Donor‐strain‐derived immature dendritic cell pre‐treatment induced hyporesponsiveness against allogeneic antigens

The maturation of antigen‐presenting dendritic cells (DCs) serves as an important determinant for the regulation of immunity, and overall immune response. We hypothesized that a reduced immune response to donor alloantigens and improved allograft survival could be induced by pre‐treating recipients with bone‐marrow‐derived donor‐strain fixed immature DCs (FIDCs). Donor‐strain‐derived mature and immature DCs were fixed before grafting to ensure that they possessed a stable immunogenic phenotype. The fixed mature DCs effectively induced allogeneic T‐cell proliferation in recipients, whereas FIDCs were unable to elicit an allogeneic T‐cell response. T cells that had previously been exposed to FIDCs maintained naïve phenotypes and were unable to extensively divide after injection into lethally irradiated donor‐strain mice. The pre‐treatment of recipients with donor‐strain FIDCs markedly prolonged the survival of islet as well as skin allografts. However, T‐cell hyporesponsiveness induced by FIDC injection was abrogated by the depletion of CD4+ CD25+ T cells. Consequently, FIDC‐induced T‐cell hyporesponsiveness could reflect anergy rather than specific deletion. Our findings suggest that FIDCs of donor strain could be used to induce long‐term graft survival.

[1]  A. Thomson,et al.  Allostimulatory activity of bone marrow-derived plasmacytoid dendritic cells is independent of indoleamine dioxygenase but regulated by inducible costimulator ligand expression. , 2009, Human immunology.

[2]  T. Zal,et al.  In Vivo Anergized T Cells Form Altered Immunological Synapses In Vitro , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[3]  T. Strom,et al.  Specificity of CD4+CD25+ Regulatory T Cell Function in Alloimmunity1 , 2006, The Journal of Immunology.

[4]  M. Nussenzweig,et al.  Inducing and expanding regulatory T cell populations by foreign antigen , 2005, Nature Immunology.

[5]  Y. Lacasse,et al.  From the authors , 2005, European Respiratory Journal.

[6]  Sebastian Amigorena,et al.  Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity , 2004, Nature Immunology.

[7]  C. Figdor,et al.  Dendritic cell immunotherapy: mapping the way , 2004, Nature Medicine.

[8]  Hervé Groux,et al.  Role of dendritic cells in the generation of regulatory T cells. , 2004, Seminars in immunology.

[9]  S. Henrickson,et al.  T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases , 2004, Nature.

[10]  R. Offringa,et al.  Prolongation of skin graft survival by modulation of the alloimmune response with alternatively activated dendritic cells1 , 2003, Transplantation.

[11]  T. Utsugi,et al.  CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. , 2003, Immunity.

[12]  A. Rudensky,et al.  Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation. , 2003, Blood.

[13]  R. Steinman,et al.  Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells , 2003, The Journal of experimental medicine.

[14]  M. Claesson,et al.  Dendritic cells in peripheral tolerance and immunity , 2003, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[15]  H. Groux,et al.  Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. , 2003, Immunity.

[16]  L. Adorini.  Tolerogenic Dendritic Cells Induced by Vitamin D Receptor Ligands Enhance Regulatory T Cells Inhibiting Autoimmune Diabetes , 2003, Annals of the New York Academy of Sciences.

[17]  M. Uskoković,et al.  Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases , 2003 .

[18]  S. Turley.  Dendritic cells: inciting and inhibiting autoimmunity. , 2002, Current opinion in immunology.

[19]  R. Steinman,et al.  Immune Tolerance After Delivery of Dying Cells to Dendritic Cells In Situ , 2002, The Journal of experimental medicine.

[20]  P. Robbins,et al.  Marked Prolongation of Cardiac Allograft Survival by Dendritic Cells Genetically Engineered with NF-κB Oligodeoxyribonucleotide Decoys and Adenoviral Vectors Encoding CTLA4-Ig1 , 2002, The Journal of Immunology.

[21]  S. Specht,et al.  Immature and Mature CD8α+ Dendritic Cells Prolong the Survival of Vascularized Heart Allografts1 , 2002, The Journal of Immunology.

[22]  Z. Yurkovetsky,et al.  Mechanisms of dendritic cell-induced T cell proliferation in the primary MLR assay. , 2001, Immunology letters.

[23]  L. Adorini,et al.  Regulatory T Cells Induced by 1α,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance1 , 2001, The Journal of Immunology.

[24]  E. Palmer,et al.  Quantifying the Frequency of Alloreactive T Cells In Vivo: New Answers to an Old Question1 , 2001, The Journal of Immunology.

[25]  G. Schuler,et al.  Immature dendritic cells generated with low doses of GM‐CSF in the absence of IL‐4 are maturation resistant and prolong allograft survival in vivo , 2000, European journal of immunology.

[26]  R. Offringa,et al.  Glucocorticoids transform CD40-triggering of dendritic cells into an alternative activation pathway resulting in antigen-presenting cells that secrete IL-10. , 2000, Blood.

[27]  R. Steinman,et al.  The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells , 2000, The Journal of experimental medicine.

[28]  R. Gorczynski,et al.  Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival1 , 2000, The Journal of Immunology.

[29]  T M Jovin,et al.  Dynamics of molecules involved in antigen presentation: effects of fixation. , 1999, Molecular immunology.

[30]  P. Huie,et al.  Monocyte-derived dendritic cell precursors facilitate tolerance to heart allografts after total lymphoid irradiation. , 1998, Transplantation.

[31]  H. Gudmundsdottir,et al.  Following the fate of individual T cells throughout activation and clonal expansion. Signals from T cell receptor and CD28 differentially regulate the induction and duration of a proliferative response. , 1997, The Journal of clinical investigation.

[32]  A. Rudensky,et al.  Deficient positive selection of CD4 T cells in mice displaying altered repertoires of MHC class II-bound self-peptides. , 1997, Immunity.

[33]  H. Benediktsson,et al.  Post-transplant hypertension and chronic renal allograft failure. , 1995, Kidney international. Supplement.

[34]  C. Carpenter,et al.  Long-term failure of renal transplants: adding insult to injury. , 1995, Kidney international. Supplement.

[35]  P. Nickerson,et al.  IL-2 knockout recipient mice reject islet cell allografts. , 1995, Journal of immunology.

[36]  R. Steinman,et al.  Resting and sensitized T lymphocytes exhibit distinct stimulatory (antigen-presenting cell) requirements for growth and lymphokine release , 1984, The Journal of experimental medicine.

[37]  D. Wilson,et al.  Histocompatibility antigen-activated cytotoxic T lymphocytes. I. Estimates of the absolute frequency of killer cells generated in vitro , 1977, The Journal of experimental medicine.

[38]  R. A. Phillips,et al.  Quantitative studies on the precursors of cytotoxic lymphocytes. I. Characterization of a clonal assay and determination of the size of clones derived from single precursors. , 1977, Journal of immunology.

[39]  A. Thomson,et al.  Dendritic cells,tolerance and therapy of organ allograft rejection. , 2005, Contributions to nephrology.

[40]  Ranjeny Thomas,et al.  Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. , 2003, Immunity.