Favorably Tipping the Balance Between Cytopathic and Regulatory T Cells to Create Transplantation Tolerance

Immunity. 2003 Oct;19(4):503-14. doi: 10.1016/s1074-7613(03)00259-0.

Abstract

Therapeutic application of broadly reactive anti-T cell antibodies can lead not only to potent immunosuppression but also to profound and long-lived T cell depletion. We reasoned that a strategy that almost exclusively targets activated cytopathic donor reactive T cells and spares immunoregulatory networks might prove to be an exceptionally potent and highly selective means of producing long-term engraftment and tolerance. Herein we show that the combined administration of rapamycin and agonist IL-2- and antagonist IL-15-related cytolytic fusion proteins provides for long-term engraftment/tolerance in exceptionally stringent allotransplant models by (1) limiting the early expansion of activated T cells, (2) preserving and even exaggerating their subsequent apoptotic clearance, and (3) further amplifying the depletion of these activated T cells by antibody-dependent mechanisms, while (4) preserving CD4+CD25+ T cell-dependent immunoregulatory networks.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Apoptosis / physiology
  • CD4-Positive T-Lymphocytes / metabolism
  • Interleukin-2 / metabolism
  • Mice
  • Receptors, Interleukin-2 / metabolism
  • T-Lymphocytes, Cytotoxic / physiology*
  • T-Lymphocytes, Helper-Inducer / physiology*
  • Transplantation Tolerance / immunology
  • Transplantation Tolerance / physiology*
  • ral Guanine Nucleotide Exchange Factor / metabolism

Substances

  • Interleukin-2
  • Receptors, Interleukin-2
  • Rgl3 protein, mouse
  • ral Guanine Nucleotide Exchange Factor