HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

Transplantation Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, USA.
New England Journal of Medicine (Impact Factor: 55.87). 02/2008; 358(4):353-61. DOI: 10.1056/NEJMoa071074
Source: PubMed


Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA.

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    • "Besides, it is unclear whether higher levels of chimerism per se are more likely to induce full tolerance. In the clinical setting, it was shown that tolerance toward renal allografts can be achieved with transient chimerism.2 Also, it was found that T-cell chimerism correlates with the development of donor-specific tolerance and that high levels of hematopoietic (non–T-cell) chimerism are not necessarily associated with donor-specific tolerance.18,25,26 "
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    ABSTRACT: The mixed chimerism approach induces donor-specific tolerance in both pre-clinical models and clinical pilot trials. However, chronic rejection of heart allografts and acute rejection of skin allografts were observed in some chimeric animals despite persistent hematopoietic chimerism and tolerance toward donor antigens in vitro. We tested whether additional cell therapy with regulatory T cells (Tregs) is able to induce full immunologic tolerance and prevent chronic rejection. We recently developed a murine "Treg bone marrow (BM) transplantation (BMT) protocol" that is devoid of cytoreductive recipient pre-treatment. The protocol consists of a moderate dose of fully mismatched allogeneic donor BM under costimulation blockade, together with polyclonal recipient Tregs and rapamycin. Control groups received BMT under non-myeloablative irradiation and costimulation blockade without Treg therapy. Multilineage chimerism was followed by flow cytometry, and tolerance was assessed by donor-specific skin and heart allografts. Durable multilineage chimerism and long-term donor skin and heart allograft survival were successfully achieved with both protocols. Notably, histologic examination of heart allografts at the end of follow-up revealed that chronic rejection is prevented only in chimeras induced with the Treg protocol. In a mouse model of mixed chimerism, additional Treg treatment at the time of BMT prevents chronic rejection of heart allografts. As the Treg-chimerism protocol also obviates the need for cytoreductive recipient treatment it improves both efficacy and safety over previous non-myeloablative mixed chimerism regimens. These results may significantly impact the development of protocols for tolerance induction in cardiac transplantation.
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    • "In human, Kawai and coworkers have reported tolerance induction across HLA-mismatched barriers with a periconditioning treatment using pharmacological immunosuppression and thymic irradiation. This protocol allowed the removal of long-term immunosuppressive therapy achieving full acceptance of the transplanted organ up to five years after transplant [77]. However, one of the main obstacles in the induction of mixed chimerism using the aforementioned protocol is the presence of the memory T cells that can cross-react with alloantigens [78]. "
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    ABSTRACT: One of the greatest advances in medicine during the past century is the introduction of organ transplantation. This therapeutic strategy designed to treat organ failure and organ dysfunction allows to prolong the survival of many patients that are faced with no other treatment option. Today, organ transplantation between genetically dissimilar individuals (allogeneic grafting) is a procedure widely used as a therapeutic alternative in cases of organ failure, hematological disease treatment, and some malignancies. Despite the potential of organ transplantation, the administration of immunosuppressive drugs required for allograft acceptance induces severe immunosuppression in transplanted patients, which leads to serious side effects such as infection with opportunistic pathogens and the occurrence of neoplasias, in addition to the known intrinsic toxicity of these drugs. To solve this setback in allotransplantation, researchers have focused on manipulating the immune response in order to create a state of tolerance rather than unspecific immunosuppression. Here, we describe the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance.
    Clinical and Developmental Immunology 05/2013; 2013(5062):210506. DOI:10.1155/2013/210506 · 2.93 Impact Factor
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    • "Its potential has been shown in many different mouse models (Baranyi et al. 2009). Moreover, clinical observations of tolerance induction through cellular chimerism in transplant patients underline the potential of chimerism as future treatment strategy (Fudaba et al. 2006; Kawai et al. 2008). "
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