence method that tests their ability to block the binding of OKT3 to normal T cells. The production of OKT3 antibodies has been shown to be affected by concomitantly administered immunosuppressive agents. Studies have demonstrated that OKT3 can be successfully reused in allograft recipients who do not present anti-idiotypic blocking antibodies. The acute clinical syndrome regularly observed upon the first OKT3 injection is related to massive, although transient, release of several cytokines, which may be easily monitored with currently available radioimmunologic or immunoenzymatic tests.

Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical transplantation. They are potent inhibitors of immune function and may be administered in association with conventional immunosuppressive drugs. However, their use has been complicated by the severe clinical syndrome that invariably follows the first injections of the antibody. We have shown that this reaction relates to transient T cell activation, with production of a cohort cytokines. This in vivo activating effect is unique to anti-CD3 MoAbs. Furthermore, this property is highly monocyte-dependent, engaging Fc receptors, and thus varies according to the isotype of the administered MoAb. Another anti-T cell MoAb such as the BMA031 directed towards monomorphic determinants of the T cell receptor (TCR) does not promote such massive in vivo activation.