Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning.

BMC Immunology
Luis GracaHerman Waldmann

Abstract

A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.

References

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Jun 26, 2004·Proceedings of the National Academy of Sciences of the United States of America·Luis GracaHerman Waldmann

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Citations

Sep 9, 2005·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Stephen P Cobbold
Feb 12, 2017·Stem Cells Translational Medicine·Esma S YolcuNadir Askenasy
Mar 29, 2007·European Journal of Immunology·Bin LuoColin C Anderson
Jun 29, 2007·International Archives of Allergy and Immunology·Ines PreeThomas Wekerle
Oct 3, 2008·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Z KoporcT Wekerle
Jan 1, 2010·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·R G NadorS Strober
Feb 13, 2010·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·N PilatT Wekerle
Sep 3, 2010·Nature Reviews. Nephrology·Nina Pilat, Thomas Wekerle
Mar 19, 2015·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·N PilatT Wekerle
Sep 11, 2008·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·S R DaleyH Waldmann
Jun 3, 2015·European Journal of Immunology·Luis Graca
Nov 3, 2016·Current Opinion in Organ Transplantation·Min HuShounan Yi
Jun 15, 2011·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·R N BarthS T Bartlett
May 4, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhuangzhi Wang, Joanna D Davies
Jun 26, 2020·Cellular Immunology·Herman Waldmann, Luis Graca

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Methods Mentioned

BETA
flow cytometry
electrophoresis

Software Mentioned

CellQuest

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