Thesis (Ph. D.)--University of Missouri--Columbia, 1998. / "July 1998." Typescript. Vita. Includes bibliographical references (leaves 190-217). Also available on the Internet.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Ce travail de thèse a été axé sur l’étude de la réponse immunitaire T chez des patients atteints d’artérite à cellules géantes (ACG) et de pseudo-polyarthrite rhizomélique (PPR). Plusieurs études cliniques successives interrégionales ont permis d’inclure de nombreux patients (57 ACG et 27 PPR) des Centres Hospitaliers (CH) Universitaires et des CH de l’interrégion Est. Les échantillons sanguins ont été étudiés dans le laboratoire de l’unité INSERM U1098. Tout d’abord, nous avons confirmé l’implication des lymphocytes Th17 dans la pathogénie de l’ACG et avons montré pour la première fois leur implication au cours de la PPR. De plus, notre étude des lymphocytes T (LT) CD4+CD161+ a permis de mieux comprendre les mécanismes de plasticité entre les réponses Th1 et Th17 au cours de ces deux pathologies. Nous avons complété ces travaux par l’étude de la réponse T régulatrice en montrant qu’il existe un déficit quantitatif en Treg au cours de l’ACG et la PPR. Dans la suite de ce travail, nous avons mis en évidence, chez des patients atteints de polyarthrite rhumatoïde, que le blocage de la voie de signalisation de l’IL-6 par un anticorps monoclonal dirigé contre le récepteur de l’IL-6 permet de corriger le déséquilibre de la balance Th17/Treg, en diminuant la réponse Th17 et en augmentant simultanément la réponse T régulatrice, à l’inverse des corticoïdes qui diminuent le pourcentage de Th17 sans corriger le déficit en Treg. Enfin, dans la dernière partie de ce travail, nous avons montré pour la première fois que les LT CD8+ étaient également impliqués dans la pathogénie de l’ACG et la PPR. Ces résultats ont permis de progresser dans les connaissances physiopathologiques de l’ACG et la PPR en évoluant d’un modèle articulé autour d’un déséquilibre de la balance Th1/Th2 vers celui d’un déséquilibre de la balance Th17/Treg et permettent de proposer des thérapeutiques mieux ciblées pour l’ACG et la PPR. / The aim of this thesis was to investigate the T-cell immune response in the course of giant-cell arteritis (GCA) and polymyalgia rheumatica (PMR). Several studies conducted by our team allowed us to obtain blood samples from many patients affected by GCA (n=57) and PMR (n=28). Immunological studies were performed in INSERM U1098, University Of Burgundy, Dijon, France. We firstly demonstrated the implication of Th17 and CD4+CD161+ T cells in the pathogenesis of these two diseases, thus extending the knowledge in the plasticity mechanisms arising between Th1 and Th17 cell-immune responses in GCA and PMR. Furthermore, we investigated the regulatory T cell immune response in these two affections, demonstrating that although being functional, the percentage of circulating Treg was decreased in GCA and PMR patients. As interleukin-6 (IL-6) had been shown to control the Th17/Treg balance, we studied Th17 and Treg frequencies in rheumatoid arthritis patients treated with an anti-IL-6 receptor antibody (tocilizumab). We showed that the blockade of the IL-6 pathway was able to correct the Th17/Treg imbalance by decreasing the number of Th17 cells and simultaneously increasing that of Treg. Finally, we demonstrated for the first time the implication of CD8+ T cells in the pathogenesis of GCA and PMR. This thesis allowed us to progress in the knowledge of the pathogenesis of GCA making the pathogenesis model progress from a Th1/Th2 to a Th17/Treg imbalance model. Altogether, these data deciphering the immune response in the pathogenesis of GCA and PMR bring new knowledge which will lead to better targeted therapies.

Le PAF (Platelet-Activating Factor) est un médiateur reconnu pour son implication dans plusieurs effets physiologiques et pathologiques, particulièrement les états inflammatoires. À l'instar du PAF, les lymphocytes T Th17 sont aussi reconnus comme exerçant un rôle majeur dans la physiopathologie des maladies auto-immunes. L'objectif de ce projet est de déterminer s'il existe un lien entre ces deux composants. En fait, nous avons émis l'hypothèse que le PAF pourrait provoquer une production de cytokines spécifiques par les cellules présentatrices d'antigène qui elles, interagissant avec les lymphocytes T, pourraient mener ultimement à une différentiation en Th17. En effet, les cellules T ne peuvent interagir directement avec le PAF puisqu'elles n'expriment pas de récepteur pour celui-ci à leur surface. Les cellules T Th17 expriment un facteur de transcription spécifique RORr, nécessitent absolument la sous-unité IL-23p19 pour leur expansion et produisent IL-17. Nous avons donc, dans un premier temps, regardé la capacité d'un type de cellules présentatrices d'antigène, les cellules de Langerhans à produire IL-23p19 en réponse au PAF. Ensuite, nous avons mis en contact ces cellules de Langerhans pré-stimulées au PAF avec des lymphocytes T activés pendant 5 jours pour vérifier l'expression de RORII et la production d'IL-17 dans ces lymphocytes T, plus précisément les lymphocytes T CD4 + . Cette étude nous a permis de mettre en évidence que certains éléments impliqués dans les processus inflammatoires sont possiblement inséparables et interagissent probablement les uns avec les autres pour mener aux séquelles multiples de l'inflammation.

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

Chlamydia is an obligate intracellular bacterial pathogen that causes a wide spectrum of diseases worldwide. At present, there are no vaccines to prevent chlamydial infections due to poor understanding of how anti-chlamydial immunity ensues. In this study, we employed a variety of in vitro and in vivo systems, including knockout (KO) mice and adoptive transfer, to investigate the role of lung dendritic cells (LDCs) and their relationship with innate lymphocytes, natural killer (NK) and invariant NKT (iNKT) cells, in host defense against chlamydial lung infections in mice. We found that iNKT cells altered the phenotype and cytokine production pattern of LDCs following C. pneumoniae infection. Adoptive transfer of LDCs from infected Jα18-KO mice, which lack iNKT cells, into naïve wild-type (WT) mice promoted Th2 (IL-4) immunity following infection challenge, whereas the transfer of LDCs from the infected WT mice induced protective Th1/Tc1 (IFN-γ) immunity. On the other hand, upon adoptive transfer, LDCs from C. muridarum-infected NK-cell-depleted mice (NK-LDCs) conferred reduced protection after chlamydial challenge than the recipients of LDCs from infected sham-treated mice (NK+LDCs). NK+LDC recipients exhibited an enhanced Th1/Th17, in contrast to Th2, response compared to the NK-LDC recipients. In coculture experiments, NK cells isolated from the infected mice promoted IL-12p70, IL-6, and IL-23 production by LDCs through NKG2D receptor signaling. These findings indicate that iNKT and NK cells condition LDCs to confer protective Th1/Tc1/Th17 immunity against chlamydial lung infection. We also analyzed the contribution of major LDC subsets, CD103+ and CD11bhi LDCs, in host defense against C. muridarum infection. We found that CD103+ and CD11bhi LDC subsets expanded following chlamydial infection. CD103+ LDCs showed higher expression of costimulatory molecules and greater production of Th1- and Th17-inducing cytokines (IL-12, IL-6 and IL-23) than CD11bhi LDCs. Coculture of Chlamydia-specific CD4+ T cells with LDC subsets revealed that the T cells cultured with CD103+ LDCs produced larger amounts of IFN-γ and IL-17 compared to those with CD11bhi LDCs. To test their function in vivo, we isolated CD103+ and CD11bhi LDC subsets from infected mice and transferred them into naïve syngeneic mice that received chlamydial challenge. CD103+ LDC-recipients showed better protection, as evidenced by their reduced body weight loss, bacterial burden and lung pathology, than CD11bhi LDC recipients. Mice that received CD103+, compared to CD11bhi, LDCs produced enhanced Th1/Th17 cytokines (IFN-γ and IL-17) in the lung and the MLNs. In conclusion, these findings demonstrate that CD103+ LDCs are more efficient in inducing Th1/Th17 immunity to chlamydial infection than CD11bhi LDCs. Taken together, our findings have provided direct in vivo evidence on the role of LDCs and their conditioning by iNKT and NK cells in generating mucosal T-cell immunity against a bacterial lung infection. The findings have added new knowledge to the field of lung immunology, which have implications for developing prophylactic and/or therapeutic strategies against respiratory diseases. / October 2015

The presence of the purine nucleotide inosine monophosphate (IMP) was studied in direct relationship to the development and expression of cell mediated immunity in guinea pigs using DNCB or Histoplasma capsulatum as sensitizing antigens. The IMP content of T-cell enriched lymphocytic lysates was measured by isocratic high pressure liquid chromatography (HPLC). Intracellular IMP levels of cells from homologously skin tested sensitized animals were significantly increased one day after skin testing when compared to the concentrations found in these cells during the period following sensitization. Concurrent with these observations were the findings that the absolute lymphocyte counts and histoplasmin stimulated in vitro blastogenic responses increased following sensitization while the PHA-induced proliferative response decreased slightly. One day after skin testing, when IMP levels had increased, there was a slight decrease in lymphocyte numbers and a marked decrease in the PHA response. Cells collected at this time and cultured in vitro with histoplasmin responded with increased levels of protein production and increased IMP levels. These data suggest (1) the proliferative response of cells from sensitized animals appears to be associated with lower levels of intracellular IMP, and (2) sensitized cells stimulated in vivo with antigen appear to have characteristically higher IMP concentrations.

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