88 results on '"Heslan, M."'
Search Results
2. An Immunomodulatory Role for Follistatin‐Like 1 in Heart Allograft Transplantation
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Le Luduec, J.B., Condamine, T., Louvet, C., Thebault, P., Heslan, J.‐M., Heslan, M., Chiffoleau, E., and Cuturi, M.‐C.
- Published
- 2008
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3. Role of IFNγ in Allograft Tolerance Mediated by CD4+CD25+ Regulatory T Cells by Induction of IDO in Endothelial Cells
- Author
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Thebault, P., Condamine, T., Heslan, M., Hill, M., Bernard, I., Saoudi, A., Josien, R., Anegon, I., Cuturi, M.C., and Chiffoleau, E.
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- 2007
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4. P089 Extensive characterisation of cellular sources of IL-22BP in inflammatory bowel diseases indicates that T cells do not express IL-22BP
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Fantou, A, primary, Abidi, A, additional, Delbos, L, additional, Podevin, J, additional, Jarry, A, additional, Heslan, M, additional, Martin, J, additional, Bourreille, A, additional, and Josien, R, additional
- Published
- 2019
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5. What’s New in Psoriasis
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Voorhees, J. J., Christophers, E., Dubertret, L., Schubert, C., Bertaux, B., Coulomb, B., Saiag, P., Heslan, M., Kragballe, K., Fisher, G. J., Ohkawara, A., Iizuka, H., Farber, E. M., Reusch, M. K., Naukkarinen, A., Wastek, G. J., Karasek, M. A., Ellis, C. N., Gupta, A. K., Brown, M. D., Cooper, K. D., Orfanos, Constantin E., editor, Stadler, Rudolf, editor, and Gollnick, Harald, editor
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- 1988
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6. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis
- Author
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Martin, J C, primary, Bériou, G, additional, Heslan, M, additional, Bossard, C, additional, Jarry, A, additional, Abidi, A, additional, Hulin, P, additional, Ménoret, S, additional, Thinard, R, additional, Anegon, I, additional, Jacqueline, C, additional, Lardeux, B, additional, Halary, F, additional, Renauld, J-C, additional, Bourreille, A, additional, and Josien, R, additional
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- 2016
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7. The Mixed Epidermal Cell Lymphocyte Reaction Allows the Detection of Alloreactivities Before Graft in HLA Identical Siblings
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Bagot, M., primary, Cordonnier, C., additional, Heslan, M., additional, Tilkin, A. F., additional, Dubertret, L., additional, Vernant, J. P., additional, and Levy, J. P., additional
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- 1985
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8. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid
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Martin, J CJ, primary, Bériou, G, additional, Heslan, M, additional, Chauvin, C, additional, Utriainen, L, additional, Aumeunier, A, additional, Scott, C L, additional, Mowat, A, additional, Cerovic, V, additional, Houston, S A, additional, Leboeuf, M, additional, Hubert, F X, additional, Hémont, C, additional, Merad, M, additional, Milling, S, additional, and Josien, R, additional
- Published
- 2014
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9. INVOLVEMENT OF PDCS IN THE TOLEROGENIC FUNCTION OF CD8+CD45RCLOW TREG AFTER CD40-CD40L BLOCKADE IN A RAT HEART ALLOTRANSPLANTATION MODEL
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LI, X L., primary, Ménoret, S, additional, Chabannes, D, additional, Hill, M, additional, Heslan, M, additional, Usal, C, additional, Angin, M, additional, Josien, R, additional, Le Mauff, B, additional, and Anegon, I, additional
- Published
- 2008
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10. TLR9 ligand enhances proliferation of rat CD4+ T cell and modulates suppressive activity mediated by CD4+ CD25+ T cell
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Chiffoleau, E., primary, Heslan, J.-M., additional, Heslan, M., additional, Louvet, C., additional, Condamine, T., additional, and Cuturi, M.-C., additional
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- 2006
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11. Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution.
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Bertaux, B., Prost, C., Heslan, M., and Dubertret, L.
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CANTHARIDES ,EPIDERMOLYSIS bullosa ,PRESERVATION of organs, tissues, etc. ,EPITHELIAL cells ,PROTEASE inhibitors ,PROTEOLYTIC enzymes ,ORGANS (Anatomy) - Abstract
Using a method which allowed us to study the morphological consequences of the expression and the inhibition of proteases in living tissues, we demonstrated that the primary detectable cellular event in cantharide acantholysis is the dissolution of the dense plaque, leading to the detachment of tonofilaments from desmosomes. This process is inhibited by neutral serine protease inhibitors. This suggests that the desmosome-tonofilament complex, more precisely the desmosomal dense plaque, is the primary target of activated proteases during cantharide acantholysis, and can be disrupted by a specific epidermal protease-anti protease system. Cantharide acantholysis may be a useful model for studying desmosomal turnover. [ABSTRACT FROM AUTHOR]
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- 1988
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12. A new method for studying epidermalization <em>in vitro</em>.
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Coulomb, B., Saiag, P., Bell, E., Breitburd, F., Lebreton, C., Heslan, M., and Dubertret, L.
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EPIDERMIS ,KERATINIZATION ,LANGERHANS cells ,BIOPSY ,FIBROBLASTS ,COLLAGEN ,EXTRACELLULAR matrix proteins - Abstract
A new method for studying epidermalization in vitro is described. It consists of inserting a punch biopsy that serves as a source of epidermis into dermal equivalent freshly made up, with fibroblasts mixed in a collagen matrix. Fibroblasts cling to collagen fibrils and contract the matrix, leading in 3 days to a resistant dermal equivalent holding the punch biopsy firmly in place. At day 5, a culture medium favouring epidermal growth was used and a fringe of a new epidermis appeared around the punch, the area of which grew linearly with time. This new epidermis showed a pattern of differentiation similar to epidermis in vivo, with cuboidal basal cells, keratohyalin granules, membrane coating granules and the expression of the 65–67 kd keratin subset. The method seems to combine the advantages of the explant technique and of classical keratinocyte cultures, providing the researcher with a large quantity of differentiated epidermis, the pharmacologist with simple and quantitative system in which to study modifications of growth and differentiation of epidermis, and the plastic surgeon with a possible material for skin grafting. [ABSTRACT FROM AUTHOR]
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- 1986
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13. Antigen-presenting properties of human epidermal cells compared with peripheral blood mononuclear cells.
- Author
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Bagot, M., Heslan, M., Dubertret, L., Roujeau, J. C., Touraine, R., and Levy, J. P.
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SKIN ,ANTIGENS ,EPIDERMIS ,DENDRITIC cells ,LYMPHOCYTES ,LYMPHOID tissue ,T cells - Abstract
The initiating event of several immune effector functions in the skin is the presentation of antigens to lymphoid immunocornpetent cells. Two kinds of antigen-presenting cells have been identified in normal human epidermis: Langerhans cells (LC) and indeterminate cells (Rowden, Phillips & Lewis, 1979). They display a dendritic morphology, bear class II HLA-DR molecules, and are necessary for T-cell activation and proliferation. The role of these epidermal dendritic cells in epidermal cell-lymphocyte interactions and their antigen-presenting proper- tics have been studied in vitro in the mixed epidermal cell-lymphocyte reaction (MECLR). [ABSTRACT FROM AUTHOR]
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- 1985
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14. Indirect CD4+ TH1 Response, Antidonor Antibodies and Diffuse C4d Graft Deposits in Long-Term Recipients Conditioned by Donor Antigens Priming
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Ballet, C., Renaudin, K., Degauque, N., Mai, H. L., Boëffard, F., Lair, D., Berthelot, L., Feng, C., Smit, H., Usal, C., Heslan, M., Josien, R., Brouard, S., and Soulillou, J.-P.
- Abstract
Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.Dumolecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibody-mediated rejection in human.
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- 2009
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15. Indirect CD4+TH1 Response, Antidonor Antibodies and Diffuse C4d Graft Deposits in Long-Term Recipients Conditioned by Donor Antigens Priming
- Author
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Ballet, C., Renaudin, K., Degauque, N., Mai, H.L., Boëffard, F., Lair, D., Berthelot, L., Feng, C., Smit, H., Usal, C., Heslan, M., Josien, R., Brouard, S., and Soulillou, J.-P.
- Abstract
Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.Dumolecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4+indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibody-mediated rejection in human.
- Published
- 2009
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16. Role of IFN? in Allograft Tolerance Mediated by CD4CD25Regulatory T Cells by Induction of IDO in Endothelial Cells
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Thebault, P., Condamine, T., Heslan, M., Hill, M., Bernard, I., Saoudi, A., Josien, R., Anegon, I., Cuturi, M. C., and Chiffoleau, E.
- Abstract
Regulatory T cells have been described to specifically accumulate at the site of regulation together with effector T cells and antigen-presenting cells, establishing a state of local immune privilege. However the mechanisms of this interplay remain to be defined. We previously demonstrated, in a fully MHC mismatched rat cardiac allograft combination, that a short-term treatment with a deoxyspergualine analogue, LF15-0195, induces long-term allograft tolerance with a specific expansion of regulatory CD4CD25T cells that accumulate within the graft. In this study, we show that following transfer of regulatory CD4T cells to a secondary irradiated recipient, regulatory CD25Foxp3and CD25Foxp3?CD4T cells accumulate at the graft site and induce graft endothelial cell expression of Indoleamine 2, 3-dioxygenase (IDO) by an IFN?-dependent mechanism. Moreover, in vivotransfer of tolerance can be abrogated by blocking IFN? or IDO, and anti-IFN? reduces the survivalexpansion of alloantigen-induced regulatory Foxp3CD4T cells. Together, our results demonstrate interrelated mechanisms between regulatory CD4CD25T cells and the graft endothelial cells in this local immune privilege, and a key role for IFN? and IDO in this process.
- Published
- 2007
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17. 'Critical Requirement for Graft Passenger Leukocytes in Allograft Tolerance Induced by Donor Blood Transfusion.' Blood, December 15, 1998;92(12):4539-4544
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Josien, R., Heslan, M., Brouard, S., Soulillou, J.P., and Cuturi, M.C.
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Blood transfusion -- Physiological aspects -- Research ,Immunological tolerance -- Research -- Physiological aspects ,Health ,Physiological aspects ,Research - Abstract
According to the authors' abstract of an article published in Blood, 'Tolerance to a vascularized allograft can be induced in adult animals by pregraft donor-specific blood transfusion (DST). Mechanisms underlying [...]
- Published
- 1999
18. Reconstruction in vitro of a human living skin equivalent
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Dubertret L, Coulomb B, Saiag P, Bertaux B, Corinne LEBRETON, Heslan M, Breitburd F, Bell E, Baruch J, and Guilbaud J
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Culture Techniques ,Skin Physiological Phenomena ,Animals ,Humans ,Skin Transplantation ,Epidermis ,Models, Biological ,Transplantation, Autologous ,Skin - Published
- 1985
19. Reconstructed human epidermis: absence of Langerhans cells and failure to stimulate allogeneic lymphocytes in vitro
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Bagot, M, Bertaux, B, Heslan, M, Coulomb, B, and Dubertret, L
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integumentary system ,Epidermal Cells ,Culture Techniques ,Langerhans Cells ,Humans ,Lymphocyte Culture Test, Mixed ,Lymphocyte Activation ,Models, Biological ,Research Article ,Skin - Abstract
Whole human skin can be reconstructed in vitro, using dermal equivalents made of fibroblasts in a collagen matrix. We recently described a new method of epidermalization of dermal equivalents, based on the insertion of punch biopsies and the migration of epidermal cells (EC) on the reconstructed dermis. In the present study, we show that no MHC class II or T6 positive Langerhans cells (LC) can be detected in this new epidermis. Functional studies with EC of this reconstructed epidermis show that these EC completely fail to induce proliferation of allogeneic lymphocytes in mixed epidermal cell lymphocyte reactions and to raise an allogeneic T cell response. In contrast, fresh EC from the same donors induce a strong proliferative and cytotoxic response of the same effector cells. Moreover, the addition of fresh LC-containing EC autologous to effector lymphocytes does not restore an allogeneic proliferative and cytotoxic response directed against class I different EC of the new epidermis. Such a non-immunogenic whole skin model composed of two compartments, dermis and epidermis, completely devoid of class II-bearing antigen presenting cells, is thus a very promising technique for allogeneic skin grafting in the treatment of burns.
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- 1988
20. A new method for studying epidermalization in vitro
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COULOMB, B., primary, SAIAG, P., additional, BELL, E., additional, BREITBURD, F., additional, LEBRETON, C., additional, HESLAN, M., additional, and DUBERTRET, L., additional
- Published
- 1986
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21. Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model.
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Broquet A, Jacqueline C, Davieau M, Besbes A, Roquilly A, Martin J, Caillon J, Dumoutier L, Renauld JC, Heslan M, Josien R, and Asehnoune K
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- Animals, Disease Models, Animal, Mice, Interleukin-22, Interleukins analysis, Lung pathology, Neutrophil Infiltration, Pneumonia, Bacterial pathology, Pseudomonas Infections pathology, Receptors, Interleukin analysis
- Abstract
Pseudomonas aeruginosa is a major threat for immune-compromised patients. Bacterial pneumonia can induce uncontrolled and massive neutrophil recruitment ultimately leading to acute respiratory distress syndrome and epithelium damage. Interleukin-22 plays a central role in the protection of the epithelium. In this study, we aimed to evaluate the role of interleukin-22 and its soluble receptor IL-22BP in an acute Pseudomonas aeruginosa pneumonia model in mice. In this model, we noted a transient increase of IL-22 during Pseudomonas aeruginosa challenge. Using an antibody-based approach, we demonstrated that IL-22 neutralisation led to increased susceptibility to infection and to lung damage correlated with an increase in neutrophil accumulation in the lungs. On the contrary, rIL-22 administration or IL-22BP neutralisation led to a decrease in mouse susceptibility and lung damage associated with a decrease in neutrophil accumulation. This study demonstrated that the IL-22/IL-22BP system plays a major role during Pseudomonas aeruginosa pneumonia by moderating neutrophil accumulation in the lungs that ultimately leads to epithelium protection.
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- 2017
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22. Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16- Human Blood Monocytes in Serum-Free Condition.
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Picarda G, Chéneau C, Humbert JM, Bériou G, Pilet P, Martin J, Duteille F, Perrot P, Bellier-Waast F, Heslan M, Haspot F, Guillon F, Josien R, and Halary FA
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- Antigens, Neoplasm metabolism, Cell Adhesion Molecules metabolism, Cell Differentiation, Cells, Cultured, Humans, Isoantigens immunology, Lipopolysaccharide Receptors metabolism, Lymphocyte Activation, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, IgG metabolism, Self Tolerance, Ultraviolet Rays, Axl Receptor Tyrosine Kinase, Blood Cells physiology, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Keratinocytes physiology, Langerhans Cells immunology, Monocytes physiology, T-Lymphocytes immunology, Transforming Growth Factor beta1 metabolism
- Abstract
Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerin(high) LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerin(high)-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerin(high)-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerin(high) MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerin(high) MDLCs as a relevant model to address LC biology-related questions., (Copyright © 2016 by The American Association of Immunologists, Inc.)
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- 2016
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23. Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents.
- Author
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Durand J, Huchet V, Merieau E, Usal C, Chesneau M, Remy S, Heslan M, Anegon I, Cuturi MC, Brouard S, and Chiffoleau E
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- Allografts, Animals, Antigens, CD immunology, Cytokines immunology, Isoantigens immunology, Male, Rats, T-Lymphocytes, Regulatory immunology, B-Lymphocytes, Regulatory immunology, CD40 Antigens immunology, Granzymes immunology, Heart Transplantation, Plasma Cells immunology, Signal Transduction immunology, Transplantation Tolerance
- Abstract
Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24(int)CD38(+)CD27(+)IgD(-)IgM(+/low) subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-β1-dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD(-)IgM(+/low) B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3(+)CD4(+)CD25(+) regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3(+)CD4(+)CD25(+) regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic., (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Published
- 2015
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24. Receptor activating NF-κB ligand (RANKL) is a constitutive intracellular protein in resting human basophils and is strongly induced on their surface by interleukin 3.
- Author
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Poli C, Martin JC, Braudeau C, Bériou G, Hémont C, Charrier C, Guérin S, Heslan M, and Josien R
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- Cell Communication, Cell Differentiation, Cells, Cultured, Humans, Interleukin-3 immunology, Protein Transport immunology, RANK Ligand genetics, Up-Regulation immunology, Basophils immunology, Bone Resorption immunology, Cell Membrane metabolism, Dendritic Cells immunology, Intracellular Space metabolism, Osteoclasts physiology, RANK Ligand metabolism
- Abstract
Receptor activating NF-κB ligand (RANKL) is a member of the TNF superfamily that plays a pivotal role in bone homeostasis as being the major osteoclastogenesis factor. RANKL also has pleiotropic effects in the immune system in which it is expressed by activated T and B cells and some innate lymphoid cells. RANKL-RANK interactions mediate lymph node organogenesis and immunoregulatory functions in autoimmune disease and carcinogenesis as well as cross talk between the immune system and bone. In this study, we show that basophils were the strongest RANKL mRNA-expressing cells amongst major leukocyte subsets in human blood. RANKL was preformed as an intracellular protein in resting basophils and was rapidly and strongly expressed on their surface upon stimulation with IL-3, but not other stimuli. This expression was stable for at least 6 days. Activated basophils could also release soluble RANKL in small quantities upon interaction with DCs or monocytes. In the blood, basophils were the sole cells to express membrane RANKL in response to IL-3. This study indicates that basophils should be considered as new players in the pleiotropic and complex RANKL-RANK interaction system and suggests a role for RANKL in the interaction between basophils and immune cells in inflammatory allergic tissues and secondary lymphoid organs., (Copyright © 2014 Elsevier GmbH. All rights reserved.)
- Published
- 2015
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25. Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness.
- Author
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Hémont C, Neel A, Heslan M, Braudeau C, and Josien R
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- Antigen Presentation, Antigens, CD genetics, Antigens, CD1 genetics, Antigens, CD1 immunology, Cells, Cultured, Cytokines metabolism, Dendritic Cells classification, Dendritic Cells cytology, Flow Cytometry, Glycoproteins genetics, Glycoproteins immunology, Humans, Immunomagnetic Separation, Immunophenotyping, Protein Isoforms classification, Protein Isoforms genetics, Protein Isoforms immunology, Toll-Like Receptors classification, Toll-Like Receptors genetics, Antigens, CD immunology, Cytokines immunology, Dendritic Cells immunology, Toll-Like Receptors immunology
- Abstract
Human blood DCs encompass pDCs and two subsets of mDCs: CD1c(+) mDCs and CD141(+) mDCs. The rare CD141(+) DC population is thought to be the equivalent of mouse CD8α(+) cDCs that play a significant role in antigen cross-presentation. Here, we analyzed by Q-PCR TLR1-10 expression in blood DC subsets. Whereas CD1c(+) DCs express all TLR except TLR9, CD141(+) DCs present a more restricted pattern with high expression of TLR3 and -10, expression of TLR1,-2, -6, and -8, and lack of TLR4, -5, -7, and -9. The in vitro analysis of isolated mDC subset reponsiveness to an extensive panel of TLR ligands confirmed these results, with CD141(+) DCs responding only to TLR1/2, -3, and -7/8. The cytokine/chemokine production profile of isolated CD141(+) DCs was also more restricted, as they produced mainly proinflammatory cytokines but no IL-12 and to a lower level, in comparison with CD1c(+) DCs, except for CXCL10, CCL5, and IFN-β. In contrast, with the use of a whole blood assay, we found that CD141(+) DCs produce IL-12 in response to TLR1/2, -3, and more surprisingly, -9. Finally, both mDC subsets are potent inducers of Th1 response, particularly after TLR3 triggering. Taken together, these data confirmed functional differences between blood mDC subsets. The major response of CD141(+) mDCs to TLR3 ligand and their cytokine production pattern suggest a role for these cells in antiviral immunity.
- Published
- 2013
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26. Modulation of regulatory T cell-Th17 balance by plasmacytoid dendritic cells.
- Author
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Gautreau L, Chabannes D, Heslan M, and Josien R
- Subjects
- Animals, Cell Differentiation, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Forkhead Transcription Factors metabolism, Interleukin-17 immunology, Interleukin-2 Receptor alpha Subunit metabolism, Interleukin-6 metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Rats, Rats, Inbred Lew, T-Lymphocytes metabolism, Dendritic Cells immunology, Interleukin-17 metabolism, T-Lymphocytes immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Tregs represent an interesting therapeutic tool to modulate immune responses that could be deleterious in autoimmune diseases and in transplantation. However, phenotype and functions of Tregs do not seem to be stable, and recent data suggest that FoxP3-expressing Tregs can be driven to produce IL-17. In this study, we have analyzed the role of pDCs versus cDCs on Treg responses and underlined that pDCs have an intrinsic, unique capacity to induce IL-17 secretion from T cells. We showed in rats that FoxP3(+) Tregs were able to secrete IL-17 only when stimulated by allogeneic, mature pDCs but not cDCs. In addition, in rats and mice, mature pDCs but not cDCs inhibited in vitro Treg-suppressive functions and in the presence of Tregs, supported Th17 differentiation from naive T cells through secretion of high amounts of IL-6. These data suggest an important role for pDCs in modulating or switching Treg function and allowing Th17 differentiation.
- Published
- 2011
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27. Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance.
- Author
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Li XL, Ménoret S, Bezie S, Caron L, Chabannes D, Hill M, Halary F, Angin M, Heslan M, Usal C, Liang L, Guillonneau C, Le Mauff B, Cuturi MC, Josien R, and Anegon I
- Subjects
- Adenoviridae genetics, Adoptive Transfer, Animals, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes cytology, Cell Proliferation, Dendritic Cells cytology, Dendritic Cells immunology, Flow Cytometry, Genetic Vectors genetics, Heart Transplantation methods, Male, Models, Animal, Rats, Rats, Inbred Lew, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Spleen cytology, Spleen immunology, T-Lymphocytes, Regulatory cytology, Transduction, Genetic, Transplantation, Homologous, CD8-Positive T-Lymphocytes immunology, Heart Transplantation immunology, Immune Tolerance immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Despite accumulating evidence for the importance of allospecific CD8(+) regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8(+) Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8(+) Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8(+) Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8(+) Tregs to suppress CD4(+) effector cells responses to first-donor Ags in vitro. When tolerogenic CD8(+) Tregs were not in contact with CD4(+) effector cells, suppression was mediated by IDO. Contact with CD4(+) effector cells resulted in alternative suppressive mechanisms implicating IFN-gamma and fibroleukin-2. In vivo, both IDO and IFN-gamma were involved in tolerance induction, suggesting that contact with CD4(+) effector cells is crucial to modulate CD8(+) Tregs function in vivo. In conclusion, CD8(+) Tregs and pDCs interactions were necessary for suppression of CD4(+) T cells and involved different mechanisms modulated by the presence of cell contact between CD8(+) Tregs, pDCs, and CD4(+) effector cells.
- Published
- 2010
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28. Characterization of Schlafen-3 expression in effector and regulatory T cells.
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Condamine T, Le Luduec JB, Chiffoleau E, Bériou G, Louvet C, Heslan M, Tilly G, and Cuturi MC
- Subjects
- Animals, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Gene Expression Profiling, Gene Expression Regulation drug effects, Humans, Interleukin-2 Receptor alpha Subunit metabolism, Lymphocyte Activation drug effects, Mice, Proteins genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory drug effects, Transforming Growth Factor beta pharmacology, Proteins metabolism, T-Lymphocytes, Regulatory metabolism
- Abstract
Members of the Slfn protein family have been implicated in the regulation of cell growth, hematopoietic cell differentiation, and T cell development/differentiation in the thymus. Ten members of this family have been described in the mouse, and they have been divided into three subgroups based on the overall sequence homology and the size of the encoded proteins. We have identified Slfn3, a member of Subgroup II, as an overexpressed gene in CD4(+) CD25(+) T cells in the periphery. Interestingly, we demonstrate that upon activation and proliferation, Slfn3 mRNA is down-regulated in CD4(+) CD25(+) Tregs and up-regulated in CD4(+) CD25(-) Teffs. Moreover, TGF-beta inhibits the expression of Slfn3 in anti-CD3/CD28-activated CD4+ T cells, and the same conditions induce FoxP3 mRNA. Our results suggest that Slfn3 could have a role in T cell differentiation and activation.
- Published
- 2010
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29. The C-type lectin-like receptor CLEC-1, expressed by myeloid cells and endothelial cells, is up-regulated by immunoregulatory mediators and moderates T cell activation.
- Author
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Thebault P, Lhermite N, Tilly G, Le Texier L, Quillard T, Heslan M, Anegon I, Soulillou JP, Brouard S, Charreau B, Cuturi MC, and Chiffoleau E
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cells, Cultured, Endothelial Cells pathology, Gene Expression Regulation immunology, Graft Survival genetics, Graft Survival immunology, Heart Transplantation immunology, Heart Transplantation pathology, Immune Tolerance genetics, Inflammation Mediators physiology, Lectins, C-Type antagonists & inhibitors, Lectins, C-Type genetics, Lectins, C-Type physiology, Lymphocyte Activation genetics, Molecular Sequence Data, Rats, Rats, Inbred Lew, T-Lymphocyte Subsets metabolism, Endothelial Cells immunology, Endothelial Cells metabolism, Lectins, C-Type biosynthesis, Lymphocyte Activation immunology, Myeloid Cells immunology, Myeloid Cells metabolism, T-Lymphocyte Subsets immunology, Up-Regulation immunology
- Abstract
C-type lectin receptors have recently been described as playing crucial roles in immunity and homeostasis since these proteins are able to recognize pathogens as well as self-Ags. We identified the C-type lectin-like receptor-1, CLEC-1, as being overexpressed in a model of rat allograft tolerance. We previously described in this model the expression of numerous cytoprotective molecules by graft endothelial cells and their interplay with regulatory CD4(+)CD25(+) T cells. In this study, we demonstrate that CLEC-1 is expressed by myeloid cells and specifically by endothelial cells in tolerated allografts and that CLEC-1 expression can be induced in endothelial cells by alloantigen-specific regulatory CD4(+)CD25(+) T cells. Analysis of CLEC-1 expression in naive rats demonstrates that CLEC-1 is highly expressed by myeloid cells and at a lower level by endothelial cells, and that its expression is down-regulated by inflammatory stimuli but increased by the immunoregulators IL-10 or TGFbeta. Interestingly, we demonstrate in vitro that inhibition of CLEC-1 expression in rat dendritic cells increases the subsequent differentiation of allogeneic Th17 T cells and decreases the regulatory Foxp3(+) T cell pool. Additionally, in chronically rejected allograft, the decreased expression of CLEC-1 is associated with a higher production of IL-17. Taken together, our data suggest that CLEC-1, expressed by myeloid cells and endothelial cells, is enhanced by regulatory mediators and moderates Th17 differentiation. Therefore, CLEC-1 may represent a new therapeutic agent to modulate the immune response in transplantation, autoimmunity, or cancer settings.
- Published
- 2009
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30. Myeloid-derived suppressor cells accumulate in kidney allograft tolerance and specifically suppress effector T cell expansion.
- Author
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Dugast AS, Haudebourg T, Coulon F, Heslan M, Haspot F, Poirier N, Vuillefroy de Silly R, Usal C, Smit H, Martinet B, Thebault P, Renaudin K, and Vanhove B
- Subjects
- Animals, B7-1 Antigen biosynthesis, B7-2 Antigen biosynthesis, CD11b Antigen biosynthesis, Cell Adhesion, Cells, Cultured, Cytotoxicity Tests, Immunologic, Immunophenotyping, Male, Models, Immunological, Myeloid Cells metabolism, Nitric Oxide Synthase Type II biosynthesis, Nitric Oxide Synthase Type II physiology, Rats, Rats, Inbred Lew, Spleen cytology, Spleen immunology, Spleen pathology, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, Cell Differentiation immunology, Cell Movement immunology, Immune Tolerance, Kidney Transplantation immunology, Myeloid Cells cytology, Myeloid Cells immunology
- Abstract
The immune tolerance to rat kidney allografts induced by a perioperative treatment with anti-CD28 Abs is associated with a severe unresponsiveness of peripheral blood cells to donor Ags. In this model, we identified an accumulation in the blood of CD3(-)class II(-)CD11b(+)CD80/86(+) plastic-adherent cells that additionally expressed CD172a as well as other myeloid markers. These cells were able to inhibit proliferation, but not activation, of effector T cells and to induce apoptosis in a contact-dependent manner. Their suppressive action was found to be under the control of inducible NO synthase, an enzyme also up-regulated in tolerated allografts. Based on these features, these cells can be defined as myeloid-derived suppressor cells (MDSC). Interestingly, CD4(+)CD25(high)FoxP3(+) regulatory T cells were insensitive in vitro to MDSC-mediated suppression. Although the adoptive transfer of MDSC failed to induce kidney allograft tolerance in recently transplanted recipients, the maintenance of tolerance after administration of anti-CD28 Abs was found to be dependent on the action of inducible NO synthase. These results suggest that increased numbers of MDSC can inhibit alloreactive T cell proliferation in vivo and that these cells may participate in the NO-dependent maintenance phase of tolerance.
- Published
- 2008
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31. Superiority of bone marrow-derived dendritic cells over monocyte-derived ones for the expansion of regulatory T cells in the macaque.
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Moreau A, Chiffoleau E, Beriou G, Deschamps JY, Heslan M, Ashton-Chess J, Rolling F, Josien R, Moullier P, Cuturi MC, and Alliot-Licht B
- Subjects
- Animals, Antigens, CD34 immunology, Immunophenotyping, Interleukin-2 Receptor alpha Subunit immunology, Lipopolysaccharide Receptors immunology, Macaca fascicularis, Models, Animal, Bone Marrow Cells cytology, Bone Marrow Cells immunology, Dendritic Cells immunology, Lymphocyte Activation, Monocytes cytology, Monocytes immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Regulatory T cells (Treg) have been identified as playing a pivotal role in the control of tolerance and in the suppression of pathologic immune responses in autoimmune diseases, transplantation, and graft-versus-host disease. Treg expanded ex vivo by dendritic cells could be potential reagents to promote antigen-specific tolerance in vivo. However, in vivo studies have been carried out mostly in rodents and will need validation in primates before clinical application. We characterized macaque dendritic cell derived either from bone marrow with and without prior CD34+ cell selection (BMDC), or from CD14+ peripheral blood mononuclear cells (Mo-DC). We demonstrate that with a semi-mature phenotype, BMDC are superior to Mo-DC in their capacity to expand freshly isolated allogeneic macaque CD4+ CD25+ CD127- Foxp3+ Treg in vitro in the presence of interleukin-2. Moreover, the expanded Treg maintain their phenotype and suppressive activity. These data provide a step toward the use of macaque dendritic cell to expand Treg for future preclinical testing.
- Published
- 2008
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32. Differential control of T regulatory cell proliferation and suppressive activity by mature plasmacytoid versus conventional spleen dendritic cells.
- Author
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Ouabed A, Hubert FX, Chabannes D, Gautreau L, Heslan M, and Josien R
- Subjects
- Animals, B7-2 Antigen immunology, Clonal Anergy immunology, Dendritic Cells cytology, Interferon-gamma immunology, Interleukin-2 immunology, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit immunology, Plasma Cells cytology, Rats, Rats, Sprague-Dawley, Spleen cytology, T-Lymphocytes, Regulatory cytology, Toll-Like Receptor 7 immunology, Toll-Like Receptor 9 immunology, Cell Proliferation, Dendritic Cells immunology, Plasma Cells immunology, Spleen immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Anergy and suppression are cardinal features of CD4(+)CD25(+)Foxp3(+) T cells (T regulatory cells (Treg)) which have been shown to be tightly controlled by the maturation state of dendritic cells (DC). However, whether lymphoid organ DC subsets exhibit different capacities to control Treg is unclear. In this study, we have analyzed, in the rat, the role of splenic CD4(+) and CD4(-) conventional DC and plasmacytoid DC (pDC) in allogeneic Treg proliferation and suppression in vitro. As expected, in the absence of exogenous IL-2, Treg did not expand in response to immature DC. Upon TLR-induced maturation, all DC became potent stimulators of CD4(+)CD25(-) T cells, whereas only TLR7- or TLR9-matured pDC induced strong proliferation of CD4(+)CD25(+)Foxp3(+) T cells in the absence of exogenous IL-2. This capacity of pDC to reverse Treg anergy required cell contact and was partially CD86 dependent and IL-2 independent. In suppression assays, Treg strongly suppressed proliferation and IL-2 and IFN-gamma production by CD4(+)CD25(-) T cells induced by mature CD4(+) and CD4(-) DC. In contrast, upon stimulation by mature pDC, proliferating Treg suppressed IL-2 production by CD25(-) cells but not their proliferation or IFN-gamma production. Taken together, these results suggest that anergy and the suppressive function of Treg are differentially controlled by DC subsets.
- Published
- 2008
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33. IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells.
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Hill M, Tanguy-Royer S, Royer P, Chauveau C, Asghar K, Tesson L, Lavainne F, Rémy S, Brion R, Hubert FX, Heslan M, Rimbert M, Berthelot L, Moffett JR, Josien R, Grégoire M, and Anegon I
- Subjects
- Cell Differentiation immunology, Cells, Cultured, Dendritic Cells cytology, Dendritic Cells immunology, Humans, Immunohistochemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase immunology, Lipopolysaccharides immunology, Lymphocyte Culture Test, Mixed, NF-kappa B, Reactive Oxygen Species metabolism, Tryptophan metabolism, Dendritic Cells enzymology, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Lymphocyte Activation immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory immunology
- Abstract
We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-alpha + poly(I:C)-induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPS-induced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPS-treated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-kappaB activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4(+)CD25(high) regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4(+)CD25(high) regulatory T cells.
- Published
- 2007
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34. Variation in numbers of CD4+CD25highFOXP3+ T cells with normal immuno-regulatory properties in long-term graft outcome.
- Author
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Braudeau C, Racape M, Giral M, Louis S, Moreau A, Berthelot L, Heslan M, Ashton-Chess J, Soulillou JP, and Brouard S
- Subjects
- Adult, Aged, Cell Proliferation, Disease Progression, Female, Follow-Up Studies, Graft Rejection blood, Graft Rejection pathology, Humans, Immune Tolerance, Kidney Transplantation pathology, Male, Middle Aged, Prognosis, Time Factors, CD4 Antigens immunology, Forkhead Transcription Factors immunology, Graft Rejection immunology, Immunity, Cellular immunology, Interleukin-2 Receptor alpha Subunit immunology, Kidney Transplantation immunology, T-Lymphocytes immunology
- Abstract
Chronic rejection (CR) is a major cause of long-term graft loss that would be avoided by the induction of tolerance. We previously showed that renal transplant patients with CR have lower numbers of peripheral CD4(+)CD25(high) T cells than operationally tolerant patients, patients with stable graft function and healthy volunteers (HV). We explored here the profile of CD4(+)CD25(high) blood T cells in these patients focusing on their expression of the regulatory T cells (Treg) gene Forkhead Box P3 (FOXP3) and their suppressive function. We show that CR is associated with a decreased number of CD4(+)CD25(high)FOXP3(+)T cells with normal regulatory profile, whereas graft acceptance is associated with CD4(+)CD25(high)FOXP3(+)T cell numbers similar to HVs. These data suggest that Treg numbers, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of renal transplants.
- Published
- 2007
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35. CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase.
- Author
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Guillonneau C, Hill M, Hubert FX, Chiffoleau E, Hervé C, Li XL, Heslan M, Usal C, Tesson L, Ménoret S, Saoudi A, Le Mauff B, Josien R, Cuturi MC, and Anegon I
- Subjects
- Adoptive Transfer, Animals, Graft Survival drug effects, Graft Survival immunology, Heart Transplantation immunology, Immune Tolerance drug effects, Rats, Rats, Inbred Lew, Transplantation, Homologous immunology, Graft Survival physiology, Heart Transplantation physiology, Indoleamine-Pyrrole 2,3,-Dioxygenase physiology, Interferon-gamma physiology, Recombinant Fusion Proteins therapeutic use, T-Lymphocytes immunology
- Abstract
Treatment with CD40Ig results in indefinite allograft survival in a complete MHC-mismatched heart allograft model in the rat. Here we show that serial second, third, and fourth adoptive transfers of total splenocytes from CD40Ig-treated recipients into secondary recipients led to indefinite donor-specific allograft acceptance. Purification of splenocyte subpopulations from CD40Ig-treated recipients demonstrated that only the adoptively transferred CD8(+)CD45RC(low) subset resulted in donor-specific long-term survival, whereas CD8(+)CD45RC(low) T cells from naive animals did not. Accepted grafts displayed increased indoleamine 2,3-dioxygenase (IDO) expression restricted in the graft to ECs. Coculture of donor ECs with CD8(+)CD45RC(low) T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-gamma. Neutralization of IFN-gamma or IDO triggered acute allograft rejection in both CD40Ig-treated and adoptively transferred recipients. This study demonstrates for what we believe to be the first time that interference in CD40-CD40 ligand (CD40-CD40L) interactions induces allospecific CD8(+) Tregs that maintain allograft survival. CD8(+)CD45RC(low) T cells act through IFN-gamma production, which in turn induces IDO expression by graft ECs. Thus, donor alloantigen-specific CD8(+) Tregs may promote local graft immune privilege through IDO expression.
- Published
- 2007
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36. TLR9 ligand enhances proliferation of rat CD4+ T cell and modulates suppressive activity mediated by CD4+ CD25+ T cell.
- Author
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Chiffoleau E, Heslan JM, Heslan M, Louvet C, Condamine T, and Cuturi MC
- Subjects
- Animals, CD4-Positive T-Lymphocytes metabolism, Cell Proliferation, CpG Islands, Interleukin-2 Receptor alpha Subunit metabolism, Ligands, Oligodeoxyribonucleotides, RNA, Messenger analysis, Rats, Rats, Inbred Lew, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets metabolism, CD4-Positive T-Lymphocytes immunology, T-Lymphocyte Subsets immunology, Toll-Like Receptor 9 biosynthesis
- Abstract
Toll-like receptors (TLRs) play a crucial role in the initiation of innate responses following microbial infection and also in adaptive immune responses by orchestrating the activation of different cell populations. TLRs are expressed at high levels in antigen-presenting cells and recent studies have demonstrated the expression and biological role of TLRs in mouse and human CD4(+) T cells. In this study, we analyzed TLR mRNA expression in rat CD4(+) T cells using stringent quantitative reverse transcription-PCR conditions enabling a direct comparison of the levels of each TLR. We show that TLR3, 5, 6 and 9 mRNAs are the highest TLRs expressed in rat CD4(+) T cells and that TLR5 mRNA is highly expressed in regulatory CD4(+) CD25(+) T cells. In addition, we show that the TLR9 ligand (TLR9L), CpG oligodeoxynucleotide, synergizes with anti-CD3 to induce proliferation of both CD4(+) CD25(-) and regulatory CD4(+) CD25(+) T cells and that TLR9L partially abrogates the suppressive activity mediated by regulatory CD4(+) CD25(+) T cells. This loss of suppression is in part due to the direct effect of TLR9L on effector T cells that are rendered more resistant to the regulation exerted by regulatory T cells. To our knowledge, this is the first study describing the expression of TLR mRNA in rat CD4(+) T cells and the capacity of TLR9L to directly regulate rat T cell responses. Thus, TLR9L may rapidly increase the host's adaptive immunity by expanding effector cells and also by attenuating the suppressive activity mediated by regulatory T cells.
- Published
- 2007
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37. Differential pattern recognition receptor expression but stereotyped responsiveness in rat spleen dendritic cell subsets.
- Author
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Hubert FX, Voisine C, Louvet C, Heslan JM, Ouabed A, Heslan M, and Josien R
- Subjects
- Animals, Cell Differentiation immunology, Cell Separation, Cell Survival immunology, Cells, Cultured, Cytokines biosynthesis, Dendritic Cells classification, Dendritic Cells cytology, Interleukin-10 biosynthesis, Interleukin-12 biosynthesis, Interleukin-12 Subunit p40, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins physiology, Leukocyte Count, Ligands, Lymphocyte Culture Test, Mixed, Nod2 Signaling Adaptor Protein, Protein Subunits biosynthesis, RNA, Messenger biosynthesis, Rats, Rats, Inbred BN, Rats, Inbred Lew, Rats, Sprague-Dawley, Spleen cytology, Toll-Like Receptors genetics, Toll-Like Receptors metabolism, Tumor Necrosis Factor-alpha biosynthesis, Dendritic Cells immunology, Dendritic Cells metabolism, Intracellular Signaling Peptides and Proteins metabolism, Spleen immunology, Spleen metabolism, Toll-Like Receptors biosynthesis
- Abstract
Dendritic cells (DC) are a heterogeneous population of APC endowed with specific functions. The nature of the DC subset involved in the course of an immune response to a specific pathogen might be important for inducing the appropriate effectors. In addition, each DC subset might also exhibit intrinsic functional plasticity. In the rat, spleen DC can be separated into three morphological and phenotypical distinct subsets, namely CD4+, CD4-, and plasmacytoid DC (pDC), whose frequencies are strain dependent. We correlated the expression of TLR and nucleotide-binding oligomerization domain 2 (NOD2) in these DC subsets to their in vitro responsiveness to specific ligands. CD4- DC expressed high levels of TLR1, 2, 3, and 10 mRNA, low TLR4, 5, 6, 7, and 9, and very low, if any, TLR8. pDC had a restricted repertoire characterized by high TLR7 and 9. CD4+ DC expressed all TLR and 10-fold higher levels of NOD2 mRNA than CD4- and pDC. Upon stimulation by TLR and NOD2 ligands, each DC subset responded in quite a stereotyped fashion. TLR2/6, 3, 4, 5, 9, and NOD2 triggering induced CD4- DC to mature and produce high IL-12p40, low IL-10, and TNF-alpha. TLR7/8 and 9 triggering induced pDC to mature and produce copious amounts of IL-6, IL-12p40, and TNF-alpha and low IFN-alpha. CD4+ DC were very poor producers of inflammatory cytokines. This study suggests that the nature of spleen DC responses to pathogens is dependent on subset specific-stimulation rather than intrinsic plasticity.
- Published
- 2006
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38. Anti-CD28 antibody-induced kidney allograft tolerance related to tryptophan degradation and TCR class II B7 regulatory cells.
- Author
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Haspot F, Séveno C, Dugast AS, Coulon F, Renaudin K, Usal C, Hill M, Anegon I, Heslan M, Josien R, Brouard S, Soulillou JP, and Vanhove B
- Subjects
- Animals, Apoptosis, CD28 Antigens biosynthesis, CD28 Antigens immunology, Cell Proliferation, Cytokines, Dose-Response Relationship, Drug, Flow Cytometry, Graft Rejection prevention & control, Graft Survival, Immunohistochemistry, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Isoantibodies chemistry, Kidney pathology, Killer Cells, Natural immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Culture Test, Mixed, Male, Nitric Oxide Synthase Type II antagonists & inhibitors, Phenotype, Rats, Rats, Inbred Lew, Time Factors, B7-1 Antigen biosynthesis, CD28 Antigens chemistry, Histocompatibility Antigens Class II biosynthesis, Kidney Transplantation methods, Receptors, Antigen, T-Cell biosynthesis, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transplantation Conditioning methods, Transplantation Tolerance, Tryptophan metabolism
- Abstract
B7/CTLA-4 interactions negatively regulate T-cell responses and are necessary for transplant tolerance induction. Tolerance induction may therefore be facilitated by selectively inhibiting the B7/CD28 pathway without blocking that of B7/CTLA-4. In this study, we selectively inhibited CD28/B7 interactions using a monoclonal antibody modulating CD28 in a rat model of acute kidney graft rejection. A short-term treatment abrogated both acute and chronic rejection. Tolerant recipients presented few alloantibodies against donor MHC class II molecules, whereas untreated rejecting controls developed anti-MHC class I and II alloantibodies. PBMC from tolerant animals were unable to proliferate against donor cells but could proliferate against third-party cells. The depletion of B7+, non-T cells fully restored this reactivity whereas purified T cells were fully reactive. Also, NK cells depletion restored PBMC reactivity in 60% of tolerant recipients. Conversely, NK cells from tolerant recipients dose-dependently inhibited alloreactivity. PBMC anti-donor reactivity could be partially restored in vitro by blocking indoleamine-2,3-dioxygenase (IDO) and iNOS. In vivo, pharmacologic inhibition of these enzymes led to the rejection of the otherwise tolerated transplants. This study demonstrates that an initial selective blockade of CD28 generates B7+ non-T regulatory cells and a kidney transplant tolerance sustained by the activity of IDO and iNOS.
- Published
- 2005
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39. Identification of a new member of the CD20/FcepsilonRIbeta family overexpressed in tolerated allografts.
- Author
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Louvet C, Chiffoleau E, Heslan M, Tesson L, Heslan JM, Brion R, Bériou G, Guillonneau C, Khalife J, Anegon I, and Cuturi MC
- Subjects
- Adenoviridae genetics, Amino Acid Sequence, Animals, Antigens, CD20 chemistry, Blood Transfusion, Bone Marrow Cells cytology, Cell Lineage, Chromosome Mapping, Cloning, Molecular, DNA, Complementary metabolism, Dendritic Cells cytology, Down-Regulation, Gene Transfer Techniques, Graft Rejection, Green Fluorescent Proteins metabolism, Humans, Immunohistochemistry, Interleukin-12 metabolism, Interleukin-12 Subunit p40, Lymphocyte Activation, Macrophages cytology, Macrophages metabolism, Mice, Molecular Sequence Data, Monocytes cytology, Multigene Family, Nucleic Acid Hybridization, Oligonucleotides chemistry, Phylogeny, Polymerase Chain Reaction, Protein Subunits metabolism, RNA, Messenger metabolism, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Receptors, IgE chemistry, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Amino Acid, Spleen metabolism, Time Factors, Transplantation Tolerance, Antigens, CD20 metabolism, Receptors, IgE metabolism, Transplantation, Homologous methods
- Abstract
We identified a novel rat gene specifically overexpressed in tolerated heart allografts in a model of tolerance induced by donor-specific blood transfusion (DST). We named this gene TORID, for tolerance-related and induced transcript. We show that TORID expression can be attributed to non-T cells infiltrating tolerated grafts. Interestingly, TORID overexpression was also observed in long-term grafts from a different model of tolerance in which chronic rejection does not occur. Comparison of the predicted amino acid sequence of TORID and of its human counterpart LR8 showed an homology with the four-transmembrane CD20/FcepsilonRIbeta family proteins. We investigated TORID expression in naive rat immune cells and lymphoid tissues. TORID was found to be preferentially expressed in cells of the myeloid lineage such as macrophages and dendritic cells (DCs). Its expression dramatically decreased following activation/maturation. Similar results were obtained in human monocyte-derived DCs. Interestingly, TORID overexpression in bone marrow-derived DCs alters expression of MHC II and CD86 and production of IL12p40 following activation. These results suggest that TORID may be involved in the control of DC maturation and may, therefore, play a role in the induction or maintenance of allograft tolerance.
- Published
- 2005
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40. Immature CD4- CD103+ rat dendritic cells induce rapid caspase-independent apoptosis-like cell death in various tumor and nontumor cells and phagocytose their victims.
- Author
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Trinité B, Chauvin C, Pêche H, Voisine C, Heslan M, and Josien R
- Subjects
- Adaptor Proteins, Signal Transducing physiology, Animals, Cell Communication immunology, Cell Death immunology, Cell Line, Cell Line, Tumor, Dendritic Cells metabolism, Fas-Associated Death Domain Protein, Histocompatibility Antigens Class II metabolism, Humans, Jurkat Cells, Lymph Nodes cytology, Lymph Nodes immunology, Lymph Nodes metabolism, Protein Biosynthesis immunology, Proteins physiology, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Receptor-Interacting Protein Serine-Threonine Kinases, Spleen cytology, Spleen immunology, Spleen metabolism, Antigens, CD biosynthesis, Apoptosis immunology, CD4 Antigens metabolism, Caspases physiology, Cell Differentiation immunology, Cytotoxicity Tests, Immunologic, Dendritic Cells immunology, Integrin alpha Chains biosynthesis, Phagocytosis immunology
- Abstract
We previously reported the characterization of a MHC class II(low) CD4- CD103+ (CD4-) subset of dendritic cells (DC) in rat spleen that exhibit a Ca2+-, Fas ligand-, TRAIL- and TNF-alpha-independent cytotoxic activity against specific targets in vitro. In this study, we demonstrate that this DC subset was also found in lymph nodes. Freshly extracted and, therefore, immature CD4- DC exhibited a potent cytotoxic activity against a large panel of tumor cell lines as well as primary endothelial cells. The cytotoxic activity of immature CD4- DC required cell-to-cell contact and de novo protein expression. CD4- DC-mediated cell death resembled apoptosis, as evidenced by outer membrane phosphatidylserine exposure and nuclear fragmentation in target cells, but was caspase as well as Fas-associated death domain and receptor-interacting protein independent. Bcl-2 overexpression in target cells did not protect them against DC-mediated cell death. Immature CD4- DC phagocytosed efficiently apoptotic cells in vitro and, therefore, rapidly and specifically engulfed their victims following death induction. Maturation induced a dramatic down-regulation of the killing and phagocytic activities of CD4- DC. In contrast, CD4+ DC were both unable to kill target cells and to phagocytose apoptotic cells in vitro. Taken together, these data indicate that rat immature CD4- CD103+ DC mediate an unusual cytotoxic activity and can use this function to efficiently acquire Ag from live cells.
- Published
- 2005
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41. Rat plasmacytoid dendritic cells are an abundant subset of MHC class II+ CD4+CD11b-OX62- and type I IFN-producing cells that exhibit selective expression of Toll-like receptors 7 and 9 and strong responsiveness to CpG.
- Author
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Hubert FX, Voisine C, Louvet C, Heslan M, and Josien R
- Subjects
- Animals, CD11b Antigen analysis, CD4 Antigens analysis, DNA-Binding Proteins genetics, Dendritic Cells chemistry, Histocompatibility Antigens Class II analysis, Immunophenotyping, Interferon Type I analysis, Lymphocyte Activation, Oligodeoxyribonucleotides pharmacology, RNA, Messenger analysis, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Spleen cytology, T-Lymphocytes cytology, Th2 Cells cytology, Toll-Like Receptor 7, Toll-Like Receptor 9, Antigens, Differentiation analysis, CpG Islands immunology, Dendritic Cells immunology, Interferon Type I biosynthesis, Receptors, Cell Surface genetics
- Abstract
We have identified in the rat a new subset of MHC class II(+) CD4(+)CD3(-)CD11b(-) leukocytes that produce high amounts of type I IFN upon viral stimulation and that appeared homologous to plasmacytoid DC (pDC) previously described in humans and mice. These cells exhibited the following phenotype: CD5(+),CD90(+),CD45R(+),CD45RC(+),CD11c(-),CD161a(+),CD200(+),CD172a(+),CD32(+),CD86(+). Rat pDC did not express the DC-specific marker OX62 and were more abundant in the spleen than the classical CD4(+) and CD4(-) subsets of OX62(+)CD11b(+) DC we previously described that produced very little, if any, type I IFN. Spleen pDC exhibited an undifferentiated morphology and rapidly died in vitro, but showed extensive dendrite formation, survival, maturation, and moderate type I IFN production upon stimulation by oligonucleotides containing type B CpG motifs (CpG ODN). Type A CpG ODN and CD40 ligand induced pDC to produce large amounts of type I IFN, but did not promote maturation. CpG ODN and CD40 ligand, but not influenza virus, induced IL-12p40 and IL-6 secretion. Spleen pDC did not produce IL-12p70, TNF-alpha, IL-1beta, or IL-10 using these stimulation conditions. Correlating with their strong responsiveness to virus and CpG ODN, rat pDC specifically expressed Toll-like receptor 7 and 9 mRNA. Fresh spleen pDC were poor stimulators of allogenic CD4(+) and CD8(+) T cells, but became potent inducers of allogenic T cell proliferation as well as Th1 differentiation after stimulation by type B CpG. Therefore, rat pDC appear very similar to human pDC, indicating that the specific phenotype and functions of pDC have been highly conserved between species.
- Published
- 2004
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42. The role of TNF-related activation-induced cytokine-receptor activating NF-kappa B interaction in acute allograft rejection and CD40L-independent chronic allograft rejection.
- Author
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Guillonneau C, Louvet C, Renaudin K, Heslan JM, Heslan M, Tesson L, Vignes C, Guillot C, Choi Y, Turka LA, Cuturi MC, Anegon I, and Josien R
- Subjects
- Acute Disease, Animals, Antibodies, Blocking administration & dosage, CD40 Ligand biosynthesis, CD40 Ligand genetics, CD40 Ligand immunology, Carrier Proteins antagonists & inhibitors, Carrier Proteins biosynthesis, Carrier Proteins genetics, Cell Line, Chronic Disease, Cytokines biosynthesis, Glycoproteins biosynthesis, Glycoproteins genetics, Glycoproteins metabolism, Graft Enhancement, Immunologic methods, Graft Rejection metabolism, Graft Survival immunology, Heart Transplantation immunology, Humans, Male, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins biosynthesis, Membrane Glycoproteins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Osteoprotegerin, RANK Ligand, RNA, Messenger biosynthesis, Rats, Rats, Inbred Lew, Receptor Activator of Nuclear Factor-kappa B, Receptors, Cytoplasmic and Nuclear biosynthesis, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Tumor Necrosis Factor metabolism, CD40 Ligand physiology, Carrier Proteins physiology, Glycoproteins physiology, Graft Rejection immunology, Membrane Glycoproteins physiology, NF-kappa B metabolism, Receptors, Cytoplasmic and Nuclear physiology, Receptors, Tumor Necrosis Factor physiology
- Abstract
We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.
- Published
- 2004
- Full Text
- View/download PDF
43. Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection.
- Author
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Pêche H, Heslan M, Usal C, Amigorena S, and Cuturi MC
- Subjects
- Animals, Endosomes immunology, Endosomes transplantation, Heart Transplantation pathology, Isoantibodies blood, Male, Rats, Rats, Inbred Lew, T-Lymphocytes immunology, Time Factors, Transplantation, Homologous immunology, Antibody Formation, Bone Marrow Cells immunology, Dendritic Cells immunology, Graft Rejection immunology, Graft Survival immunology, Heart Transplantation immunology, Major Histocompatibility Complex, Tissue Donors
- Abstract
Background: Dendritic cells secrete a population of "antigen-presenting vesicles," called exosomes, expressing functional class I and II major histocompatibility complex (MHC) and co-stimulatory molecules. The subcutaneous administration of syngeneic exosomes expressing tumor antigens has been shown to induce specific antitumor immune responses in vivo. The authors hypothesized that antigen presentation by exosomes, depending on the context of their administration, may induce tolerance rather than immunity., Methods: The authors therefore tested the capacity of exosomes derived from donor bone marrow dendritic cells, given before transplantation, to modulate heart allograft rejection., Results: The authors show here that donor type but not syngeneic exosomes induced a significant prolongation of allograft survival, with a few recipients having long-term graft survival. During the first week after transplantation, allografts from exosome-treated rats displayed a significant decrease in graft-infiltrating leukocytes and in the expression of interferon-gamma mRNA compared with allografts from untreated animals. Moreover, when tested in vitro, spleen CD4+ T cells from exosome-treated recipients displayed a significant decrease in anti-donor responses, suggesting a decrease in anti-donor T-cell responses. However, the authors also found that allogeneic donor-derived exosomes increased anti-donor MHC class II alloantibody production., Conclusions: The authors demonstrate an effect of allogeneic exosomes on the modulation of immune responses in vivo, suggesting that, like donor cells, exosomes can stimulate or regulate antigen-specific immune responses.
- Published
- 2003
- Full Text
- View/download PDF
44. Two phenotypically distinct subsets of spleen dendritic cells in rats exhibit different cytokine production and T cell stimulatory activity.
- Author
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Voisine C, Hubert FX, Trinité B, Heslan M, and Josien R
- Subjects
- Animals, CD4 Antigens biosynthesis, CD4 Antigens genetics, CD5 Antigens biosynthesis, CD5 Antigens genetics, Cell Differentiation immunology, Cell Separation methods, Cell Survival immunology, Cells, Cultured, Dendritic Cells cytology, Flow Cytometry, Interleukin-12 biosynthesis, Interleukin-12 Subunit p40, Lymphocyte Culture Test, Mixed, Membrane Glycoproteins biosynthesis, Membrane Glycoproteins genetics, Myeloid Cells cytology, Neural Cell Adhesion Molecules biosynthesis, Neural Cell Adhesion Molecules genetics, Protein Subunits, RNA, Messenger biosynthesis, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Spleen metabolism, T-Lymphocytes, Helper-Inducer cytology, Tumor Necrosis Factor-alpha biosynthesis, Antigens, Differentiation, Cytokines biosynthesis, Dendritic Cells immunology, Dendritic Cells metabolism, Immunophenotyping, Lymphocyte Activation immunology, Neural Cell Adhesion Molecule L1, Receptors, Immunologic, Spleen cytology, Spleen immunology, T-Lymphocyte Subsets immunology
- Abstract
We recently reported that splenic dendritic cells (DC) in rats can be separated into CD4(+) and CD4(-) subsets and that the CD4(-) subset exhibited a natural cytotoxic activity in vitro against tumor cells. Moreover, a recent report suggests that CD4(-) DC could have tolerogenic properties in vivo. In this study, we have analyzed the phenotype and in vitro T cell stimulatory activity of freshly isolated splenic DC subsets. Unlike the CD4(-) subset, CD4(+) splenic DC expressed CD5, CD90, and signal regulatory protein alpha molecules. Both fresh CD4(-) and CD4(+) DC displayed an immature phenotype, although CD4(+) cells constitutively expressed moderate levels of CD80. The half-life of the CD4(-), but not CD4(+) DC in vitro was extremely short but cells could be rescued from death by CD40 ligand, IL-3, or GM-CSF. The CD4(-) DC produced large amounts of the proinflammatory cytokines IL-12 and TNF-alpha and induced Th1 responses in allogeneic CD4(+) T cells, whereas the CD4(+) DC produced low amounts of IL-12 and no TNF-alpha, but induced Th1 and Th2 responses. As compared with the CD4(+) DC that strongly stimulated the proliferation of purified CD8(+) T cells, the CD4(-) DC exhibited a poor CD8(+) T cell stimulatory capacity that was substantially increased by CD40 stimulation. Therefore, as previously shown in mice and humans, we have identified the existence of a high IL-12-producing DC subset in the rat that induces Th1 responses. The fact that both the CD4(+) and CD4(-) DC subsets produced low amounts of IFN-alpha upon viral infection suggests that they are not related to plasmacytoid DC.
- Published
- 2002
- Full Text
- View/download PDF
45. Recombinant IFN-gamma abrogates allograft tolerance induced by donor-specific blood transfusion by restoring alloantibody production.
- Author
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Josien R, Cuturi MC, Douillard P, Heslan M, Heslan JM, and Soulillou JP
- Subjects
- Animals, Base Sequence, Blood Transfusion, Cytokines genetics, DNA Primers genetics, Heart Transplantation immunology, Immunoglobulin G biosynthesis, In Vitro Techniques, Lymphocyte Activation, Macrophage Activation, Male, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Inbred Lew, Recombinant Proteins, Th1 Cells immunology, Tissue Donors, Transforming Growth Factor beta genetics, Transplantation, Homologous, Immune Tolerance drug effects, Interferon-gamma pharmacology, Isoantibodies biosynthesis, Transplantation Immunology drug effects
- Abstract
Donor-specific tolerance to heart allograft was induced in adult Lewis rats by pregraft donor-specific blood transfusion (DST). We previously showed that this tolerant state is characterized by a dramatic inhibition of T cell and macrophage activation. In addition, tolerant animals could not mount an efficient anti-donor humoral response whereas transfer of sera from rejecting animals triggered rejection in tolerant animals. This tolerance can be abrogated by daily post-graft administration of recombinant IFN-gamma (rIFN-gamma). To elucidate the mechanisms of action of rIFN-gamma, T cell, macrophage and B cell functions were assessed in allograft recipients. IFN-gamma did not restore the expression of Th1-related cytokine mRNA or the activated macrophage product inducible nitric oxide synthase in allografts. Importantly, rIFN-gamma treatment promptly restored the anti-donor humoral response in DST-treated recipients. We conclude that rIFN-gamma treatment in DST-treated allograft recipients cannot reverse the unresponsive state of Th1 cells and macrophages infiltrating the graft, but can provide B cell help for IgG alloantibody production which is lacking in these animals.
- Published
- 1999
- Full Text
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46. Critical requirement for graft passenger leukocytes in allograft tolerance induced by donor blood transfusion.
- Author
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Josien R, Heslan M, Brouard S, Soulillou JP, and Cuturi MC
- Subjects
- Animals, COS Cells, Cyclophosphamide pharmacology, Dendritic Cells immunology, Dendritic Cells transplantation, Graft Survival immunology, Heart Transplantation immunology, Immune Tolerance drug effects, Immunosuppressive Agents pharmacology, Male, Rats, Rats, Inbred Lew, Skin Transplantation immunology, Spleen cytology, T-Lymphocytes, Helper-Inducer immunology, Time Factors, Blood Transfusion, Immune Tolerance immunology, Leukocytes immunology, Transplantation, Homologous immunology
- Abstract
Tolerance to a vascularized allograft can be induced in adult animals by pregraft donor-specific blood transfusion (DST). Mechanisms underlying this effect appear to depend on unresponsiveness of alloreactive T-helper cells. In this study, we examined the roles of DST and cellular components of the allograft that are important in inducing T-cell unresponsiveness in a rat model. DST alone did not tolerize alloreactive recipient T-helper cells, but the combination of DST and heart allograft induced profound inhibition of the antidonor proliferative response in spleen but not in lymph node cells. When heart allografts were depleted of passenger leukocytes by pretreating the donor with cyclophosphamide or by parking the graft for 2 months in a tolerant recipient, tolerance induction in DST-treated recipients was abrogated. Tolerance could then be restored in a majority of DST-treated recipients of passenger leukocytes depleted grafts by injecting them at the time of grafting with donor, but not third-party, dendritic cells. This indicates that graft passenger leukocytes, most likely dendritic cells, are required for DST-induced allograft tolerance.
- Published
- 1998
47. Rat spleen dendritic cells express natural killer cell receptor protein 1 (NKR-P1) and have cytotoxic activity to select targets via a Ca2+-dependent mechanism.
- Author
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Josien R, Heslan M, Soulillou JP, and Cuturi MC
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antigens, Surface immunology, Antigens, Surface isolation & purification, Calcium immunology, Cells, Cultured, Cytotoxicity Tests, Immunologic, Dendritic Cells immunology, Male, NK Cell Lectin-Like Receptor Subfamily B, Precipitin Tests, Rats, Rats, Inbred Lew, Rats, Sprague-Dawley, Rats, Wistar, Spleen, Up-Regulation immunology, Antigens, Surface biosynthesis, Calcium physiology, Cytotoxicity, Immunologic, Dendritic Cells metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lectins, C-Type, Receptors, IgG biosynthesis
- Abstract
Dendritic cells (DC) are a subset of leukocytes whose major function is antigen presentation. We investigated the phenotype and function of enriched (95-98.5%) rat DC. We show that both spleen and thymus DC express the natural killer cell receptor protein 1 (NKR-P1) as a disulfide linked homodimer of 60 kD. Freshly isolated DC express a low level of NKR-P1, which is strongly upregulated after overnight culture. Spleen, but not thymus DC, were able to kill the NK-sensitive YAC-1 cell line in vitro, and since this killing was Ca2+ dependent, a Fas ligand-Fas interaction was probably not involved. Besides their potent antigen-presenting function, DC can thus be cytotoxic for some tumor targets.
- Published
- 1997
- Full Text
- View/download PDF
48. Impaired antigen presentation in toxic epidermal necrolysis.
- Author
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Bagot M, Charue D, Heslan M, Wechsler J, Roujeau JC, and Revuz J
- Subjects
- Adolescent, Adult, Cytotoxicity, Immunologic, Female, Flow Cytometry, HLA-DR Antigens analysis, Humans, Immunophenotyping, Killer Cells, Natural immunology, Lymphocyte Activation, Lymphocyte Culture Test, Mixed, Male, Middle Aged, T-Lymphocytes, Cytotoxic immunology, Antigen-Presenting Cells immunology, Stevens-Johnson Syndrome immunology
- Abstract
BACKGROUND AND DESIGN--The pathophysiology of toxic epidermal necrolysis (TEN) remains largely unknown. Toxic epidermal necrolysis is considered a hypersensitivity reaction to drugs, but direct evidence of an immunologic mechanism is still lacking. Lymphopenia and a decrease in the numbers of circulating CD3- and CD4-positive lymphocytes have been reported in acute phase, but, to our knowledge, no study of cellular immune functions of patients with TEN has been reported so far. Herein, we investigated several T-cell functions in a series of 11 patients with TEN. Peripheral blood mononuclear cells (PBMC) obtained in the acute phase were tested together with PBMC obtained after the patient's recovery and compared with those of age- and sex-matched healthy control subjects. RESULTS--Phytohemagglutinin-induced proliferations and lymphocyte responses in allogeneic mixed lymphocyte reactions were not impaired in the acute phase compared with those after recovery in the same patients and with those in control subjects. In contrast, natural killer cytotoxicity and allogeneic cytotoxic responses were significantly decreased in early TEN. The most striking feature was the significantly impaired ability of acute-phase lymphoid cells to activate allogeneic T cells. Patient PBMC in acute-phase TEN did not inhibit the proliferation induced by patient PBMC after recovery, suggesting that their defect was not related to the presence of radioresistant suppressor cells. The phenotypic expression of HLA-DR, -DQ, and -DP antigens on circulating peripheral blood lymphocytes was then assessed by immunoalkaline phosphatase staining and flow cytometry. Results showed decreased percentages of HLA-DR-positive mononuclear cells and a decreased density of HLA-DR antigens, mainly on monocytes, in acute-phase TEN. CONCLUSIONS--These results demonstrate that peripheral blood lymphocytes of patients with TEN have an impaired ability to activate allogeneic T cells. This defective antigen presentation is not secondary to the presence of suppressor lymphocytes, but it is probably related to a decreased expression of HLA-DR antigens on circulating mononuclear cells in acute-phase TEN.
- Published
- 1993
49. Production of paf-acether by human epidermal cells.
- Author
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Michel L, Denizot Y, Thomas Y, Jean-Louis F, Heslan M, Benveniste J, and Dubertret L
- Subjects
- Acetyl Coenzyme A pharmacology, Calcimycin pharmacology, Cells, Cultured, Chromatography, High Pressure Liquid methods, Epidermis chemistry, Epidermis metabolism, Humans, Platelet Activating Factor analogs & derivatives, Platelet Activating Factor analysis, Platelet Activating Factor pharmacology, Epidermal Cells, Platelet Activating Factor metabolism
- Abstract
The production of the inflammatory mediator paf-acether (paf) from human epidermal cells was investigated in vitro. Human epidermal cells, freshly isolated from normal skin or in culture, were incubated in Tyrode's buffer containing 0.25% lipid-free bovine serum albumin in the presence of 2 microM calcium ionophore A23187, at 37 degrees C, for 1 to 60 min. Paf production slightly began at the first min of stimulation, was significant after 10 min, reached a maximum at 20 min (251 +/- 25 pg/l X 10(6) cells, mean +/- 1 SD), and decreased thereafter. About 50% of the paf amount produced by epidermal cells was recovered in supernatants. Addition of the non-acetylated paf precursor 1-O-octadecyl-sn-glycero-3-phosphocholine, i.e., lyso-paf, at 0.1 microM to epidermal cells during A23187-stimulation did not alter this production. In contrast, addition of acetyl-coenzyme A at 0.1 mM enhanced paf production by 5 times. The material produced by epidermal cells was identical to synthetic paf because: 1) the aggregation of aspirin-treated and ADP-insensitive washed rabbit platelets it induced was inhibited by BN 52021, an antagonist of the paf putative receptor; 2) the factor was inactivated by phospholipase A2 but was insensitive to lipase from Rhizopus arrhizus; 3) it exhibited the same retention time as synthetic paf during standard and reverse-phase (RP) high-pressure liquid chromatography (HPLC) elution. The paf precursors, i.e., lyso-paf and 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine, were also detected in epidermal cells, stimulated with A23187 or not. As determined by RP-HPLC analysis and confirmed by gas chromatography analysis, these precursors and the paf produced by epidermal cells exhibited more than 90% of a hexadecyl chain at the sn-1 position of the molecule. The present results demonstrate the synthesis and release of paf by normal human epidermal cells. Paf production within the epidermis might account for the development of cutaneous inflammation and the pathogenesis of many skin disorders.
- Published
- 1990
- Full Text
- View/download PDF
50. T-cell receptor-gamma/delta bearing lymphocytes in normal and inflammatory human skin.
- Author
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Dupuy P, Heslan M, Fraitag S, Hercend T, Dubertret L, and Bagot M
- Subjects
- Antibodies, Monoclonal, Dermatitis immunology, Humans, Lymphocytes pathology, Receptors, Antigen, T-Cell, gamma-delta, Reference Values, T-Lymphocytes immunology, Dermatitis pathology, Lymphocytes immunology, Receptors, Antigen, T-Cell immunology, Skin pathology
- Abstract
Murine dendritic epidermal T cells (DETC) were recently reported to express T-cell receptor (TCR)-gamma/delta chains. In a search for the human equivalent of these cells, we tested normal and lesional skin with MoAb which react with the TCR-gamma/delta heterodimer. We performed indirect immunofluorescence (IF) on epidermal sheets, and alkaline-phosphatase-anti-alkaline-phosphatase complex (APAAP) on epidermal cell smears. Frozen skin sections from normal skin and various cutaneous lymphocyte infiltrates were also studied. A few CD3+ T lymphocytes were consistently found in normal epidermis. Most of these cells appeared to be TCR-alpha/beta +, and some CD4+ or CD8+. On epidermal sheets and cell smears, only a very small TCR-gamma/delta + cell population was visualized (less than 0.1% of the total). On normal skin sections, we observed 0 to 3 gamma/delta + cells per section. When present, they were often located in the epidermal basal layer, and were round or dendritic. Double immunolabeling revealed that gamma/delta + cells differed from CD1+ Langerhans cells, and that they had a similar phenotypic pattern as gamma/delta + peripheral lymphocytes (PBL): CD2+, CD3+, CD4-, and CD8-. Immunostaining from various inflammatory skin lesions showed that the dermal infiltrates included CD3+ T lymphocytes but virtually no gamma/delta + cells. Only a few gamma/delta + cells were found in some end-evolutive infiltrates. Taken together, these results strongly suggest that normal human epidermis occasionally harbors TCR-gamma/delta complex bearing lymphocytes, which constitute a small fraction of the CD3+ cutaneous T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
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