title: Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of alpha beta-TCR+ and CD4+ cells negates the effect.
abstract: Bone marrow transplantation blocks diabetes pathogenesis and reverses autoimmunity in nonobese diabetic (NOD) mice. However, there is a greater barrier to engraftment in the context of autoimmunity. In the present study, we characterized which recipient cells influence engraftment in prediabetic NOD mice, with the goal to replace myelotoxic conditioning with antigen-specific deletion of reactive host cells. Preconditioning of NOD mice with anti-CD8 and anti-CD154 monoclonal antibodies (mAbs) synergistically enhanced engraftment and significantly reduced the minimum total body irradiation (TBI) dose for engraftment. Strikingly, preconditioning with anti-CD4 mAb significantly impaired engraftment, negating the beneficial effect of anti-CD8, and resulted in a requirement for more TBI-based conditioning compared with controls conditioned with TBI alone. Similarly, more TBI was required when anti-T-cell receptor beta (TCRbeta) mAb was administered as preconditioning. The addition of anti-CD152 to CD154 preconditioning abrogated the engraftment-enhancing effect of anti-CD154. Taken together, these data indicate a role for CD4+ regulatory T cells in vivo which require signaling via CD152 in the induction of chimerism and tolerance in NOD recipients. Notably, disease prevention and reversal of autoimmunity was absolutely correlated with the establishment of chimerism. These studies have important implications for the design of novel clinical approaches to treat type 1 diabetes.
authors.affiliation: Institute for Cellular Therapeutics, Department of Pathology, University of Louisville, 570 South Preston St, Suite 404, Louisville, KY 40202-1760, USA. stilds01@louisville.edu
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
authors.forename: Paula M
authors.initials: PM
authors.lastname: Chilton
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Michele A
authors.initials: MA
authors.lastname: Domenick
authors.forename: Mukunda B
authors.initials: MB
authors.lastname: Ray
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning
chemical_list: D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand