Depletion of CD8 memory T cells for induction of tolerance of a previously transplanted kidney allograft

Am J Transplant. 2007 May;7(5):1055-61. doi: 10.1111/j.1600-6143.2006.01703.x. Epub 2007 Feb 7.

Abstract

Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti-CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide 'proof of principle' that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antilymphocyte Serum / pharmacology
  • Biopsy
  • CD146 Antigen / immunology
  • CD8 Antigens / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Chimerism
  • Graft Survival / immunology
  • Immunologic Memory / drug effects*
  • Kidney / immunology
  • Kidney / pathology
  • Kidney Transplantation / immunology
  • Kidney Transplantation / methods*
  • Kidney Transplantation / pathology
  • Macaca fascicularis
  • Male
  • Thymus Gland / radiation effects
  • Transplantation Tolerance / immunology*
  • Transplantation, Homologous
  • Whole-Body Irradiation

Substances

  • Antibodies, Monoclonal
  • Antilymphocyte Serum
  • CD146 Antigen
  • CD8 Antigens