BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Luis Graca; Sara Thompson; Chun-Yen Lin; Elizabeth Adams; Stephen P Cobbold; Herman Waldmann Journal: J Immunol Date: 2002-06-01 Impact factor: 5.422
Authors: A B Adams; M M Durham; L Kean; N Shirasugi; J Ha; M A Williams; P A Rees; M C Cheung; S Mittelstaedt; A W Bingaman; D R Archer; T C Pearson; E K Waller; C P Larsen Journal: J Immunol Date: 2001-07-15 Impact factor: 5.422
Authors: Z Koporc; N Pilat; P Nierlich; P Blaha; S Bigenzahn; I Pree; E Selzer; M Sykes; F Muehlbacher; T Wekerle Journal: Am J Transplant Date: 2008-10 Impact factor: 8.086
Authors: Kia J Langford-Smith; Zara Sandiford; Alex Langford-Smith; Fiona L Wilkinson; Simon A Jones; J Ed Wraith; Robert F Wynn; Brian W Bigger Journal: PLoS One Date: 2013-10-17 Impact factor: 3.240