Alefacept promotes immunosuppression-free renal allograft survival in nonhuman primates via depletion of recipient memory T cells

Am J Transplant. 2013 Dec;13(12):3223-9. doi: 10.1111/ajt.12500. Epub 2013 Oct 24.

Abstract

Renal allograft tolerance has been achieved in MHC-mismatched primates via nonmyeloablative conditioning beginning 6 days prior to planned kidney and donor bone marrow transplantation (DBMT). To extend the applicability of this approach to deceased donor transplantation, we recently developed a novel-conditioning regimen, the "delayed protocol" in which donor bone marrow (DBM) is transplanted several months after kidney transplantation. However, activation/expansion of donor-reactive CD8(+) memory T cells (TMEM) occurring during the interval between kidney and DBM transplantation impaired tolerance induction using this strategy. In the current study, we tested whether, Alefacept, a fusion protein which targets LFA-3/CD2 interactions and selectively depletes CD2(high) CD8(+) effector memory T cells (TEM) could similarly induce long-term immunosuppression-free renal allograft survival but avoid the deleterious effects of anti-CD8 mAb treatment. We found that Alefacept significantly delayed the expansion of CD2(high) cells including CD8(+) TEM while sparing naïve CD8(+) T and NK cells and achieved mixed chimerism and long-term immunosuppression-free renal allograft survival. In conclusion, elimination of CD2(high) T cells represents a promising approach to prevent electively the expansion/activation of donor-reactive TEM and promotes tolerance induction via the delayed protocol mixed chimerism approach.

Keywords: Kidney transplantation; memory T cells; mixed hematopoietic chimerism; nonhuman primates; tolerance.

Publication types

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

MeSH terms

  • Alefacept
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Transplantation
  • CD2 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • Genotype
  • Graft Survival
  • Immune Tolerance
  • Immunologic Memory / drug effects*
  • Immunosuppression Therapy
  • Interferon-gamma / immunology
  • Kidney Transplantation*
  • Macaca fascicularis
  • Major Histocompatibility Complex
  • Recombinant Fusion Proteins / chemistry*
  • Transplantation Chimera
  • Transplantation Conditioning / methods*
  • Transplantation Tolerance / immunology

Substances

  • CD2 Antigens
  • Recombinant Fusion Proteins
  • Interferon-gamma
  • Alefacept