Rôle des lymphocytes T CD4+ et des lymphocytes T régulateurs dans l'immunothérapie et la physiopathologie de la maladie d'Alzheimer : études chez la souris

Cerebral accumulation of aggregated Aβ40-42 peptides is among the major pathological hallmarks of Alzheimer's disease (AD). In spite of encouraging results of Aβ vaccination in preclinical mouse models, the first human clinical trial had to be interrupted because of the occurence of meningoencephalitides in 6% of the cases, supposedly related to inappropriate T cell responses. Thus, a better understanding of vaccination-induced anti-Aβ CD4+ T cell responses seems essential for the optimisation of future immunotherapeutical approaches. We tried to identify the genetic factors that control the magnitude and the nature of vaccination-induced Aβ-specific CD4+ T cell responses in mice. Both MHC-dependent and MHC-independent genetic factors are critical parameters. Among MHC-independent genetic factors, those that determine the individual propensity of generating Aβ-specific regulatory T cell (Treg) responses are important. Moreover, the vaccination-induced CD4+ T cell responses analysis in an APPPS1 mouse model of AD suggest that Tregs may inhibit anti-Aβ CD4+ T cells responses that spontaneously arise in the course of AD. These observations led us to evaluate the impact of CD4+ effector and regulatory T cell responses in the pathophysiology of AD. Using Treg depletion experiments, we evidenced the anti-neuroinflammatory functions and beneficial effects of these cells on the amyloid pathology and cognition of APPPS1 mice. Altogether, our results suggest that Treg responses may both limit vaccination efficacy and have a neuroprotective role in the course of AD.L'accumulation des peptides Aβ40-42 au niveau cérébral est un élément physiopathologique majeur de la Maladie d'Alzheimer (MA) et une cible thérapeutique potentielle. A l'issue de résultats encourageants de vaccination par Aβ dans des modèles murins de la MA, un essai clinique a été entrepris chez l'Homme. Mais il a dû être interrompu en raison de la survenue de méningo-encéphalites chez 6% des patients, supposées liées à une activation inappropriée de lymphocytes T. Une meilleure compréhension des réponses T CD4+ induites par la vaccination semble donc primordiale pour l'optimisation des stratégies vaccinales. Nous avons cherché à identifier les facteurs génétiques qui pourraient avoir un rôle sur l'amplitude et la nature des réponses vaccinales T CD4+ anti-Aβ chez la souris. Nous avons mis en évidence que l'amplitude de la réponse variait en fonction des haplotypes H-2 mais aussi de facteurs génétiques indépendants du CMH et liés à la capacité de générer des réponses T régulatrices (Tregs) anti-Aβ. De plus, l'analyse des réponses vaccinales dans un modèle murin de MA (souris APPPS1) semble suggérer qu'une réponse Treg inhiberait des réponses T CD4 effectrices anti- Aβ spontanées. Ces observations nous ont conduits à rechercher l'impact de ces réponses effectrices et régulatrices dans la physiopathologie de la maladie. En inactivant les cellules Tregs, nous avons pu mettre en évidence les fonctions anti-neuroinflammatoires et les effets bénéfiques de ces cellules sur la pathologie amyloïde et la cognition. Ensemble, nos résultats suggèrent donc que les réponses Treg pourraient limiter l'efficacité vaccinale mais auraient une action neuroprotectrice dans la physiopathologie de la MA

Rôle des lymphocytes T CD4+ et des lymphocytes T régulateurs dans l immunothérapie et la physiopathologie de la maladie d Alzheimer (Etudes chez la souris)

L accumulation des peptides A 40-42 au niveau cérébral est un élément physiopathologique majeur de la Maladie d Alzheimer (MA) et une cible thérapeutique potentielle. A l issue de résultats encourageants de vaccination par A dans des modèles murins de la MA, un essai clinique a été entrepris chez l Homme. Mais il a dû être interrompu en raison de la survenue de méningo-encéphalites chez 6% des patients, supposées liées à une activation inappropriée de lymphocytes T. Une meilleure compréhension des réponses T CD4+ induites par la vaccination semble donc primordiale pour l optimisation des stratégies vaccinales. Nous avons cherché à identifier les facteurs génétiques qui pourraient avoir un rôle sur l amplitude et la nature des réponses vaccinales T CD4+ anti-A chez la souris. Nous avons mis en évidence que l amplitude de la réponse variait en fonction des haplotypes H-2 mais aussi de facteurs génétiques indépendants du CMH et liés à la capacité de générer des réponses T régulatrices (Tregs) anti-A . De plus, l analyse des réponses vaccinales dans un modèle murin de MA (souris APPPS1) semble suggérer qu une réponse Treg inhiberait des réponses T CD4 effectrices anti-A spontanées. Ces observations nous ont conduits à rechercher l impact de ces réponses effectrices et régulatrices dans la physiopathologie de la maladie. En inactivant les cellules Tregs, nous avons pu mettre en évidence les fonctions anti-neuroinflammatoires et les effets bénéfiques de ces cellules sur la pathologie amyloïde et la cognition. Ensemble, nos résultats suggèrent donc que les réponses Treg pourraient limiter l efficacité vaccinale mais auraient une action neuroprotectrice dans la physiopathologie de la MA.Cerebral accumulation of aggregated A 40-42 peptides is among the major pathological hallmarks of Alzheimer s disease (AD). In spite of encouraging results of A vaccination in preclinical mouse models, the first human clinical trial had to be interrupted because of the occurence of meningoencephalitides in 6% of the cases, supposedly related to inappropriate T cell responses. Thus, a better understanding of vaccination-induced anti-A CD4+ T cell responses seems essential for the optimisation of future immunotherapeutical approaches. We tried to identify the genetic factors that control the magnitude and the nature of vaccination-induced A -specific CD4+ T cell responses in mice. Both MHC-dependent and MHC-independent genetic factors are critical parameters. Among MHC-independent genetic factors, those that determine the individual propensity of generating A -specific regulatory T cell (Treg) responses are important. Moreover, the vaccination-induced CD4+ T cell responses analysis in an APPPS1 mouse model of AD suggest that Tregs may inhibit anti-A CD4+ T cells responses that spontaneously arise in the course of AD. These observations led us to evaluate the impact of CD4+ effector and regulatory T cell responses in the pathophysiology of AD. Using Treg depletion experiments, we evidenced the anti-neuroinflammatory functions and beneficial effects of these cells on the amyloid pathology and cognition of APPPS1 mice. Altogether, our results suggest that Treg responses may both limit vaccination efficacy and have a neuroprotective role in the course of AD.PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

MHC-Independent Genetic Factors Control the Magnitude of CD4+ T Cell Responses to Amyloid- Peptide in Mice through Regulatory T Cell-Mediated Inhibition

International audienceAccumulation of amyloid-β peptide (Aβ) is considered the triggering factor of pathogenic lesions in Alzheimer's disease (AD), and vaccines targeting Aβ are promising therapeutic options. However, the occurrence of meningoencephalitides attributed to T cell responses in 6% of Aβ-immunized patients underscores the need for a better understanding of T cell responses to Aβ. We characterized the parameters controlling the magnitude of Aβ-specific CD4(+) T cell responses in mice. T cell responsiveness to Aβ1-42 was highly heterogeneous between mouse strains of different H-2 haplotypes, with SJL/J (H-2(s)) mice displaying a strong response, mainly specific for Aβ10-24, and C57BL/6 (H-2(b)) mice displaying a weak response to Aβ16-30. Surprisingly, C57BL/6 mice congenic for the H-2(s) haplotype (B6.H-2(S)), which display a "permissive" MHC class II allele for presentation of the immunodominant Aβ10-24 epitope, showed a very weak CD4(+) T cell response to Aβ, suggesting that MHC-independent genes downmodulate Aβ-specific CD4(+) T cell responses in C57BL/6 background. Vaccine-induced CD4(+) T cell responses to Aβ were significantly enhanced in both C57BL/6 and B6.H-2(S) mice upon depletion of regulatory T cells (Tregs), whereas Treg-depleted SJL/J mice displayed unaltered Aβ-specific T cell responses. Finally, Treg depletion in C57BL/6 transgenic APPPS1 mice, a mouse model of AD, results in enhanced vaccine-induced CD4(+) T cell responses in AD compared with wild-type animals. We concluded that the magnitude of Aβ-specific CD4(+) T cell responses is critically controlled in both physiological and pathological settings by MHC-independent genetic factors that determine the overall potency of Aβ-specific Treg responses

Insights into anti‐D formation in carriers of RhD variants through studies of 3D intraprotein interactions

International audienceBackground: Many RhD variants associated with anti-D formation (partial D) in carriers exposed to the conventional D antigen carry mutations affecting extracellular loop residues. Surprisingly, some carry mutations affecting transmembrane or intracellular domains, positions not thought likely to have a major impact on D epitopes.Study design and methods: A wild-type Rh trimer (RhD1 RhAG2 ) was modeled by comparative modeling with the human RhCG structure. Taking trimer conformation, residue accessibility, and position relative to the lipid bilayer into account, we redefine the domains of the RhD protein. We generated models for RhD variants carrying one or two amino acid substitutions associated with anti-D formation in published articles (25 variants) or abstracts (12 variants) and for RHD*weak D type 38. We determined the extracellular substitutions and compared the interactions of the variants with those of the standard RhD.Results: The findings of the three-dimensional (3D) analysis were correlated with anti-D formation for 76% of RhD variants: 15 substitutions associated with anti-D formation concerned extracellular residues, and structural differences in intraprotein interactions relative to standard RhD were observed in the others. We discuss the mechanisms by which D epitopes may be modified in variants in which the extracellular residues are identical to those of standard RhD and provide arguments for the benignity of p.T379M (RHD*DAU0) and p.G278D (RHD*weak D type 38) in transfusion medicine.Conclusion: The study of RhD intraprotein interactions and the precise redefinition of residue accessibility provide insight into the mechanisms through which RhD point mutations may lead to anti-D formation in carriers

Effect of intravenous immunoglobulins to postpone the gestational age of first intrauterine transfusion in very severe red blood cell alloimmunization: A case-control study

Background: Early intrauterine transfusion (IUT) is associated with a higher risk of fetal loss. Our objective was to evaluate the efficiciency of intravenous immunoglobulins (IVIG) to postpone the gestational age at first IUT beyond 20 weeks of gestation (WG) compared to the previous pregnancy in case of very severe red blood cell (RBC) alloimmunization. Study design and methods: Very severe RBC alloimmunization was defined by a high titer of antibodies and a previous pregnancy complicated by a first IUT before 24 WG and/or perinatal death directly related to alloimmunization. We performed a single-center case-control study. Cases and controls were patients respectively treated with weekly IVIG infusions started before 13 WG, and without. Results: Twenty cases and 21 controls were included. Gestational age (GA) at first IUT was postponed after 20 WG in 18/20 (90 %) of patients treated with IVIG and in 15/21 (71 %) in the control group (p = 0.24). Compared to the previous pregnancy, the GA at first IUT was postponed by a median of 22 [+11; +49] days in the IVIG group and occurred in average 2 days earlier [-17 ; +12] in the non-treated group (p = 0.02). There was no difference between number of IUT and need for exchange-transfusion. IVIG treatment was associated with a significant decrease of antibodies' quantitation. Conclusion: In our series, IVIG tends to differ first IUT beyond 20 WG and have a significant effect in postponing the gestational age of the first IUT in patients with very severe RBC alloimmunization