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Regulatory T Cells Are Critical to Tolerance Induction in Presensitized Mouse Transplant Recipients Through Targeting Memory T Cells
Authors:W. Ge  J. Jiang  W. Liu  D. Lian  A. Saito  B. Garcia  X. C. Li  H. Wang
Affiliation:1. Department of Surgery, The University of Western Ontario, London, Ontario, Canada;2. Multi‐Organ Transplant Program, University Hospital, London Health Sciences Centre, London, Ontario, Canada;3. Department of Pathology, The University of Western Ontario, London, Ontario, Canada;4. Department of Medicine, Harvard Medical School, Boston, MA;5. Transplantation, Immunity and Regenerative Medicine, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
Abstract:Memory T cells are a significant barrier to induction of transplant tolerance. However, reliable means to target alloreactive memory T cells have remained elusive. In this study, presensitization of BALB/c mice with C57BL/6 skin grafts generated a large number of OX40+CD44hieffector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti‐OX40L monoclonal antibody (mAb) (α‐OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, α‐OX40L was added to the combined treatment protocol of LF15–0195 (LF) and anti‐CD45RB (α‐CD45RB) mAb—a protocol that induced heart allograft tolerance in non‐presensitized recipients but failed to induce tolerance in presensitized recipients. Interestingly, this triple therapy restored donor‐specific heart allograft tolerance in our presensitized model that was associated with induction of tolerogenic dendritic cells and CD4+CD25+Foxp3+ T regulatory cells (Tregs). Of note, CD25+ T cell depletion in triple therapy recipients prevented establishment of allograft tolerance. In addition, adoptive transfer of donor‐primed effector/memory T cells into tolerant recipients markedly reduced levels of Tregs and broke tolerance. Our findings indicated that targeting memory T cells, by blocking OX40 costimulation in presensitized recipients was very important to expansion of Tregs, which proved critical to development of tolerance.
Keywords:Allograft tolerance  memory T cells  regulatory T cells  sensitized recipients  transplantation
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