Chimerism and Tolerance Without GVHD or Engraftment Syndrome in HLA-Mismatched Combined Kidney and Hematopoietic Stem Cell Transplantation

Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
Science translational medicine (Impact Factor: 15.84). 03/2012; 4(124):124ra28. DOI: 10.1126/scitranslmed.3003509
Source: PubMed


The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.

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Available from: Lorenzo Gallon, Dec 13, 2014
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    • "Kawai et al. (2013) showed that combined bone marrow and kidney transplants from HLA single haplotype mismatched living donors resulted in mixed chimerism and donor unresponsiveness in four out of five patients, facilitating withdrawal of immunosuppression . Leventhal et al. (2012) showed mobilized stem cell graft and nonmyeloablative conditioning induces durable chimerism and donor-specific tolerance in solid organ transplant recipients. Leucocyte depletion with alemtuzumab has been shown to induce tolerance in Campath1-H pilot study (Trzonkowski et al., 2008). "
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    ABSTRACT: The 3rd International Transplant Conference took place on 31st October and 1st November 2014 at the University of Warwick, Coventry, UK. Key focal points of the meeting were the exploration of the molecular basis of antibody-antigen interactions and their relation to clinical practice and to share experiences and knowledge regarding strategies to transplant the 'high-risk' patient. In addition, lively debate sessions were hosted where controversial clinical and immunological themes were discussed by leading experts in the field. © 2015 John Wiley & Sons Ltd.
    International Journal of Immunogenetics 02/2015; 42(2). DOI:10.1111/iji.12184 · 1.25 Impact Factor
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    • "Hematopoietic chimerism is another attractive therapeutic option to induce allograft tolerance and therefore eliminate or minimize TV related to chronic rejection. This has been successfully accomplished in animal models undergoing heart transplantation and in human models undergoing renal transplantation [Pasquet et al., 2011, 2013; Leventhal et al., 2012, 2013; Yamada et al., 2012; Kawai and Sachs, 2013]. Advances in regenerative tissue engineering using autologous stem or progenitor cells hold great potential to create a bioartifical heart [Taylor, 2009]. "
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    Journal of Cellular Biochemistry 07/2014; 115(7). DOI:10.1002/jcb.24782 · 3.26 Impact Factor
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    • "Recently, a modified reduced induction regimen with infusion of a facilitating cell population has been described with positive results. Persistent graft chimerism and stable allograft function appear to be present at one-year follow-up, but longer-term results are pending (36). "
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