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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Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Yale J Biol Med. 2001;74:179–84.
Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001;79:704–12.
Glassberg J. Evidence-based management of sickle cell disease in the emergency department. Emerg Med Pract. 2011;13:1–20. quiz 20.
Centre for Disease Control and Prevention. Data and statistics of sickle cell disease (SCD). https://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed 21 Oct 2019.
Esham KS, Rodday AM, Smith HP, Noubary F, Weidner RA, Buchsbaum RJ, et al. Assessment of health-related quality of life among adults hospitalized with sickle cell disease vaso-occlusive crisis. Blood Adv. 2020;4:19–27.
El Hoss S, Cochet S, Marin M, Lapoumeroulie C, Dussiot M, Bouazza N, et al. Insights into determinants of spleen injury in sickle cell anemia. Blood Adv. 2019;3:2328–36.
Badawy SM, Payne AB. Association between clinical outcomes and metformin use in adults with sickle cell disease and diabetes mellitus. Blood Adv. 2019;3:3297–306.
Reeves SL, Jary HK, Gondhi JP, Kleyn M, Dombkowski KJ. Health outcomes and services in children with sickle cell trait, sickle cell anemia, and normal hemoglobin. Blood Adv. 2019;3:1574–80.
Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120:4285–91.
Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transpl. 2013;19:820–30.
Fitzhugh CD, Hsieh MM, Taylor T, Coles W, Roskom K, Wilson D, et al. Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Blood Adv. 2017;1:652–61.
Shenoy S, Eapen M, Panepinto JA, Logan BR, Wu J, Abraham A, et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016;128:2561–7.
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transpl. 2008;14:641–50.
La Nasa G, Giardini C, Argiolu F, Locatelli F, Arras M, De Stefano P, et al. Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes. Blood. 2002;99:4350–6.
Li C, Wu X, Feng X, He Y, Liu H, Pei F, et al. A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation. Blood. 2012;120:3875–81.
Or-Geva N, Reisner Y. The evolution of T-cell depletion in haploidentical stem-cell transplantation. Br J Haematol. 2016;172:667–84.
Rachamim N, Gan J, Segall H, Krauthgamer R, Marcus H, Berrebi A, et al. Tolerance induction by “megadose” hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation. 1998;65:1386–93.
Miller RG. An immunological suppressor cell inactivating cytotoxic T-lymphocyte precursor cells recognizing it. Nature. 1980;287:544–6.
Reisner Y, Or-Geva N. Veto cells for safer nonmyeloablative haploidentical HSCT and CAR T cell therapy. Semin Hematol. 2019;56:173–82.
Ophir E, Eidelstein Y, Afik R, Bachar-Lustig E, Reisner Y. Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo-induced central memory CD8 T cells. Blood. 2010;115:2095–104.
Ophir E, Or-Geva N, Gurevich I, Tal O, Eidelstein Y, Shezen E, et al. Murine anti-third-party central-memory CD8(+) T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells. Blood. 2013;121:1220–8.
Kean LS, Durham MM, Adams AB, Hsu LL, Perry JR, Dillehay D, et al. A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex–mismatched bone marrow transplantation. Blood. 2002;99:1840–9.
Pestina TI, Hargrove PW, Zhao H, Mead PE, Smeltzer MP, Weiss MJ, et al. Amelioration of murine sickle cell disease by nonablative conditioning and gamma-globin gene-corrected bone marrow cells. Mol Ther Methods Clin Dev. 2015;2:15045.
Hulbert ML, Shenoy S. Hematopoietic stem cell transplantation for sickle cell disease: progress and challenges. Pediatr Blood Cancer. 2018;65:e27263.
Javazon EH, Radhi M, Gangadharan B, Perry J, Archer DR. Hematopoietic stem cell function in a murine model of sickle cell disease. Anemia. 2012;2012:387385.
Shenoy S. Hematopoietic stem cell transplantation for sickle cell disease: current practice and emerging trends. Hematol Am Soc Hematol Educ Program. 2011;2011:273–9.
Robinson TM, Fuchs EJ. Allogeneic stem cell transplantation for sickle cell disease. Curr Opin Hematol. 2016;23:524–9.
Brodsky RA, Luznik L, Bolaños-Meade J, Leffell MS, Jones RJ, Fuchs EJ. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transpl. 2008;42:523–7.
Park SH, Lee CM, Dever DP, Davis TH, Camarena J, Srifa W, et al. Highly efficient editing of the beta-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. Nucleic Acids Res. 2019;47:7955–72.
Romero Z, Lomova A, Said S, Miggelbrink A, Kuo CY, Campo-Fernandez B, et al. Editing the sickle cell disease mutation in human hematopoietic stem cells: comparison of endonucleases and homologous donor templates. Mol Ther. 2019;27:1389–406.
Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med. 2000;6:114.
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 2003;48:719–27.
Vincenti F. What’s in the pipeline? New immunosuppressive drugs in transplantation. Am J Transpl. 2002;2:898–903.
Shock A, Burkly L, Wakefield I, Peters C, Garber E, Ferrant J, et al. CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study. Arthritis Res Ther. 2015;17:234.
Reich-Zeliger S, Zhao Y, Krauthgamer R, Bachar-Lustig E, Reisner Y. Anti-third party CD8+ CTLs as potent veto cells: coexpression of CD8 and FasL is a prerequisite. Immunity. 2000;13:507–15.
Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30:832–44.
Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105:4743–8.
Qu Y, Zhang B, Zhao L, Liu G, Ma H, Rao E, et al. The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice. Transpl Immunol. 2007;17:153–61.
Hale DA, Gottschalk R, Fukuzaki T, Wood ML, Maki T, Monaco AP. Extended skin allo- and xenograft survival in mice treated with rapamycin, antilymphocyte serum, and donor-specific bone marrow transfusion. Transpl Proc. 1996;28:3269.
Hale DA, Gottschalk R, Fukuzaki T, Wood ML, Maki T, Monaco AP. Superiority of sirolimus (rapamycin) over cyclosporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow. Transplantation. 1997;63:359–64.
Hale DA, Gottschalk R, Umemura A, Maki T, Monaco AP. Establishment of stable multilineage hematopoietic chimerism and donor-specific tolerance without irradiation. Transplantation. 2000;69:1242–51.
Pilat N, Klaus C, Gattringer M, Jaeckel E, Wrba F, Golshayan D, et al. Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model. Transplantation. 2011;92:280–8.
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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