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Correction of murine sickle cell disease by allogeneic haematopoietic cell transplantation with anti-3rd party veto cells

Bone Marrow Transplantation volume 56, pages 1818–1827 (2021)Cite this article

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Abstract

Despite advances in gene therapy allogeneic hematopoietic stem cell transplants (HSCT) remains the most effective way to cure sickle cell disease (SCD). However, there are substantial challenges including lack of suitable donors, therapy-related toxicity (TRM) and risk of graft-versus-host disease (GvHD). Perhaps the most critical question is when to do a transplant for SCD. Safer transplant protocols for HLA-disparate HSCT is needed before transplants are widely accepted for SCD. Although risk of GvHD and TRM are less with T-cell-deplete HSCT and reduced-intensity conditioning (RIC), transplant rejection is a challenge. We have reported graft rejection of T cell-depleted non-myeloablative HSCT can be overcome in wild type fully mis-matched recipient mice, using donor-derived anti-3rd party central memory CD8-positive veto cells combined with short-term low-dose rapamycin. Here, we report safety and efficacy of this approach in a murine model for SCD. Durable donor-derived chimerism was achieved using this strategy with reversal of pathological parameters of SCD, including complete conversion to normal donor-derived red cells, and correction of splenomegaly and the levels of circulating reticulocytes, hematocrit, and hemoglobin.

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Fig. 1: Chimerism induction in SCD (H-2Kb) recipient mice following transplantation of megadose T cell-depleted allo-HSCT (Nude-Balb/c; H-2Kd) combined with donor-derived veto CD8+ T cells and short-term rapamycin.
Fig. 2: Long-term follow-up of donor chimerism and SS hemoglobin posttransplant.
Fig. 3: Chimerism in SCD mice following transplantation of high-dose T-cell-depleted H2-mis-matched bone marrow with donor-derived veto CD8 T-cells and rapamycin.
Fig. 4: Hematological co-variates in chimeric mice compared to C57BL/c (host type), Balb/c mice (donor), and SCD mice.
Fig. 5: Histo-pathology.

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Acknowledgements

Funded by Cell Source Inc.

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Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Aloukick Kumar Singh, Elias Schetzen, Sandeep Kumar Yadav, Esther Bachar Lustig, Wei-Hsin Liu, Raj Kumar Yadav, Kathryn McGinnis & Yair Reisner

  2. Centre for Haematology Research Imperial College London, London, UK

    Robert Peter Gale

  3. CPRIT Scholar in Cancer Research, Houston, TX, USA

    Yair Reisner

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  1. Aloukick Kumar Singh
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Contributions

Y.R. conceived, designed, analyzed, interpret the data and wrote the typescript. A.K.S. helped design the study. A.K.S. performed and organized most of the experiments. A.K.S., Y.R., and, E.S. analyzed and interpreted the data. Y.R., R.P.G., and A.K.S. co-wrote the typescript. S.K.Y., W.-H.L., and E.B.L. assisted with experiments and typescript preparation. A.K.S., K.M., S.K.Y., R.K.Y., and W.-H.L. performed the hemoglobin electrophoreses and E.S. and A.K.S., the histopathology.

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Correspondence to Yair Reisner.

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Y.R. is a consultant and shareholder of Cell Source Inc.

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Singh, A.K., Schetzen, E., Yadav, S.K. et al. Correction of murine sickle cell disease by allogeneic haematopoietic cell transplantation with anti-3rd party veto cells. Bone Marrow Transplant 56, 1818–1827 (2021). https://doi.org/10.1038/s41409-021-01237-6

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