Allogeneic Bone Marrow Transplantation With Co-Stimulatory Blockade Induces Macrochimerism and Tolerance Without Cytoreductive Host Treatment

Nat Med. 2000 Apr;6(4):464-9. doi: 10.1038/74731.

Abstract

Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.

Publication types

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

MeSH terms

  • Abatacept
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / immunology
  • Bone Marrow Transplantation*
  • CD40 Ligand
  • CTLA-4 Antigen
  • Female
  • Immune Tolerance*
  • Immunoconjugates*
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Transplantation Chimera / immunology*
  • Transplantation Immunology / immunology*
  • Transplantation, Homologous

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ctla4 protein, mouse
  • Immunoconjugates
  • Membrane Glycoproteins
  • Receptors, Antigen, T-Cell, alpha-beta
  • CD40 Ligand
  • Abatacept