Étude du lymphocyte B au cours du rejet d'allogreffe rénale

Le rejet d allogreffe représente un obstacle majeur en transplantation rénale humaine. Le lymphocyte B (LB) joue un rôle lors de cette réaction contre le greffon, mal défini à ce jour. Notre objectif a été de caractériser et identifier son implication dans le rejet humoral chronique (cABMR) et le rejet cellulaire aigu (ACR). Dans une première partie, la caractérisation phénotypique des LB par cytométrie en flux chez ces patients a mis en évidence d importantes différences dans la distribution des sous-populations de LB uniquement chez les patients cABMR. Chez les patients ACR, dont la distribution des LB n est pas altérée, l analyse de coupes de biopsies rénales a permis de mettre en évidence un infiltrat cellulaire constitué de lymphocytes B et T. Dans une seconde partie, l activité fonctionnelle et régulatrice des LB issus de patients cABMR et ACR a été évaluée à l aide d un modèle in vitro de coculture entre des LB et des LT. Cette étude a révélé que les LB, issus des patients cABMR uniquement, sont dépourvus d activités régulatrices sur la fonction des LT autologues. Cette étude a aussi mis en exergue que les LB des patients cABMR présentaient une déficience dans la sécrétion de molécules immunosuppressives telles que le TGFb et l indoleamine 2,3-dioxygénase (IDO). Ce défaut conduit à une incapacité à générer des lymphocytes T régulateurs. Finalement, notre étude a clairement démontré le rôle du LB dans les mécanismes physiopathologiques conduisant au rejet. Ces travaux ont donc permis de générer d éventuelles perspectives pour définir de nouvelles stratégies thérapeutiques dans la lutte contre le rejet d allogreffe.Allograft rejection is one of the main obstacles in human kidney transplantation. The role of B lymphocytes in the response against the allograft is poorly understood. Our aim is to identify and clarify its involvement in chronical humoral and cellular rejection. First of all, we identify profound changes in the distribution of B lymphocytes in cABMR patients which was not the case for ACR patients. In those last ones, we were able to detect on kidney biopsies an important cellular infiltrate composed with B and T cells. In the second part of this work, the functional and regulatory functions of B cells from both groups of patients were analyzed by using an in vitro coculture model between B and T cells. It appeared that B lymphocytes isolated from cABMR patients were unable to inhibit autologous T cell activity. This study showed those cells failed to produce immunosuppressive molecules as TGFb and indoleamine 2,3-dioxygenase (IDO) leading to a default in the generation of regulatory T cells. To conclude, this study clearly showed the roles of B cells in physiopathological mechanisms of allograft rejection and helped to define new therapeutical strategies to prevent or reduce its consequences for the patients.BREST-SCD-Bib. electronique (290199901) / SudocSudocFranceF

Regulatory B Cells: An Exciting Target for Future Therapeutics in Transplantation.

International audience: Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrate on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting antibody, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg) cells or B10 cells has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches

Regulatory B Cells: An Exciting Target for Future Therapeutics in Transplantation.

International audience: Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrate on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell-depleting antibody, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg) cells or B10 cells has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches

Discrepancies in the Tumor Microenvironment of Spontaneous and Orthotopic Murine Models of Pancreatic Cancer Uncover a New Immunostimulatory Phenotype for B Cells.

B cells are salient features of pancreatic ductal adenocarcinoma (PDAC) tumors, yet their role in this disease remains controversial. Murine studies have indicated a protumoral role for B cells, whereas clinical data show tumor-infiltrating B cells are a positive prognostic factor, both in PDAC and other cancers. This disparity needs to be clarified in order to develop effective immunotherapies. In this study, we provide new evidence that reconcile human and mouse data and highlight the importance of using relevant preclinical tumor models when assessing B cell function. We compared B cell infiltration and activation in both a genetic model of murine PDAC (KPC mouse) and an injectable orthotopic model. A pronounced B cell infiltrate was only observed in KPC tumors and correlated with T cell infiltration, mirroring human disease. In contrast, orthotopic tumors exhibited a relative paucity of B cells. Accordingly, KPC-derived B cells displayed markers of B cell activation (germinal center entry, B cell memory, and plasma cell differentiation) accompanied by significant intratumoral immunoglobulin deposition, a feature markedly weaker in orthotopic tumors. Tumor immunoglobulins, however, did not appear to form immune complexes. Furthermore, in contrast to the current paradigm that tumor B cells are immunosuppressive, when assessed as a bulk population, intratumoral B cells upregulated several proinflammatory and immunostimulatory genes, a distinctly different phenotype to that of splenic-derived B cells; further highlighting the importance of studying tumor-infiltrating B cells over B cells from secondary lymphoid organs. In agreement with the current literature, genetic deletion of B cells (μMT mice) resulted in reduced orthotopic tumor growth, however, this was not recapitulated by treatment with B-cell-depleting anti-CD20 antibody and, more importantly, was not observed in anti-CD20-treated KPC mice. This suggests the result from B cell deficient mice might be caused by their altered immune system, rather than lack of B cells. Therefore, our data indicate B cells do not favor tumor progression. In conclusion, our analysis of relevant preclinical models shows B cells to be active members of the tumor microenvironment, producing immunostimulatory factors that might support the adaptive antitumor immune response, as suggested by human PDAC studies

Role of B lymphocytes in allograft rejection

Le rejet d’allogreffe représente un obstacle majeur en transplantation rénale humaine. Le lymphocyte B (LB) joue un rôle lors de cette réaction contre le greffon, mal défini à ce jour. Notre objectif a été de caractériser et identifier son implication dans le rejet humoral chronique (cABMR) et le rejet cellulaire aigu (ACR). Dans une première partie, la caractérisation phénotypique des LB par cytométrie en flux chez ces patients a mis en évidence d’importantes différences dans la distribution des sous-populations de LB uniquement chez les patients cABMR. Chez les patients ACR, dont la distribution des LB n’est pas altérée, l’analyse de coupes de biopsies rénales a permis de mettre en évidence un infiltrat cellulaire constitué de lymphocytes B et T. Dans une seconde partie, l’activité fonctionnelle et régulatrice des LB issus de patients cABMR et ACR a été évaluée à l’aide d’un modèle in vitro de coculture entre des LB et des LT. Cette étude a révélé que les LB, issus des patients cABMR uniquement, sont dépourvus d’activités régulatrices sur la fonction des LT autologues. Cette étude a aussi mis en exergue que les LB des patients cABMR présentaient une déficience dans la sécrétion de molécules immunosuppressives telles que le TGFβ et l’indoleamine 2,3-dioxygénase (IDO). Ce défaut conduit à une incapacité à générer des lymphocytes T régulateurs. Finalement, notre étude a clairement démontré le rôle du LB dans les mécanismes physiopathologiques conduisant au rejet. Ces travaux ont donc permis de générer d’éventuelles perspectives pour définir de nouvelles stratégies thérapeutiques dans la lutte contre le rejet d’allogreffe.Allograft rejection is one of the main obstacles in human kidney transplantation. The role of B lymphocytes in the response against the allograft is poorly understood. Our aim is to identify and clarify its involvement in chronical humoral and cellular rejection. First of all, we identify profound changes in the distribution of B lymphocytes in cABMR patients which was not the case for ACR patients. In those last ones, we were able to detect on kidney biopsies an important cellular infiltrate composed with B and T cells. In the second part of this work, the functional and regulatory functions of B cells from both groups of patients were analyzed by using an in vitro coculture model between B and T cells. It appeared that B lymphocytes isolated from cABMR patients were unable to inhibit autologous T cell activity. This study showed those cells failed to produce immunosuppressive molecules as TGFβ and indoleamine 2,3-dioxygenase (IDO) leading to a default in the generation of regulatory T cells. To conclude, this study clearly showed the roles of B cells in physiopathological mechanisms of allograft rejection and helped to define new therapeutical strategies to prevent or reduce its consequences for the patients

Étude du lymphocyte B au cours du rejet d'allogreffe rénale

Allograft rejection is one of the main obstacles in human kidney transplantation. The role of B lymphocytes in the response against the allograft is poorly understood. Our aim is to identify and clarify its involvement in chronical humoral and cellular rejection. First of all, we identify profound changes in the distribution of B lymphocytes in cABMR patients which was not the case for ACR patients. In those last ones, we were able to detect on kidney biopsies an important cellular infiltrate composed with B and T cells. In the second part of this work, the functional and regulatory functions of B cells from both groups of patients were analyzed by using an in vitro coculture model between B and T cells. It appeared that B lymphocytes isolated from cABMR patients were unable to inhibit autologous T cell activity. This study showed those cells failed to produce immunosuppressive molecules as TGFβ and indoleamine 2,3-dioxygenase (IDO) leading to a default in the generation of regulatory T cells. To conclude, this study clearly showed the roles of B cells in physiopathological mechanisms of allograft rejection and helped to define new therapeutical strategies to prevent or reduce its consequences for the patients.Le rejet d’allogreffe représente un obstacle majeur en transplantation rénale humaine. Le lymphocyte B (LB) joue un rôle lors de cette réaction contre le greffon, mal défini à ce jour. Notre objectif a été de caractériser et identifier son implication dans le rejet humoral chronique (cABMR) et le rejet cellulaire aigu (ACR). Dans une première partie, la caractérisation phénotypique des LB par cytométrie en flux chez ces patients a mis en évidence d’importantes différences dans la distribution des sous-populations de LB uniquement chez les patients cABMR. Chez les patients ACR, dont la distribution des LB n’est pas altérée, l’analyse de coupes de biopsies rénales a permis de mettre en évidence un infiltrat cellulaire constitué de lymphocytes B et T. Dans une seconde partie, l’activité fonctionnelle et régulatrice des LB issus de patients cABMR et ACR a été évaluée à l’aide d’un modèle in vitro de coculture entre des LB et des LT. Cette étude a révélé que les LB, issus des patients cABMR uniquement, sont dépourvus d’activités régulatrices sur la fonction des LT autologues. Cette étude a aussi mis en exergue que les LB des patients cABMR présentaient une déficience dans la sécrétion de molécules immunosuppressives telles que le TGFβ et l’indoleamine 2,3-dioxygénase (IDO). Ce défaut conduit à une incapacité à générer des lymphocytes T régulateurs. Finalement, notre étude a clairement démontré le rôle du LB dans les mécanismes physiopathologiques conduisant au rejet. Ces travaux ont donc permis de générer d’éventuelles perspectives pour définir de nouvelles stratégies thérapeutiques dans la lutte contre le rejet d’allogreffe

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