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The excellent results of Transplantation over the last decades have highlighted new challenges to be solved in the next years. (1) Modify the storage of harvested organs to improve their quality. (2) Modify strategies by taking into account the immunodeficiency in front of news infections like the one with Sars CoV-2. (3) Better understand the mechanisms of chronic rejection, in particular the role of innate immunity. (4) Rethink immunosuppressive strategies to prevent and to treat chronic rejections.

International audience; Primary antibody deficiency (PAD) is characterized by a defective immunoglobulin production and recurrent infections, mostly involving respiratory and gastrointestinal tracts. Chronic or recurrent diarrhea is reported in up to 23%. Campylobacter infection is a common cause of infectious diarrhea, reported in 1.2% to 7.5% of patients with common variable immunodefi-ciency (CVID), the most frequent PAD. The aim of this study was to describe Campylobacter infection in patients with PAD included in a large nationwide study and analyze factors associ-ated with susceptibility to this pathogen. The DEFI (DEFicit Immunitaire) study is an ongoing large cross-sectional French multicentric study of adults with PAD, with retrospective collection of clinical data. All patients with a history of bacteriologically documented Campylobacter infection were identified, and clinical data were collected for each episode. Factors associated with recurrent infection were assessed as oddsratio (OR) and 95% confidence interval (CI), calculated by means of simple regression analysis. In patients with available material, strains of each episode were characterized using molecular analysis and compared (Table E1, available in this article’s Online Repository at www.jaci-inpractice.org). A com-parison of immunodeficiency-related characteristics of patients with and without Campylobacter infection was performed in the homogeneous group of patients with CVID. The control group included patients with CVID from DEFI centers who confirmed that patients did not develop Campylobacter infection after enrollment (Figure E1, available in this article’s Online Repository at www.jaci-inpractice.org). After correction for multiple comparisons, P

Background Intravenous immunoglobulin (IVIg) reduces acute rejection episodes in kidney transplantation, but adverse events (AEs) are common. The aim of this study was to assess whether human IVIg enhances immunosuppressive effects without increasing AEs in the prevention of acute kidney graft rejection. Methods Patients receiving a second or third kidney graft were treated with standard immunosuppressant therapy with (n = 18) or without (n = 10) IVIg. The primary efficacy endpoint was biopsy-proven acute rejection (BPAR) rate at 3 months, and secondary endpoints included acute rejection rate at 12 months, intensity of rejection, and patient survival. Results Patients in the experimental arm received 3 infusions of IVIg. The BPAR rate decreased with IVIg versus standard immunosuppression alone over 12 months of follow-up. Experimental versus control rates of survival without BPAR were 94% versus 63% and 82% versus 63% at 3 and 12 months. The intensity of the acute rejection episodes (BANFF 97 grade) was similar between groups. One patient from each group died during the 12-month follow-up period. Treatment-emergent AEs were reported in 100% and 94.4% of the control and experimental arms. Most AEs were considered unrelated or unlikely to be related to treatment. Conclusions This study supports the efficacy and safety of IVIg in highly sensitized transplant patients for improving transplant rates and reducing graft rejection episodes.

International audience; BACKGROUND:In 2014, the European Society for Immune Deficiencies (ESID) revised the common variable immunodeficiency (CVID) diagnosis criteria by incorporating new clinical and biological markers. The new definition appeared more restrictive but had not yet been evaluated in a large cohort of patients.OBJECTIVE:The objective of this study was to evaluate the impact of this new definition in a large cohort of patients with primary hypogammaglobulinemia.METHODS:Evaluation of 3 different CVID definitions (ESID/Pan-American Group for Immunodeficiency [PAGID] 1999, ESID 2014, DEFI 2015) in 521 patients included in the French DEFI study with a diagnosis of primary hypogammaglobulinemia.RESULTS:Using the ESID/PAGID 1999 definition, 351 patients were classified as CVID. The new ESID 2014 definition excluded 62 (18%) patients. Most of them (n = 56; 90%) had a less severe disease, whereas 6 (10%) presented with a severe disease with major T-cell defect. We propose different criteria (occurrence of opportunistic infection or very low naive CD4+ T-cell count) to define this population with severe T-cell defect. Sixty-two patients fulfilled these criteria, represented 20% of the initial CVID population but accounted for 77% of the deaths, with a 5-year overall survival of 67.6% (95% confidence interval, 51.0-79.6), and were considered as late onset combined immunodeficiency (LOCID).CONCLUSIONS:The new ESID definition for CVID still fails to exclude a large number of patients with severe T-cell defect. We propose a new definition (DEFI 2015) that excluded more patients with a T-cell defect and consider these patients as LOCID. This population has a poor outcome and should be considered as a distinct group requiring specific care.

Introduction Le diagnostic des formes pulmonaires pures du syndrome de Goodpasture n’est pas aise et il faut discuter une ponction biopsie renale en cas de negativite des anticorps anti- membrane basale glomerulaire car l’evolution peut se faire spontanement vers une hemorragie intra-alveolaire massive pouvant etre fatale. Le traitement des formes pneumo renales associant corticoides, cyclophosphamide et echanges plasmatiques doit etre applique aux formes pulmonaires pour maitriser l’hemorragie et prevenir une recidive precoce. Observation Nous rapportons ici le cas d’un patient atteint d’un syndrome de Goodpasture a forme pulmonaire pure ou le diagnostic a ete retarde par la negativite du premier dosage des anticorps en immunofluorescence indirecte. Apres une rechute precoce et grave, la remission a ete obtenue grâce a un traitement complet et un sevrage tabagique. Conclusion Si le diagnostic est fait sans retard et que le traitement est conduit de facon complete, le pronostic de ces patients reste bon avec 80 a 90 % de guerison.

Anti-CD25 monoclonal antibodies are largely used in clinical transplantation to prevent acute allograft rejection episodes. Although their effects on T lymphocytes have been extensively studied, their impact on human dendritic cells (DCs) has been less reported. Furthermore, the role of the interleukin-2 in DC functions has not yet been fully elucidated. In this study, we observed that stimulation of human monocyte-derived DCs with lipopolysa ccharide or CD40L strongly induced the expression of CD25. We showed that pretreatment of DC with anti-CD25 diminished their ability to prime T-helper cells. In contrast, humanized anti-CD25 monoclonal antibodies did not affect the up-regulation of CD86, CD80, CD83, HLA-DR, or CD40 induced by lipopolysaccharide stimulation. This study supported previously unrecognized effects of anti-CD25 monoclonal antibodies on DCs that may contribute to their clinical efficacy.

Calcineurin inhibitors (CNIs) and steroids, the cornerstone of most immunosuppressive regimens in the past 20 years, have undesirable long-term side effects. This has led to the investigation of potential new strategies with sirolimus (SRL) and mycophenolate mofetil (MMF). In the SPIESSER study, de novo CNI avoidance and early steroid withdrawal were evaluated in 145 renal recipients randomized to receive either SRL (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal anti-thymocyte globulin (ATG) for 5 days, MMF, and steroids withdrawn at 6 months. At 12 months, patient and graft survival, incidence of biopsy-proven acute rejection (BPAR), and rates of steroid withdrawal were not statistically different (97% vs 97%, 90% vs 93%, 14.3% vs 8.6%, and 82.8% vs 84.1%, respectively). In patients who remained on treatment according to the protocol, estimated glomerular filtration rate (eGFR) was significantly higher with SRL (69 +/- 19 vs 60 +/- 14 mL/min; P.01). In the CONCEPT study, early conversion from CsA to SRL was evaluated. One hundred ninety-two renal recipients were prospectively randomized at week 12 to switch from CsA to SRL (n = 95) or to continue CsA (n = 97). At 12 months, patient survival rates (100% vs 100%) and graft survival rates (100% vs 98%), incidence of acute rejection (17% vs 8%), and rates of steroid withdrawal (72% vs 78%) were not significantly different between the SRL and the CsA groups. eGFR was significantly higher with SRL (68.9 vs 64.4 mL/min; P = .017; intent-to-treat analysis). In both studies, a significant improvement in renal function was observed at 12 months in patients receiving a maintenance regimen with SRL and MMF. In addition, steroids could be withdrawn in 70% of these patients.

Resume Introduction La ciclosporine est un medicament immunosuppresseur majeur dans la prevention de rejet des greffes et dans certaines affections auto-immunes. La prescription de cette molecule est limitee par de nombreux effets parmi lesquels on note des cas de neuropathies et de myopathies, rapportees notamment lorsque la ciclosporine est associee a des medicaments inhibant la co-enzyme A reductase. Observation Nous rapportons le cas d’une patiente de 67 ans qui a developpe quelques mois apres une greffe renale un deficit sensitivo-moteur rapidement evolutif en rapport avec une neuromyopathie. Bien que la ciclosporine fut prescrite seule dans les taux therapeutiques, l’elimination des autres etiologies responsables d’un tel tableau conduisait a privilegier l’hypothese d’une toxicite induite exclusivement par la ciclosporine. Cette hypothese fut confirmee par l’amelioration de l’etat neurologique apres arret de cette prescription. Conclusion Cette observation souligne donc la neurotoxicite potentielle de la ciclosporine meme lorsqu’elle est prescrite en monotherapie aux taux therapeutiques.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6), a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. We examined the effects of polyunsaturated fatty acids (PUFA) on the production of IL-6 by human unstirnulated EC and by EC stimulated with TNF-α (100U/ml), IL-4 (100U/ml), LPS (1 μg/ml), or allogeneic peripheral blood lymphocytes (PBL). Immunoreactive IL-6 of twenty-four hour culture Supernatants was measured by sandwich ELISA. We demonstrated that the production of IL-6 was potentiated when EC were stimulated with TNF-α, IL-4, LPS, or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFA to the culture medium (100 pglml DHA or EPA) significantly reduced the production of IL-6 by unstimulated EC and by EC stimulated with TNF-α, IL4, LPS or depleted PBL, whereas the n-6 PUFA (Arachidonic acid), even used at a similar concentration, was ineff...

International audience; The structure and stability of the flows in an annular channel sheared by a rotating lid are investigated experimentally, theoretically and numerically. The channel has a square section, and a small curvature parameter: the ratio Γ of the inter-radii to the mean radius is 9.5%. The sidewalls and the bottom of the channel are integral and can rotate independently of the lid, permitting pure shear, co-rotation and counter-rotation cases. The basic flows obtained at small shear are characterized. In the absence of co-rotation, the centrifugal force linked with the curvature of the system plays an important role, whereas, when co-rotation is fast, the Coriolis force dominates. These basic flows undergo some instabilities when the shear is increased. These instabilities lead to supercritical traveling waves in the pure shear and co-rotation cases, but to weak turbulence in the counter-rotation case. The Reynolds number for the onset of instabilities, constructed with the velocity difference between the lid and bottom at mid-radius, and the height of the channel, increases from 1000 in the counter-rotation case to 1260 in the pure shear case and higher and higher values when co-rotation increases, i.e., when the Coriolis effect increases. The relevance of uni-dimensional Ginzburg-Landau models to describe the dynamics of the waves is studied. The domain of validity of these models turns out to be quite narrow.

IL-4 and TNF-alpha increase endothelial cell adhesiveness for PBL by promoting the expression of adhesion molecules. We investigated the intracellular cAMP involvement in the increased endothelial cell adhesivity induced by IL-4 or TNF-alpha. We showed that both IL-4 and TNF-alpha increased intracellular cAMP in endothelial cells (EC). Furthermore, dibutyryl-cAMP and forskolin (which increased intracellular cAMP) increased basic EC adhesivity for PBL. The co-stimulation of EC with cAMP elevating agents and TNF-alpha, but not IL-4, resulted in an additive increase in EC adhesiveness. 2',5' dideoxyadenosine, an inhibitor of adenylate cyclase, decreased PBL adhesion to IL-4- but not TNF-alpha-treated EC. Similarly, HA1004, a protein kinase A inhibitor, totally reversed the IL-4 but not TNF-alpha effect on EC adhesiveness, whereas H7, a protein kinase C inhibitor, did not antagonise cytokine-enhanced EC adhesivity. These results indicate that IL-4, but not TNF-alpha, uses a cAMP-dependent pathway to increase PBL adhesion. Furthermore, we showed that cAMP elevation in EC did not induce vascular cell adhesion molecule 1, the only identified adhesion molecule induced by IL-4, indicating that a rise in cAMP in EC promotes an as yet unidentified adhesion pathway. Our results show that IL-4 increases EC adhesiveness for PBL through activation of protein kinase A by promoting an unidentified adhesion pathway.

Calcineurin inhibitors (CNIs) and steroids, the cornerstone of most immunosuppressive regimens in the past 20 years, have undesirable chronic effects. This has led to the use of new strategies with sirolimus (SRL) and mycophenolate mofetil (MMF). In the SPIESSER study, de novo CNI avoidance and early steroid withdrawal were evaluated in 145 renal recipients randomized to receive either SRL (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antithymocyte globulin for 5 days, MMF, and steroids withdrawn at 6 months. At 12 months, the incidence of biopsy-proven acute rejection was low (14.3% for SRL vs 8.6% for CsA). At 3 years, renal function (Nankivell) was better in the SRL group, particularly in patients who remained on treatment according to the protocol (71 ± 22 vs 60 ± 17 mL/min; P < .01). Steroids were withdrawn in 70.5% of SRL-treated patients and in 66.7% of CsA-treated patients. In the CONCEPT study, early conversion from CsA to SRL was evaluated in 192 renal recipients prospectively randomized at week 12 to switch from CsA to SRL (n = 95) or to continue CsA (n = 97). At 12 months, estimated glomerular filtration rate (Modification of Diet in Renal Disease) was significantly higher with SRL (61 ± 16 vs 54 ± 15 mL/min; P = .002, intent-to-treat analysis). The significant improvement in renal function was maintained at 30 months. In both studies graft and patient survival were similar, with better renal function and a tendency for fewer cancers observed at follow-up in patients receiving a maintenance regimen with SRL and MMF. At 30 months, steroids had been withdrawn in 72% of SRL-treated patients and in 70% of CsA-treated patients.

A number of factors interfere with the outcome of renal transplantation. Revealing genetic factors that impact on graft outcome may have consequences for clinical practice. Interleukin-12 (IL-12), by stimulating interferon gamma (IFNγ) production, plays a crucial role in immune responses against both graft and viral agents. An A-to-C single nucleotide polymorphism (SNP) within the 3′-untranslated region (3′UTR) of the IL-12p40 gene has been reported to be both functionally and clinically relevant. Since the impact of this SNP on kidney graft outcome has never been reported, we investigated the impact of the 3′UTR polymorphism on clinical events after transplantation among 253 kidney recipients transplanted between 1995 and 2003. The polymorphism was genotyped using the restriction fragment length polymorphism method. Our results showed that the 3′UTR polymorphism affected neither graft survival ( P = .768) nor the occurrence of delayed graft function (DGF; P = .498). C allele carriers in our study displayed more acute rejections in the first year than patients with the A/A genotype, but it did not reach statistical significance ( P = .108). In contrast, the C allele appeared to be a significant risk factor for cytomegalovirus infection (odds ratio = 1.77; P = .027). In conclusion, IL12B 3′UTR polymorphism did not affect graft survival, DGF, or acute rejection episodes, but had an impact on the occurrence of cytomegalovirus infection.

International audience; Orientation of the immune response toward Th1, Th2, Th17 or Treg plays all important role in self-tolerance and defence against pathogens and tumors. However, this orientation has not been fully characterised in the pig and little is known about the influence of maturation stimulus Oil the capacity of dendritic cells selectively to direct different types of Th cell responses. Dendritic cell (DC) Maturation Call be induced by different agents such as inflammatory cytokines, TLR ligands and CD40L. However, the role of the latter in the maturation of pig DC has never been reported. In this study we analysed how different maturation agents influence the capacity of DC to skew the immune response. Monocyte-derived porcine DCs were matured with human CD40L-transfected L-cells, Lipopolysaccharide (LIPS) alone or LIPS in combination with Tumor necrosis factor-alpha (TNF alpha) and interferon-alpha (IFN alpha). We found that human CD40L induced DC maturation characterised by increased expression of co-stimulatory CD80/86 molecules, high production of IL-12p40 in DC and induction of IFN-gamma and t-bet mRNA in T cells, suggesting a Th I orientation. Moreover we report for the first time the appearance of CD25 after activation of porcine DC. Futhermore, DC activated with TNF + LPS + IFN showed the highest allo-stimulatory capacity of allogeneic lymphocytes and induced IL-17 mRNA in T lymphocytes, Suggesting a Th17 orientation that has never been previously reported in the pig. We also showed that immature DCs did not produce any IL-10 or IL-12 and induced both GATA-3 and IL-13 transcription in allogeneic MLR Suggesting a Th2 orientation. This study therefore underlines that the nature of the stimulus Strongly influences the capacity of DC to steer the immune response in the pig. (C) 2008 Elsevier Ltd. All rights reserved.

The results provide new insights into the role of IL-2/IL-2R pathway in DC. We report that stimulation of human monocyte-derived DC with LPS strongly upregulated CD25 (α chain of the IL-2R) expression. In addition, by using a humanized monoclonal antibody against CD25, we demonstrated that the IL-2 signalling in DC upregulated both IL-12 and γIFN production but decreased IL-10 synthesis. Anti-CD25 treatment reduced the ability of LPS-DC to induce allogeneic CD4(+) T cell proliferation as compared to LPS-matured DC. In addition, LPS-matured DC treated with IL-2 had a higher allostimulatory capacity compared to LPS-DC. We also found that LPS-matured DC produced IL-2. Thus, IL-2 seems to contribute actively to DC activation through an autocrine pathway. Moreover, IL-2 pathway in DC is involved in T helper priming. These findings might be useful for protocols in cellular therapy and a valuable tool to understand graft rejection versus the acquisition of peripheral tolerance.

The diagnosis of the pulmonary forms of Goodpasture's syndrome is not easy and requires a renal biopsy when no anti-glomerular basement membrane antibodies are detected, since the disease can lead to spontaneous massive intra-alveolar haemorrhage that can be fatal. Treatment for the pulmonary-renal form combining corticosteroids, cyclophosphamide and plasmapheresis should be applied to the pulmonary form to control haemorrhage and prevent relapse.We report the case of a patient suffering from the localised pulmonary form of Goodpasture's syndrome in whom the diagnosis was delayed due to a negative indirect immunofluorescent antibody bioassay. After a serious early relapse remission was achieved with comprehensive treatment and a tobacco withdrawal programme.If there is no delay in diagnosis and comprehensive treatment is given, the prognosis for these patients is good with a recovery rate of 80 to 90%.

National audience; Tolerance induction in murine allogeneic transplantation is relatively easy, often by induction of regulatory T cells (Treg). Unfortunately, the implementation of these models in clinical situations has not yielded reliable protocols of tolerance induction in humans. Our project sought to create a preclinical model of tolerance induction in large animals. Our current efforts seek to induce and characterize porcine Treg, obtaining dendritic cells (DC) able to preferentially stimulate them. DCs were differentiated from blood monocytes with porcine recombinant interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GMCSF) for 6 days. These DCs were then stimulated by human CD40 ligand-transfected L cells with or without mycophenolic acid (MPA) for 48 hours. We analyzed surface marker expression, cytokine synthesis, and ability to stimulate allogeneic peripheral blood mononuclear cells (PBMC). The porcine lymphocytes underwent 4 rounds of I-week stimulation with allogeneic DC treated or not with MPA. At the end of this coculture we analyzed their capacity to suppress allogeneic PBMC proliferation induced by mature DC. Our results showed that porcine DCs pretreated with MPA display a low expression of 137 costimulatory molecules, produce low levels of IL-12, and induce weak proliferation of allogeneic lymphocytes. Moreover, after 4 rounds of stimulation with MPA-treated DCs, PBMCs were able to inhibit an alloreactive response. These preliminary results suggested induction of a regulatory T-cell population that we are currently seeking to characterize.

Treatment of post-transplant B-cell lymphomas has proved to be difficult because the decrease of the immunosuppressive therapy can lead to rejection and chemotherapy is hazardous. Anti-CD21/24 monoclonal antibody therapy has previously offered the advantages of a good tolerance and efficiency on oligoclonal lymphomas. With a better knowledge of the phenotype of post-transplant lymphomas, we tried to develop chimeric monoclonal antibodies (mAb) that could be more efficient on the lymphomas and could permit to keep the immunosuppression in order to avoid graft loss.

Cyclosporine is an immunosuppressive treatment whose side effects limit its usefulness. Among neurological side effects, neuropathies or myopathies have been reported, specially inpatients given combinations of cyclosporine with co-enzyme A reductase inhibitors.We report here the case of a 67-year-old woman who developed few months after a kidney graft sensorimotor disorders which progressed rapidly. Since all etiologies of such a disorder were ruled out, the hypothesis of toxicity exclusively induced by cyclosporine was suggested and confirmed by the improvement observed after its withdrawal.This observation highlights the fact that cyclosporine may induce neuromyopathies even when given alone at the therapeutic dosage.

The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients.This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day.At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction).Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

FUNCTIONS OF THE ENDOTHELIUM: The endothelium plays a pivotal role in regulating vasomotor tone, vessel permeability, blood cell extravasation, and antiatherogenic, antithrombogenic and antiadhesive processes.Demonstrated, in particular, by endothelium-dependent vasomotricity disorders, endothelium dysfunction occurs in many psysiological and pathological situations that lead to atherosclerosis: advanced age, menopause, high blood pressure, dyslipidemia, diabetes, smoking, elevated homocysteinemia, chronic renal failure.... These dysfunctions of the endothelium constitute the fundamental and very early step in the development of atherosclerosis.Specific treatment of functional anomalies of the endothelium can be an essential element in the prevention of atherosclerosis. In certain cases, he cause of endothelial dysfunction may be related to the presence of radical oxygen species, nitric oxide inhibitors, or increased synthesis or release of endothelin. Potential treatments should be adapted to the specific cause of the underlying endothelial anomaly: antioxidants, statins, anti-endothelins, or converting enzyme inhibitors. In clinical practice, it may be important to recognize the cause of endothelial dysfunction for adapted early drug therapy.

Renal transplant recipients experience adverse events attributed to corticosteroid therapy.This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation.There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P0.01, P0.01), triglycer. ides (P0.01, P0.01), and systolic blood pressure (P0.001, P0.001) were lower in the low/stop group. Diastolic pressure was lower (P0.01) and lumbar spine bone density was greater (P0.01) in the low/ stop group at 12 months.In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events.

A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus.In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured.At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often.Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.

The transplantation of organs from one species to another introduces a question of compatibility not seen in allotransplantation, the ability of a kidney to perform its physiological function in the new host environment. It has been assumed that an allotransplanted organ will function normally if is not rejected; ample experience supports this assumption. This luxury will not exist in the field of xenotransplantation, where the issues of comparative physiology will assume great importance. From many standpoints, the pig kidney seems an ideal donor for xenotransplantation. They are of similar size and have remarkably similar internal anatomy. Even if the immunological problems could be overcome, there is almost no direct experimental evidence to answer the question of whether or not a pig kidney can function in a human body.

We assessed the long-term (M +/- SE: 68 +/- 3 months) arterial pressure and renal function of cadaveric kidney transplant recipients with and without significant (70% diameter reduction) transplant renal artery stenosis (TRAS) at angiography. Baseline clinical, immunological and outcome data for 26 patients with TRAS (incidence of TRAS: 6.6%) before and following angioplasty and 72 patients without stenosis at angiography were reviewed and analyzed. The 2 groups were similar with respect to recipient sex ratio and age (45 vs 46), duration of transplantation (7 months), cause of renal failure, donor sex and age, HLA-antigen mismatches and titers of anti-HLA antibodies, CMV infection and anti-CMV antibodies in donors and recipients. The technical success of angioplasty was 92.3%. Restenosis was documented in 6/26 patients (23.1%). Revascularization resulted in a decrease of arterial pressure and number of antihypertensive medications and a lower serum creatinine compared to baseline values. The long-term arterial pressure and serum creatinine levels were similar in patients with and without stenosis. In conclusion, TRAS after revascularization had no detectable influence on the long-term arterial pressure control and renal function within a follow-up period of 68 +/- 3 months.

Vascular endothelium controls leukocyte recirculation and recruitment, receiving messages from underlying tissues and transforming them into informations quickly read by the passaging leukocytes. These messages induce adhesive interactions between leukocytes and endothelium via adhesion molecules. Multiple receptor-ligand pairs function in 4 steps: initial tethering and rolling of leukocytes; leukocyte triggering by chemotactic factors; arrest and strong adhesion to endothelium; and ultimately transendothelial migration (diapedesis).

Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month.Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively.Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level.Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes.

The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system.The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared.The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results.Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.

To determine the role of the terminal alpha-galactosyl residue in the endothelial damage mediated by human xenoreactive natural antibodies (IgM and IgG), we treated porcine endothelial cells in culture with green coffee bean alpha-galactosidase. A practically complete removal of terminal alpha-Gal residues (as evaluated by flow cytometry with Bandeiraea simplicifolia isolectin B4) and concomitant exposure of N-acetyllactosamine were obtained without altering cell viability. A dramatic decrease in IgM and IgG binding (from a pool of human sera) was observed, confirming the key role of the alpha-galactosyl residues. The enzyme treatment did not induce any nonspecific immunoglobulin binding sites, but led to the exposure of new epitopes for a minor fraction of IgM. The main residual IgM and IgG binding could be due to xenoantigens other than the alpha-galactosyl residues. When alpha-galactosidase-treated endothelial cells were used as targets in cytotoxicity experiments, they were less susceptible than untreated cells to complement-mediated cytotoxicity induced by fresh human serum. In contrast, they did not acquire resistance to human IgG-dependent cellular cytotoxicity, despite the decrease in IgG binding. Because it is known that antibody-dependent cytotoxicity mediated by CD16+ NK cells is dependent on IgG1 and IgG3, and not on IgG2 or IgG4, which was confirmed by blocking experiments, we studied the binding of all four subclasses to intact and alpha-galactosidase-treated endothelial cells. Two major subclasses, IgG1 and IgG2, bound to untreated endothelial cells, whereas IgG3 binding was low and IgG4 binding was negligible. A decrease in IgG1, IgG2, and IgG3 binding was observed upon alpha-galactosidase treatment, indicating that antibodies belonging to these three subclasses recognize alpha-galactosyl residues. The decrease in IgG2 binding was more pronounced than the decrease in IgG1 binding. Collectively, these data indicate that IgG1 xenoreactive natural antibodies, including those which are not directed at the alpha-galactosyl residues, could play a major role in the early delayed vascular rejection of pig xenografts.