Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells

Am J Transplant. 2010 Aug;10(8):1760-73. doi: 10.1111/j.1600-6143.2010.03186.x. Epub 2010 Jul 15.

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(+)CD44(hi)effector/memory T cells and resulted in rapid rejection of donor heart allografts. Recognizing that anti-OX40L monoclonal antibody (mAb) (alpha-OX40L) monotherapy prolonged graft survival through inhibition and apoptosis of memory T cells in presensitized recipients, alpha-OX40L was added to the combined treatment protocol of LF15-0195 (LF) and anti-CD45RB (alpha-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • Apoptosis / immunology
  • Heart Transplantation / immunology*
  • Male
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • OX40 Ligand
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • Transplantation Tolerance / immunology*
  • Tumor Necrosis Factors / immunology

Substances

  • Antibodies, Monoclonal
  • Membrane Glycoproteins
  • OX40 Ligand
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factors