La physiopathologie de la GVHa implique de nombreux mécanismes aboutissant à ces lésions tissulaires responsables d'une comorbidité majeure en allo-CSH. L'objectif principal de notre étude a été d'identifier des marqueurs précoces de GVHa et d'explorer leurs rôles dans la physiopathologie de ce phénomène. Quarante-deux cytokines ou chémokines, ont été étudiés à J0 dans le sérum de 109 patients allogreffés avec un conditionnement d'intensité réduite. Nous avons complété ce travail par une étude cinétique à différents temps de l'allo-CSH et une étude histologique de biopsies coliques de patients atteints de GVHa. A J0 de l'allo-CSH, seule la mesure de CX3CL1 J0 était significativement plus élevée chez les patients développant par la suite une GVHa en comparaison aux patients indemnes de GVHa (P=0 ,04). Cette observation persistait à J30 et J50 post allo-CSH mais pas à J100 (P=0,02, P=0,03 et P=0,12, respectivement). L'étude des dosages sériques avant le conditionnement (J-30) ne retrouvait pas de différence significative entre ces 2 groupes. L'analyse phénotypique des différents types cellulaires a mis en évidence une augmentation signification de la proportion de lymphocytes CD8+CX3CR1+ chez les patients présentant une GVHa (P=0,01). L'analyse histologique de biopsies coliques (n=12) montrait une nette augmentation de l'expression de CX3CL1 au niveau des cellules épithéliales de la muqueuse intestinale en cas de GVHa ainsi que la présence de cellules mononuclées CX3CR1+ aux contacts de ces cellules épithéliales. Les résultats de cette étude suggèrent fortement l'implication de CX3CL1 et de son récepteur CX3CR1 dans la physiopathologie de la GVHa. / This study investigated the role of cytokines and chemokines in acute graft-versus host disease (aGVHD) incidence and severity in 109 patients who underwent reduced-intensity conditioning allogeneic stem cell transplantation (HSCT). Among the 42 cytokines tested at day 0, only CX3CL1 levels at day 0 was significantly associated with grades II to IV aGVHD development (P=0.04). Increased levels of CX3CL1 at day 30 and day 50 post-HSCT were also significantly associated with aGVHD (P=0.02 and P=0.03, respectively). No such association was found before conditioning regimen or at day 100 post-HSCT. Because the receptor for CX3CL1 is CX3CR1, the number of CX3CR1+ cells was determined by flow cytometry. The CX3CR1+CD8+T cell proportion was significantly higher in patients with aGVHD than those without aGVHD (P=0.01). To investigate the distribution of the CX3CL1/CX3CR1 axis in the anatomic sites of aGVHD, CX3CL1 and CX3CR1 levels were studied using an in situ immunohistochemical analysis on gastro-intestinal biospsies of patients with intestinal aGVHD. CX3CL1 expression was significantly increased in the epithelial cells and mononuclear cells of the lamina propria. CX3CR1+ cells mononuclear cells were identified in close contact with epithelial cells. These findings strongly suggest the implication of the CX3CL1/CX3CR1 axis in the pathogenesis of aGVHD.

Display of thousands of self-antigens in the thymus is fundamental for the establishment of central tolerance as its failure can lead to the development of autoimmunity. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) constitute essential populations of antigen presenting cells (APCs) which present these self-antigens to developing T cells. While mTECs produce and present antigens in self-autonomous manner, DCs can hijack mTEC-derived antigens by the process of cooperative antigen transfer (CAT). It is well found that CAT is essential for working central tolerance, however, the overall heterogeneity of thymic APCs participating in CAT remains unclear. Using transgenic mouse models and multicolor flow cytometry analysis, we determined that APCs involved in CAT are exclusively of CD11c+ phenotype. Within these cells, we identified previously unrecognized CX3CR1+ subset of migratory DCs (mDCs) exhibiting monocyte/macrophage markers. These CX3CR1+ mDCs are more efficient in CAT than their CX3CR1- counterparts and reveal robust antigen presenting properties with the capability to present CAT-acquired antigen. Genetic ablation of CX3CR1+ mDCs resulted in increased cellularity of CD8+ and CD4+ thymocytes, indicating importance of this mDC subset for negative selection of...

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Macular neovascularization type 3, formerly known as retinal angiomatous proliferation (RAP), is a hallmark of age-related macular degeneration and is associated with an accumulation of myeloid cells, such as microglia (MG) and infiltrating blood-derived macrophages (MAC). However, the contribution of MG and MAC to the myeloid cell pool at RAP sites and their exact functions remain unknown. In this study, we combined a microglia-specific reporter mouse line with a mouse model for RAP to identify the contribution of MG and MAC to myeloid cell accumulation at RAP and determined the transcriptional profile of MG using RNA sequencing. We found that MG are the most abundant myeloid cell population around RAP, whereas MAC are rarely, if ever, associated with late stages of RAP. RNA sequencing of RAP-associated MG showed that differentially expressed genes mainly contribute to immune-associated processes, including chemotaxis and migration in early RAP and proliferative capacity in late RAP, which was confirmed by immunohistochemistry. Interestingly, MG upregulated only a few angiomodulatory factors, suggesting a rather low angiogenic potential. In summary, we showed that MG are the dominant myeloid cell population at RAP sites. Moreover, MG significantly altered their transcriptional profile during RAP formation, activating immune-associated processes and exhibiting enhanced proliferation, however, without showing substantial upregulation of angiomodulatory factors.

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