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Introduction La chirurgie bariatrique s’est beaucoup developpee en France ces quinze dernieres annees avec la necessite de chirurgie revisionnelle dans certains cas (echec de perte de poids, complications..). Cependant, peu de donnees nationales sont disponibles a ce sujet. Cet observatoire national vise a dresser un etat des lieux descriptif de la chirurgie de revision apres chirurgie bariatrique en France. Methodes Il s’agit d’une etude retrospective nationale issue et constituee a partir des donnees du Systeme national des donnees de sante (SNDS). Tous les patients operes d’une chirurgie bariatrique de premiere intention entre le 01-01-2012 et le 31-12-2014 et suivis jusqu’au 31-12-2017 ont ete inclus. Il s’agit ici des premiers resultats descriptifs. Resultats Entre 2012 et 2014, 112 809 patients ont ete operes d’une chirurgie bariatrique de premiere intention (N = 33 103 en 2012, N = 37 979 en 2013, N = 41 727 en 2014): âge moyen de 40,4 ans ± 11,9 (2,1 % âges de moins de 20 ans et 5,6 % âges de 60 ans ou plus), 81,7 % de femmes, 69,4 % avec un IMC ≥ 40 kg/m2. Pendant la periode de suivi, 4,5 % des patients (N = 5120) ont ensuite ete reoperes une premiere fois, 0,1 % (N = 123) une deuxieme fois et 4 patients une troisieme fois. Le taux de reprise est tres variable selon la technique employee en premiere intention: 15,6 % (2449/15 671) de patients apres AGA, 3,6 % (2323/64 361) apres SG/GVC, 1,8 % (4/226) apres DBP ± SD et 1,1 % (344/32 551) apres BPG. La reprise apres AGA et SG cumules represente 93,2 % (4772/5120) de l’ensemble des reinterventions. Pour les patients operes pour la premiere fois en 2012 (beneficiant pour plus de 90 % d’entre eux d’une periode de suivi de cinq ans minimum), en considerant un suivi constant censure a cinq annees apres la chirurgie initiale, le delai median entre les deux interventions etait de 35,3 mois. Conclusion Le taux de chirurgie revisionnelle apres chirurgie bariatrique en France est non negligeable et constituee essentiellement de reprise apres AGA et SG.

Innate lymphoid cells (ILC) play a fundamental role in mucosal homeostasis and immunity via expression of cytokines such as IL-22, IL-17A and IFN-γ. However, the transcriptional network that controls ILC functional identity is incompletely defined. Previously, we demonstrated that BCL6 plays a key role in transcriptional regulation in mouse intestinal ILC1 and ILC3. Here, we performed in vitro cultures of ILCs isolated from human tonsil in the presence of cytokines that promote ILC1 or ILC3 in order to assess the role of BCL6 in functional plasticity of ILCs. ILCs were treated with IL-2 and IL-12/IL-1β or IL-23/IL-1β in the presence or absence of the BCL6 inhibitor FX-1. In the context of IL-12/IL-1β ILC1-promoting culture, FX-1 inhibition of BCL6 reduced expression of Tbet and IFN-γ. In contrast, BCL6 inhibition in the context of IL-23/IL-1β ILC3-inducing conditions had no effect on Tbet, IFN-γ, or RORγt. In either context, FX-1 resulted in reduced IL-22 but increased IL-17A expression in comparison to vehicle treated cultures. Thus, our data emphasizes the role of BCL6 as a regulator of human tonsil ILC functional identity.

Atopic dermatitis (AD) is a common chronic inflammatory disease associated with skin barrier dysfunction. AD often precedes the development of atopic co-morbidities, including food allergy, asthma and allergic rhinitis. The contributions of natural killer (NK) cells to pathogenesis of AD and progression to allergic disease are unclear. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples collected from n=82 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma (MPAACH) study, a cohort of toddlers with AD. The children underwent skin prick testing to 11 aeroallergens and 6 foods, and wheezing was defined as one or more episodes of wheezing in the past 12 months. We used flow cytometry to evaluate the phenotype of NK cells in patient PBMC from MPAACH subjects. Our analyses revealed that CD56brightNK cells derived from sensitized children expressed significantly less NKG2D (73.8 ± 3.0 % versus 82.3 ± 2.7 %, respectively, p=0.020) and more TIM-3 (440 ± 462 versus 353 ± 391 median fluorescence intensity, respectively, p=0.085) compared to non-sensitized children. Increased expression of TIM-3 on CD56neg NK cells was also associated with wheezing (47.5 ± 0.51 % versus 19.2 ± 0.40 %, p=0.020). Collectively, these observations suggest that changes within the NK-cell repertoire may promote progressive development of AD and atopic co-morbidities in early life.

Asthma encompasses a spectrum of chronic respiratory symptoms, generally associated with aberrant expression of type 2 cytokines. As many as 10% of patients are classified as having severe asthma, characterized by poor control of disease symptoms and a paradoxical mixed milieu of both type 2 (IL-4 and IL-33) and type 1 (IFN-γ) cytokines. The source of IFN-g and mechanisms driving expression of this cytokine, which can exacerbate airway hyper-responsiveness, remain poorly defined. Here, we show that in human NK-cell cultures, combined IL-4 and IL-33 stimulation triggers high expression levels of IFN-g, even in the absence of STAT4 activation by prototypical type 1 stimuli like IL-12. At picomolar concentrations, IL-4 enhanced the expression of eomesodermin (Eomes), a critical transcription factor for IFN-γ expression. We performed anti-Eomes ChIP-seq in NK cells, generating a high-quality genome-wide map of Eomes binding with robust peak counts, strong overlap with T cell datasets, and strong enrichment for the Eomes DNA binding motif. These data support a model in which Eomes interacts with the IFNG locus to promote enhanced IFNG expression in NK cells. We also performed ATAC-seq and ChIP-seq following IL-4/IL-33 stimulation to reveal changes in chromatin accessibility and Eomes binding resulting from cytokine exposure. Collectively, our results reveal a novel pathway of IFN-γ induction in type 2 diseases that could contribute to exacerbated pulmonary dysfunction in severe asthma.

Group 3 innate lymphoid cells (ILC3) are critical for intestinal homeostasis. The functional activity of ILC3 must be tightly regulated as cytokines (e.g. IL-17 and IL-22) produced by these cells are critical for antimicrobial immune defense but can also contribute to intestinal disease when produced in excess. This regulation is achieved via incompletely defined transcriptional networks that include B-cell lymphoma 6 (BCL6), which we recently demonstrated is critical for maintaining ILC1- and ILC3-specific gene expression programs during homeostasis (Pokrovskii et al 2019). We now show that Bcl6-deficient small intestine lamina propria ILC3 exhibit elevated expression of the transcription factors retinoic acid receptor-related orphan nuclear receptor alpha (RORα) and RORγt. These factors are known to support ILC3 cytokine expression, potentially explaining elevated Il17a and Il17f expression by Bcl6-deficient ILC3. Of note, expression of Il22ra2 (IL-22 binding) was also markedly increased in these ILC3, likely limiting bioavailability of IL-22. Accordingly, these mice exhibit marked reduction in IL-22-dependent expression of epithelium-associated anti-microbial peptides in the terminal ileum. Of note, Bcl6ΔILC mice exhibited augmented susceptibility to dextran sodium sulfate-induced inflammatory bowel disease. Thus, BCL6 expression in ILC3-intrinsic BCL6 expression is important for mucosal immune defense and limiting intestinal inflammation.

Objective:To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2–fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals.Methods:On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)–infected; (4) HIV-infected; (5) healthy volunteers.Results:LME was detected in 56/254 non-MS cases (22%) vs 74/299 (25%) of MS cases. LME was nearly 4-fold more frequent in non-MS inflammatory neurologic conditions (18/51 cases, 35%) than in noninflammatory neurologic conditions (3/38, 8%) and healthy volunteers (5/66, 8%). The highest prevalence of LME was detected in HTLV infection (17/38 cases, 45%), particularly in the setting of HTLV-associated myelopathy (14/25 cases, 56%). LME also frequently occurred in HIV infection (13/61 cases, 21%). Unlike in MS, LME is not associated with lower brain and cortical volumes in non-MS inflammatory neurologic conditions, including HTLV and HIV infection.Conclusions:Despite its relevance to MS pathogenesis and cortical pathology, LME is not specific to MS, occurring frequently in non-MS inflammatory neurologic conditions and especially in those patients with HTLV-associated myelopathy. Overall, this strengthens the notion that LME localizes inflammation-related focal disruption of the blood–meninges barrier and associated scarring.

Background Brain- and lesion-volumes derived from magnetic resonance images (MRI) serve as important imaging markers of disease progression in neurodegenerative diseases and aging. While manual segmentation of these volumes is both tedious and impractical in large cohorts of subjects, automated segmentation methods often fail in accurate segmentation of brains with severe atrophy or high lesion loads. The purpose of this study was to develop an atlas-free brain Classification using DErivative-based Features (C-DEF), which utilizes all scans that may be acquired during the course of a routine MRI study at any center. Methods Proton-density, T2-weighted, T1-weighted, brain-free water, 3D FLAIR, 3D T2-weighted, and 3D T2*-weighted images, collected routinely on patients with neuroinflammatory diseases at the NIH, were used to optimize the C-DEF algorithm on healthy volunteers and HIV + subjects (cohort 1). First, manually marked lesions and eroded FreeSurfer brain segmentation masks (compiled into gray and white matter, globus pallidus, CSF labels) were used in training. Next, the optimized C-DEF was applied on a separate cohort of HIV + subjects (cohort two), and the results were compared with that of FreeSurfer and Lesion-TOADS. Finally, C-DEF segmentation was evaluated on subjects clinically diagnosed with various other neurological diseases (cohort three). Results C-DEF algorithm was optimized using leave-one-out cross validation on five healthy subjects (age 36 ± 11 years), and five subjects infected with HIV (age 57 ± 2.6 years) in cohort one. The optimized C-DEF algorithm outperformed FreeSurfer and Lesion-TOADS segmentation in 49 other subjects infected with HIV (cohort two, age 54 ± 6 years) in qualitative and quantitative comparisons. Although trained only on HIV brains, sensitivity to detect lesions using C-DEF increased by 45% in HTLV-I-associated myelopathy/tropical spastic paraparesis (n = 5; age 58 ± 7 years), 33% in multiple sclerosis (n = 5; 42 ± 9 years old), and 4% in subjects with polymorphism of the cytotoxic T-lymphocyte-associated protein 4 gene (n = 5; age 24 ± 12 years) compared to Lesion-TOADS. Conclusion C-DEF outperformed other segmentation algorithms in the various neurological diseases explored herein, especially in lesion segmentation. While the results reported are from routine images acquired at the NIH, the algorithm can be easily trained and optimized for any set of contrasts and protocols for wider application. We are currently exploring various technical aspects of optimal implementation of CDEF in a clinical setting and evaluating a larger cohort of patients with other neurological diseases. Improving the accuracy of brain segmentation methodology will help better understand the relationship of imaging abnormalities to clinical and neuropsychological markers in disease.

Interleukin-33 (IL-33) promotes type 2 cytokine responses in CD4 T cells, granulocytes, and innate immune lymphocytes. Although type 1 (IL-12) and type 2 (IL-33) cytokines are classically thought to counterbalance one another, a combination of IL-12 and IL-33 paradoxically promotes profound expression of type 1 effector cytokines, interferon gamma (IFN-γ), tumor necrosis alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-SCF), when administered to human natural killer (NK) cells. Mechanistically, IL-33 stimulates potent mitogen-activated protein kinase (MAPK) p38 in human NK cells, but has no impact on IL-12-induced signal transducer and activator of transcription 4 (STAT4) phosphorylation. Importantly, pharmacological inhibition of p38 MAPK significantly reduced IFN-γ and TNF-α release by IL-12 and IL-33 stimulated NK cells. Even in the absence of IL-12, IL-33 could synergize with other type 2 cytokines like IL-27 or IL-4 to trigger high expression levels of IFN-γ. The altered sensitivity of NK cells to type 1 and 2 cytokines in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, including cases of severe asthma exacerbated by respiratory viral infection.

The analysis of 182 selected anti-B cell sera on 102 cells allowed us to identifysseveral clusters of sera. They showed no correlation with HLA-A, B or C specificities but many associations with the HLA-D determinants. In 10 families, most of these sera segregated with HLA, and five recombinants showed a linkage with the BD or D end part of the MHC. The panel distribution and the family analysis indicated that at least one (the Ly-Li system) and probably two segregant series could exist close to the HLA-D locus.

Conference of 13th International Conference on Industrial Informatics, INDIN 2015 ; Conference Date: 22 July 2015 Through 24 July 2015; Conference Code:116400; International audience; Hypervision is being widely implemented in an effort to control costs and to simplify management through consolidation of servers. It has been recently unraveled that well over a third of virtualization vulnerabilities reside in the hyper-visor, mostly due to hypervisor escape. The exploitation of these vulnerabilities allows an attacker, among other things, to access and/or modify data of other Virtual Machines (VMs) by escaping from its VM and executing malicious code in the hypervisor. This paper introduces the general idea of blind hypervision, a hardware/software co-design to prevent such attackers to access private elements of other VMs. Blind hypervision limits the rights of the hypervisor regarding memory access, so that a malicious agent executing with hypervisor rights cannot access the data of the VMs.

Persistent viral infections in mice (e.g. lymphocytic choriomeningitis virus, LCMV) and humans (e.g. HIV, hepatitis C virus) are characterized by chronic inflammation. This sustained inflammatory milieu promotes T cell exhaustion, which limits harmful tissue damage but prevents effective viral control. We found that natural killer (NK) cells aid in the establishment of this tolerogenic state through cytolytic elimination of antiviral T cells. In parallel, others shown that chronic infection encourages expansion of immunoregulatory IL-10-expressing myeloid cells and bona fide myeloid-derived suppressor cells (MDSCs) that contribute to T cell inhibition immune exhaustion and cell injury. We now report that depletion of NK cells prior to persistent infection with the clone 13 strain of LCMV abrogates the expansion of immunosuppressive myeloid cells. In the absence of NK cells, the levels of myelo-stimulatory cytokines, including TNF-a, MCP-1, and IL-6 were also reduced. Furthermore, frequencies of myeloid precursor cells were reduced in the bone marrow during infection in the absence of NK cells. Our results suggest that NK cells support an inflammatory milieu promoting expansion of the myeloid niche and specifically suppressive myeloid cells during chronic infection. This cross-talk between NK cells and myeloid cells during inflammation has the potential to contribute to immune dysfunction during both chronic infection and in cancer.

Natural killer (NK) cells are critical producers of IFN-g and mediators of cytotoxicity in response to type 1 inflammatory cytokine (e.g. IL-12) rich environments. Conventional thinking therefore holds that type 2 cytokines (e.g. IL-4 and IL-13) that counter production of IL-12 would inhibit NK cell effector functions and thereby limit the antiviral role of NK cells. In contrast, IL-4 unexpectedly synergized with IL-12 to enhance IFN-g production by mouse NK cells. We now extend this observation to human NK cells, where we find that stimulation with either IL-4 or IL-13 resulted in dose-dependent enhancement of IFN-g and TNF-a expression in response to IL-12. Neither IL-4 nor IL-13 stimulated IFN-g release in the absence of IL-12, suggesting that these type 2 cytokines modulate IL-12 signaling or NK cell responsiveness to IL-12. In contrast to the effect of IL-4 on IL-12 responsiveness, IL-4 (but not IL-13) markedly reduced the expression of IFN-g and TNF-a by human NK cells following engagement of the natural cytotoxicity receptor, NKp46. Likewise, IL-4-treated NK cells demonstrated reduced cytotoxicity towards K562 cells. Our results reveal that IL-4 and IL-13 modulate NK cells in a complex manner, enhancing responsiveness to inflammatory cytokines like IL-12 while diminishing activation via natural cytotoxicity receptors. We speculate that this could have important consequences for NK cell lysis of eosinophils, IFN-g-mediated airway hyperresponsiveness, and other features of allergic or asthmatic diseases associated with aberrant type 2 cytokine production.

HMGB1 is involved in pathologies such as cellular injury and autoimmunity. Indeed, upon binding to immune-related receptors, HMGB1 promotes an inflammatory response, such as that might take part in pancreatic islet destruction during both autoimmune diabetes and islet transplant rejection. Specifically, elevated circulating HMGB1 levels were reported in patients with type 1 diabetes, and increased release of HMGB1 was found to correlate with injury degree and islet allograft survival. The anti-inflammatory and immune-modulatory acute-phase protein human α1-antitrypsin (hAAT) promotes islet survival in both transplantation and autoimmune diabetes models. While AAT binds to damage-released proteins, such as gp96 and HSP70, its tissue protective mechanism remains poorly understood. We now extend this observation that AAT protective activity is related to its interaction with HMGB1. Clinical-grade AAT (Glassia, Kamada Ltd., Israel), diminished recombinant HMGB1-induced inflammatory responses in mouse pancreatic islets (while restoring disrupted insulin inflammation-mediated release). Similar behavior was depicted in HMGB1-stimulated peritoneal macrophages introduced to hAAT. In addition, hAAT modulated HMGB1-inducible surface expression by altering its distribution. Lastly, we show by immunoprecipitation that HMGB1 associated proteins was positive for the presence of AAT, this is also supported by a direct ELISA. Our findings suggest that hAAT is a naturally-occurring regulator of inflammatory responses mediated by extracellular HMGB1, such that preclude outcomes of islet transplantation. hAAT may therefore be considered for therapy of cell damage-mediated pathologies in a clinically-safe manner.

Numerous studies suggest that immune function may be compromised by lipid emulsions rich in polyunsaturated fatty acids, especially linoleic acid. In our study, we compared the effect of a new olive oil-based lipid emulsion (ClinOleic(R)) containing 18% linoleic acid, and an emulsion based on soybean oil (Ivelip(R); 52% linoleic acid) on lymphocyte functions. Weaning Wistar rats (n= 24) were fed for 4 weeks on an oral diet that contained 12% of total energy as lipids from soybean oil. Then they received, during 6 days, a total parenteral nutrition (260 kcal/kg/d) in which 12% of total energy was brought by one of the two lipid emulsions. The fatty acid profile of spleen lymphocyte phospholipids reflected lipid intakes, with a higher content of oleic acid in ClinOleic(R) group and linoleic acid in Ivelip(R) group. A greater proportion of cells expressed the interleukin-2 receptor a-chain (CD25) after administration of ClinOleic(R) when compared to Ivelip(R) (55.43 +/- 3.47 vs 45.48 +/- 3.26%, P<< 0.05). Moreover, the CD25 expression was positively correlated with oleic acid content of spleen lymphocyte phospholipids (r= 0.500, P<< 0.018). These results show that ClinOleic(R) is able to induce, in vivo, a greater proportion of cells expressing CD25, and suggest that oleic acid could have a role in the observed effects.

The heterotopic heart of rats has been a useful model in the evaluation of immunomodulatory protocols. Graft palpation usually determines the day of rejection. We present in this paper an original method of graft monitoring in allograft rejection.Heterotopic cardiac abdominal transplantation was performed in Lewis isografts (n = 15) and in ACI to Lewis allograft (n = 15). A balloon connected to a measurement device was inserted in the left ventricle, and calculation of Dp/Dtmax was possible by recording the intra-left ventricular pressure. A ten-day follow-up was achieved with a daily comparison of palaption, ECG, and Dp/Dtmax.In transplanted hearts, Dp/Dtmax did not change in isografts but significantly decreased in allograft on posttransplantation Day 5 (PTD 5) vs PTD 0.1 and 3 (p.01). Dp/Dtmax values on PTD 5 and 6 were also statistically significant in allograft vs isograft group (p.01). Histological analysis at this time showed the occurrence of acute rejection in the allograft group. Graft palpation, and ECG remained normal until PTD 10 and no difference was observed between iso and allo groups.This study shows that daily measurement of Dp/Dtmax in heterotopic heart is made possible by our implantable system without interrupting the graft, and gives a more accurate definition of graft rejection than a combination of palpation and ECG. In addition, this method would seem desirable when differences in survival may be expected to be of lesser magnitude.

A confinement experiment in a normobaric diving chamber was undertaken to better understand the effect of confinement and isolation on human psychology and physiology. Pre- and postconfinement blood samples were obtained from four test subjects and control donors to analyze immune responses. No modification in the levels of CD2+, CD3+, CD4+, CD8+, CD19+, and CD56+ cells was observed after confinement. Mitogen-induced T-lymphocyte proliferation and interleukin-2 receptor expression were not altered significantly. Whole blood interferon-alpha and gamma-induction and plasma cortisol levels were also unchanged, as was natural killer cell activity. These data suggest that in humans, no specific components of the immune response are affected by a 2-month isolation and confinement of a small group.

we report here some preliminary results of a study concerning basic physical and metallurgical processes involved in laser-shock treatment of materials.This laser shock processing consists of the use of a high power pulsed 248 nm excimer laser to generate a short duration, high amplitude pressure which propagates inside various metallic samples, aluminium, titanium and iron alloys.Pressure measurements on the rear side of the sample have been obtained in direct ablation and water-confined plasma regimes.Experimental results are compared with an analytical model.Surface hardness, in-depth residual stresses and fatigue tests have to be compared in both the interaction regimes.

Using apparatus available in any laboratory we developed a semiautomated kinetic technique for complement activity assay. Hemolysis of sensitized red blood cells is performed in the thermostated microflow cell of a spectrophotometer connected to a computer. The computer controls, displays on the screen, and analyzes all the different phases of the assay. After definition of optimal operating conditions, we compared the results obtained by this technique and by Kabat and Mayer's. On 221 patients' sera the regression coefficient was 0.94. The values for samples deficient in one fraction or after in vitro activation were very similar. The coefficient of variation was close to 1% for within series studies and better than 3% between series. This technique is very easy to perform even in a routine nonspecialized laboratory and up to 30-40 sample/h can be tested.

The existing estimates of the recombination fraction between DR and DP are quite variable and often based on anecdotal observations. We have estimated the DR/DP crossover frequency on the basis of families typed for HLA markers and GLD. The frequency of DR/GLO crossing over was 8.7% (23/264 informative meioses), maternal recombinations being about twice as frequent as paternal ones. Of 17 DR/GLO recombinant families typed for DPwl-6, DP was informative in 11 (13 recombinations) but only one of these gave rise to a DR/DP crossover. According to these data the DR/DP recombination fraction is below I%, in contrast to some earlier published materials. HLA-DR/DP haplotypic associations on 127 informative Caucasoid haplotypes have been evaluated. In agreement with previous studies, DR3 was positively associated with DPwl and, in addition, DR7 was found to be positively associated with DP-blank (not DPwl-6). The rare DPw6 allele is possibly associated with the DR4, Dw14 allele. The DR-DP haplotype profiles suggest other associations which might become significant if larger materials are tested. The frequency of DP alleles in a random material (N = 201) was found to be in accordance with most of the previously published frequences on European Cauca-soids with DPw4 as the predominating frequency (gene frequency 40%) and a blank frequency of 21%.

Adrenal medullary tissue including chromaffin cells was grafted intrathecally in cancer patients to relieve intractable pain. The central nervous system (CNS) is considered an immune privileged site. Therefore, non-HLA-matched and unencapsulated tissue was grafted in 15 patients and 1 sham control in a series of at least 20 grafts. We observed an increase in CSF lymphocyte counts in 15/20 allografts (75%). In contrast to peripheral blood, CD4 T cells predominated in the CSF, but failed to exhibit an activated phenotype (CD25+ CD45RO+ HLA-DR+). The positive effect of graft on pain, the high met-enkephalin levels, the absence of any increase in CSF cytokine levels particularly for IFN-γ or IL-2 (but not IL-10 and IL-6), indirectly indicated that the graft was tolerated despite the presence of CSF lymphocytes. The single treatment failure and three of four cases of partial efficacy occurred in grafts where CSF lymphocytes were present. Moreover, when assayed (n = 7), the CD4+ CSF lymphocytes still retained the capacity to exhibit ex vivo a normal or enhanced frequency of T CD4 cells producing IFN-γ and IL-2. Taken together, our observations indicate that impairment of the local immunosuppressive balance can lead to activation of those CSF CD4 T cells and drive a rejection process. This study suggests further work on the purification and/or the immunoisolation of tissues grafted in the CNS will be necessary, particularly when the possibility of long-term and repeated grafting is considered.

Recent multicenter, randomized clinical trials have shown that in renal transplant patients tacrolimus (FK506) was more efficient than cyclosporine A (CsA) at preventing acute rejection. In order to try and evaluate whether this difference was related to a different in vivo T-cell suppression we assessed, in a prospective study, the frequencies of interleukin (IL)-2-, IL-4-, IL-5-, IL-6-, IL-10-, interferon-gamma (IFN-gamma)- and double-positive IL-2/IFN-gamma-producing whole T cells, CD4 + and CD8 + T-cell subsets by means of cytokine flow cytometry. This was performed after in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol myristate acetate (PMA) and ionomycin, in the presence of monensin, in 14 healthy volunteers (controls) and in 14 renal transplant patients. The immunosuppression of the latter was based either on CsA (n = 7) or on FK506 (n = 7). Cytokine-expressing T-cell frequencies were assessed immediately pretransplantation (DO), and subsequently 3 months (M3) and 6 months (M6) afterwards in fasting patients prior to the morning intake of the immunosuppressive drug. We found that at DO the frequencies of IL-2-(22 +/- 2% vs. 22.2 +/- 2%), IFN-gamma-(26 +/- 3% vs. 29 + 3.4%) and IL-4-(0.8 +/- 0.2% vs. 1.4 +/- 0.2%)-expressing T lymphocytes were not significantly different between the controls and the patients, respectively. Conversely, the frequency of IL-2/IFN-gamma double positive cells was higher in the latter (9.3 +/- 1.6%) than in the controls (5.6 +/- 0.8); p = 0.06. Finally, on D0 the frequencies of IL-5-, IL-6-, and IL-10-producing T lymphocytes were lower than 1%, in both groups, as well as after grafting, i.e. on M3 and M6. As compared to baseline (DO): (a) chronic immunosuppression significantly decreased the frequencies of IL-2-, IL-4- and IL-2/IFN-gamma-expressing T cells, whereas those of IFN-gamma, IL-5, IL-6, and IL-10 were not significantly affected; (b) the frequencies of cytokine-expressing T cells were not statistically different between M3 and M6; (c) the decrease in the frequencies of IL-2- and IL-2/IFN-gamma-expressing T cells affected CD4 + and CD8 + cells equally; (d) there was a marginal decrease in the frequency of IFN-gamma-expressing cells only in the CD4 + subset but not in the CD8 population; and (e) for CsA, but not for FK506, the frequency of the IL-2-expressing T cells was negatively correlated with the whole blood trough levels. When we compared the frequencies of cytokine-expressing cells in FK506- and CsA-treated patients, we found that the frequency of IL-2-expressing T cells was significantly lower with FK506 (10.9+/-1.61%) than with CsA (16.3 +/- 1.8%; p = 0.03), whereas the frequencies of the other cytokine-expressing cells were not statistically different between the two groups. In conclusion, our study clearly demonstrated that studied ex vivo, FK506 and CsA decrease the frequencies of cells expressing IL-2, IL-4 and IL-2/IFN-gamma in vivo but do not affect those expressing IFN-gamma. Meanwhile, the frequency of IL-2-producing T cells was more affected with FK506 than with CsA and was negatively correlated with the CsA trough level. Finally, our results regarding IL-2 might explain to some extent the higher efficiency of FK506 in vivo than CsA.

We confirm here the CD43 specificity of the CBF.78 monoclonal antibody (mAb) and compare its phenotypic and functional capacities to classical group-A mAbs (DFT1, MEM-59) and to 2 other CD43 mAbs (RDP/AD9, 161-46). It reacts with stable human CD43 transfectants in a sialic acid independent way and blocks completely cell binding of RDP/AD9 or 161-46 more or less but not DFT1 and MEM-59. Its distribution differs from all other CD43. B lymphocytes, but surprisingly the majority of granulocytes or monocytes are CBF.78 negative. CBF.78 is expressed on all T lymphocytes, but the number of CBF.78 molecules/cell is low and equally represented on resting T CD4 and CD8 cells. In comparison to naive T lymphocytes, CD45RO cells increase their CBF.78 epitopes much more than other CD43 epitopes. At a single cell level, confocal microscopy shows that CBF.78 can exist independently of other epitopes. CBF.78 is able to induce homotypic adhesion in different cell lines but not in peripheral blood lymphocytes and is unable to relocalise the targeted molecules. U937 cell line that is not agglutinated by CBF.78 (or RDP/AD9) undergoes a stronger adhesion with PMA, when this reagent is combined with this mAb. By itself CBF.78 is unable to activate T lymphocytes and to costimulate CD3 mAbs but partially blocks PMA. The phosphorylation of the tyrosine kinase p59fyn and p56lck, driven by CBF.78, is weak and almost blocked by PMA. Altogether these data support the hypothesis that there are at least 3 modes of interaction between PKC and CD43 pathways: each pathway is inhibitory towards the other but the CD43 one can also be synergistic.

Presence of HLA-DR4, rheumatoid factor, and antikeratin antibody may predict severe rheumatoid arthritis.To investigate potential associations between HLA DR4, rheumatoid factor and antikeratin antibody in rheumatoid arthritis patients.Retrospective review of 169 patients followed at the Rangueil Teaching Hospital rheumatology department for rheumatoid arthritis.No differences in prevalences of DR4 and DR1 were found between patients with and without rheumatoid factor or between patients with and without antikeratin antibody, suggesting that the production of rheumatoid factor and/or antikeratin antibody is not dependent on genetic factors. Substantial overlap was seen between rheumatoid factor and antikeratin antibody. All three parameters can be identified at first evaluation of a patient with joint disease.It would be of interest to evaluate the cumulative predictive value of DR4 or DR1, rheumatoid factor and antikeratin antibody at disease onset.

GRAFTS of adrenal medulla tissue or chromaffin cells have been proposed for the treatment of Parkinson's disease and chronic pain.1,2 It has been shown that transplanted chromaffin cells can release analgesic neuroactive substances, including catecholamines, opioid peptides, metenkephalin, somatostatin, and so on.3,4 The subarachnoid space is a favored site for the allograft since the phenomenon of immunologic privilege is classically related to the central nervous system (CNS).5 Despite this privilege phenomenon, grafts implanted in the CNS are not always tolerated, although the frequency of rejection is lower, for example, than that for skin-grafting.6 The course of the local cellular immunologic response following the transplantation of xenogeneic or allogeneic grafts into the CNS have generally been followed in animal models. Few studies have been reported in this area on humans. Our study was carried out in an attempt to identify the cellular immune response in the cerebrospinal fluid (CSF) after intrathecal grafts of chromaffin cells recovered from brain dead donors for the treatment of chronic pain in end-stage cancer patients. Our study took place between June 1993 and April 1996, with the consent of the Regional Ethical Committee and the Regional People Protection Committee, Toulouse I, in accordance with French Bioethics Law. This study population comprised 12 end-stage cancer patients; 10 had received one graft only, and a second graft had been performed in 2 patients. All the patients experienced chronic cancer-related pain which had been treated orally first and then by intrathecally-administered morphine prior the start of the study. The intrathecally-administered morphine continued for the duration of the study. A very short course of cyclosporin was given during the first 2 weeks following the transplantation. This immunosuppressive treatment commenced on the day the graft was performed (day 0).

HLA class I and II antigen frequencies were determined in two large cohorts of children with idiopathic nephrotic syndrome (NS) from Southwest France (n = 199) and Southwest Germany (n = 152) and compared with unrelated healthy individuals from the same geographical areas. Strength of HLA association was expressed by the relative risk (RR) estimated by Odd's ratio. We examined 105 steroid-resistant and 242 steroid-sensitive NS patients who were subdivided in non-relapsers, infrequent relapsers and frequent relapsers or steroid-dependent patients. In steroid-sensitive patients significant associations were found with HLA-DR7 (RR 5.1 in French, 3.2 in Germans), -DQ2 (RR 4.7/2.3) and with the phenotypic combination HLA-DR3/DR7 (RR 5.6/7.7). Significant negative associations were encountered with HLA-DR2, -DR6 and -DQ1. The associations were stronger in frequent relapsers/steroid-dependent patients than in infrequent relapsers and were not significant in non-relapsers. In steroid-resistant patients the only significant association found was with the combined occurrence of HLA-DR3/DR7. We propose that in childhood NS tissue typing for selected HLA class II antigens is helpful in prediciting the clinical course.

Adrenal medullary chromaffin cells produce high levels of endogenous opioid peptides. Recent data suggest that transplantation injected locally into the spinal subarachnoid space reduced intractable malignant pain. In order to determine the feasibility, the efficacy and the risks of using adrenal medullary tissue for control of irreducible pain, we have developed a transplantation protocol on cancer pain patients selected when they required chronic intrathecal injection of morphine and progressively increasing doses to maintain the level of analgesic effects. At the present time, our clinical trial involves 8 patients. We report here our initial results (mean follow-up: 5 months). The various data collected before and after the intrathecal administration of chromaffin cells included: 1) Pain evaluation over time, with concomitant narcotic intake, 2) CSF sampling through an implanted access port to determine the following biological parameters: biochemical assay for opioid peptides, cell count and phenotyping of lymphocytes, 3) peripheral blood samples for lymphocyte typing. The results confirm the efficacy of adrenal medullary transplantation into spinal CSF for controlling irreducible cancer pain. Complementary intrathecal and oral morphine were totally stopped in 2 cases and stabilized in 5 others. It seems essential to have an important volume of grafted tissue to achieve analgesia with high levels of metenkephalin in CSF. A progressive decrease in metenkephalin release was observed from 2 to 4 months after the transplantation. Two patients with a long-term follow-up (8 and 12 months) needed another intrathecal chromaffin cell graft.

We report characterization of CD45 isoforms expressed by CD8+ lymphocytes in peripheral blood and in the graft of 40 kidney transplanted patients who underwent kidney biopsy on the basis of clinical signs suggesting rejection. Standard histological examination of the biopsy fragments and three-color cytofluorimetric analysis of lymphocytes extracted from the same fragments by mechanical and enzymatic treatment were performed simultaneously and compared to the peripheral blood lymphocytes. In 14/40 biopsies where lymphocyte extraction succeeded, the predominant subset was CD8 (CD4/CD8 mean ratio was 0.53). Almost all CD8+ cells were activated: among these CD8+ cells, 55 percent were HLA-DR+, and 68 percent CD45RO+, i.e. of a memory cell type with cytotoxic activity. This situation resembles the in vitro observation made during mitogenic stimulation of lymphocytes by phytohemagglutinin, OKT3 or CML ("culture mixte lymphocytaire"). Beside their evident interest for the diagnosis, these data could be useful for our understanding of the physiopathology of the rejection crisis.

In 1990, 1,949 renal transplantations were performed in France, with a graft survival rate of 89% at one year and 70% at five years. To improve on these results it would be necessary to pursue a dynamic policy in all fields of transplantation: in view of the ever growing number of patients on the transplantation list, more kidneys should be collected; hyperimmunized recipients should undergo reinforced exchanges to have compatible kidneys; immunosuppression must be optimized: just a using cyclosporin and monoclonal antibodies has resulted in a significant advance, so should the discovery of new drugs, such as FK 506, or of more specific monoclonal antibodies, be a source of progress; the complications of immunosuppression must be controlled: prevention protocols and antiviral treatments have considerably reduced the incidence of viral infections. The emergence of malignant tumours directly related to the degree of immunosuppression can be prevented by a rational use of immunosuppressants and by systematic detection. All these advances make it possible to extend the indications of renal transplantation to subjects at risk, notably patients more than 60 years old, and diabetic patients who can successfully benefit from a dual kidney-pancreas transplantation.

Study of the HLA-B grouping of 193 patients with psoriatic arthropathy (PA), compared with that of a control series consisting of 2,706 healthy subjects representative of the French population, revealed a statistically significant link between PA and antigens B27, B17 and B16. In contrast to reported findings of earlier studies, the authors found no link between an HLA-B antigen and any particular topographical or anatomical form of PA. Antigen B27 was not statistically significantly linked with axial forms of PA nor did it protect against peripheral forms. There were neither more cases of peripheral involvement nor less of axial involvement among non-B27 PA patients. The only statistically significant link which could be shown was that between antigen B27 and sacroiliac involvement in recent PA, present for less than 10 years. The authors conclude that in 60 per cent of cases, PA is associated with a particular antigen: B16, B17 or B27. Involvement of the sacroiliac joints is more common in cases of B27 PA and above all occurs earlier than in others. Regardless of its HLA group, PA as it progresses shows an increasingly clear mixture of spinal, peripheral and sacroiliac lesions, which forms the basis of the originality of this condition.

The Basques were previously shown to present a high frequency of HLA-B18 and BfF1, which are known to be associated with insulin dependent diabetes mellitus (IDDM). During the VIII International Histocompatibility Workshop, we studied HLA-A, B, C, DR; Bf, C4 and GLO.I polymorphisms in 51 unrelated French Basque IDDM patients and in 50 controls. Haplotypes were established by family studies in all controls and some patients. Two haplotypes were frequently found in the controls: HLA-A1, Bw57, BfS, C4 F1S, DR7 and HLA-Aw30, Cw5, B18, Bf F1, C4Fs degree, DR3. The first one was not found in the patients. All the components of the second haplotype had increased frequencies possibly as a consequence of linkage disequilibrium with HLA-DR3: a highly significant association between IDDM and HLA-DR3 was observed (90.2% vs 24.0%, relative risk (RR) = 29.1, P less than 10(-11)). The HLA-DR4 frequency was slightly increased (37.3% vs 16.0%), and HLA-DR2 was not found. The silent allele C4s degree was particularly associated with early diagnosed IDDM (86.7% in patients with age at onset under 20 years vs 57.1% in other patients, P less than 0.02). The high relative risk for HLA-DR3/DR4 heterozygous vs that of individuals, possibly HLA-DR3 homozygous, supported the hypothesis that two HLA-DR linked genetic factors could be involved in the inheritance of IDDM susceptibility.

In the genetically homogeneous Danish population, 27 HLA-DR3,4 heterozygous patients with insulin-dependent diabetes mellitus (IDDM) and 19 DR3,4 heterozygous controls without family history of IDDM were investigated for HLA-region markers and Gm and Km immunoglobulin allotypes. The aim was to define susceptibility factors for IDDM development other than HLA-DR using a number of techniques: lymphocytotoxicity (HLA-DR and DQ antigens), cellular methods (Dw and DP typing), restriction fragment length polymorphism (DQ alleles), electrophoresis and immunofixation (BF and C4 allotypes), and passive hemagglutination inhibition (Gm and Km immunoglobulin allotypes). The complement allotype C4A3 and the HLA-DQw8 (DQw3.2) antigen were found in all of the patients, whereas this was the case for only 8 of the 19 controls (P=6 x 10−6): five lacked C4A3, five others lacked DQw8, and one of the controls lacked both of these factors. Fourteen of the patients had the complement allotype C4B3 versus three of the controls (P=0.01). Previously reported family studies suggest that these alleles are part of the following haplotype: B15, BFS, C4A3, C4B3, DR4, Dw4, DQw8, and these factors were found together in ten of the patients versus one of the controls (P=0.01). The markers usually associated with DR3 did not show significant differences between IDDM patients and controls, and the non-HLA markers studied showed no significant deviation from what was expected. In addition to the susceptibility factor DQw8, the study suggests the existence of susceptibility genes for IDDM near the complement C4 genes on DR4-carrying haplotypes. Since recent works have shown that the structural gene for the monokine tumor necrosis factor alpha (TNF-α) is located between the HLA-B and C4 loci and that TNF-α might be of importance in IDDM pathogenesis, the hypothesis is put forward that the C4-associated IDDM susceptibility reflects linkage dis-equilibrium between the C4 gene and a gene controlling TNF-α production. The high relative risk for IDDM in HLA-DR3,4 heterozygotes might be explained by the combined action of IDDM-specific susceptibility genes on DR4 haplotypes and DR3-linked susceptibility genes associated with predisposition to autoimmunity.

Using a leucocyte migration test (Clausen's direct agarose gel migration method) hypersensitivity to human encephalitogenic protein has been examined in 50 multiple sclerosis patients (group 1), 50 healthy persons (group 2) and 25 patients with other neurological diseases (group 3). In group 1, 30 MS patients (60%) show an abnormal migration index, manifested either as inhibition or stimulation of migration; 29 controls in group 2 (58%), 11 O.N.D. patients in group 3 (44%) show an abnormal migration index. These results mean that lymphocyte hypersensitivity to myelin basic protein appears neither to be constant nor specific to multiple sclerosis. Three migration index curve types at different antigen concentration are obtained: monophasic curves within the normal index zones; monophasic curves staying in the inhibition or stimulation zone and biphasic curves with dose-effect relationship. Whatever the antigen used, this dose-effect relationship implies that the test must be carried out at different concentrations. The meaning of spontaneous sensitisation in healthy controls is discussed.

Resume Les auteurs comparent les diverses methodes actuelles de depistage des anticorps d'histocompatibilite. Leur experience porte sur pres de 2000 titrages. La leuco-agglutination sur sang preleve sur sequestrene est la methode qui permet d'obtenir le plus grand nombre de resultats positifs. Chez les polytransfuses, il parait necessaire d'associer plusieurs methodes.

Resume Les resultats de notre experimentation nous paraissent mettre en lumiere deux notions. La premiere concerne la specificite de la formation des rosettes et les rapports existant entre la production des CFR et celle des anticorps seriques. La seconde, d'ordre plus pratique, a trait a la possibilite de mettre en evidence, au moment ou il se produit, un processus immunitaire actif chez certains sujets : affections auto-immunes, femmes enceintes immunisees contre le facteur Rh.

We report the study of a serum from a polytransfused patient, that contains an anti-HL-A8 antibody reacting by the platelet complement fixation microtechnique. The specificity is confirmed by a study on a panel of 112 different platelets and by experiments of absorption-elution on platelets, lymphocytes and granulocytes.

Fourteen HLA-A and 18 HLA-B antigens were studied in three samples of Pyrenean populations: 198 unrelated individuals of a “Pays Basque” group; 212 non-Basque individuals from a valley in Beam, l'Ouzom; and 73 non-Basque individuals from the neighboring valley of Bareges. The results in the Basque and the non-Basque people from l'Ouzom were comparable: the gene frequencies of HLA-A29, Aw19.2, B17 were increased and the haplotypes HLA - Aw 19.2, B18; A29, B12; A2, B5; Al, B17 were found frequently with a striking linkage disequilibrium; HLA-B18 had an increased gene frequency in all these Pyrenean populations, while Bw35 was frequent in l'Ouzom and Bareges, but not among the Basques. The characteristics of Bareges were very different: the gene frequencies of HLA-A2, All, B7 were increased while the frequency of HLA-B5 was low; the most characteristic haplotypes were HLA-A2, B12; A2, B18; All, Bw35; All, B27. It is interesting to note discrepancies between ethnic and HLA classification of the Basques and the non-Basque population of l'Ouzom. The HLA characteristics are quite different in the Bareges sample, more closely resembling those of Northern Europe.