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      A Depleting Anti-CD45 Monoclonal Antibody as Isolated Conditioning for Bone Marrow Transplantation in the Rat

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          Abstract

          Objective

          A monoclonal antibody (mAb) against the leukocyte common antigen CD45 (RT7 in rats) could facilitate bone marrow transplantation (BMT). This study in rats evaluates a depletive rat anti-RT7 a mAb as isolated tool for BMT conditioning without using irradiation or any chemotherapeutic / immunosuppressive agent.

          Methods

          The model used a CD45 di-allelic polymorphism (RT7 a/RT7 b). The anti-RT7 a mAb was intravenously administered to LEW.1W rats (RT1 uRT7 a) at 5, 10 and 15 mg/kg. 1x10 8 BM cells of MHC syngeneic (RT1 u), MHC disparate (RT1 l) or MHC haploidentical (RT1 u/l) donors were transplanted. All BM donor strains carried the RT7 b allele so that their CD45 + cells were not affected by the anti-RT7 a mAb. Recipients were monitored for reconstitution and donor-chimerism in blood leukocytes.

          Results

          mAb dosages of 5 or 10 mg/kg were myelosuppressive, whereas 15 mg/kg was myeloablative. Multi-lineage donor-chimerism at day 100 indicated engraftment of MHC syngeneic BM after any used mAb dosage (5 mg/kg: 46+/-7%; 10 mg/kg: 62+/-5%; 15 mg/kg: 80+/-4%). MHC disparate BM resulted in autologous reconstitution after conditioning by 10 mg/kg of the mAb and caused transient chimerism ending up in death associated with aplasia after conditioning by 15 mg/kg of the mAb. MHC haploidentical BM (F1 to parental) engrafted only after conditioning by 15 mg/kg (chimerism at day 100: 78+/-7%). Abandonment of α/β TCR + cell depletion from BM grafts impaired the engraftment process after conditioning using 15 mg/kg of the mAb in the MHC syngeneic setting (2 of 6 recipients failed to engraft) and the MHC haploidentical setting (3 of 6 recipients failed).

          Conclusion

          This depletive anti-RT7 a mAb is myelosuppressive and conditions for engraftment of MHC syngeneic BM. The mAb also facilitates engraftment of MHC haploidentical BM, if a myeloablative dose is used. RT7 b expressing, BM-seeded α/β TCR + cells seem to impair the engraftment process after myeloablative mAb conditioning.

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          Most cited references31

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          Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study.

          Stem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity. 16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH 24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors. Antibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease. Monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor. None.
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            Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning.

            Donor-specific tolerance induced by bone marrow transplantation (BMT) would allow organ allografting without chronic immunosuppressive therapy. However, the toxicity of conditioning regimens used to achieve marrow engraftment has precluded the clinical use of BMT for tolerance induction. We have developed a BMT strategy that achieves alloengraftment without toxic or myelosuppressive host conditioning. B6 mice received depleting anti-CD4 and anti-CD8 monoclonal antibodies, local thymic irradiation, and a high-dose (174 x 10(6)) of major histocompatibility (MHC)-mismatched B10.A bone marrow cells (BMCs) divided over days 0 through 4. High levels of donor cells were observed among white blood cells (WBCs) of all lineages. Permanent, multilineage mixed chimerism; donor-specific skin-graft tolerance; and in vitro tolerance were observed in most animals. Large numbers of donor class II(high) cells were detected in thymuses of long-term chimeras, and their presence was associated with intrathymic deletion of donor-reactive host thymocytes. The treatment was not associated with significant myelosuppression, toxicity, or graft-versus-host disease (GVHD). Thus, high levels of allogeneic stem-cell engraftment can be achieved without myelosuppressive host conditioning. As stem-cell mobilization and in vitro culture techniques have increased the feasibility of administering high doses of hematopoietic cells to humans, this approach brings hematopoietic cell transplantation closer to clinical use for the induction of central deletional T-cell tolerance.
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              Preformed antibody, not primed T cells, is the initial and major barrier to bone marrow engraftment in allosensitized recipients.

              Multiply-transfused individuals are at higher risk for BM rejection. We show that whereas allosensitization resulted in the priming of both cellular and humoral immunity, preformed antibody was the major barrier to engraftment. The generation of cross-reactive alloantibody led to rejection of BM of a different MHC-disparate strain. Imaging studies indicated that antibody-mediated rejection was very rapid (<3 hours) in primed recipients, while T-cell-mediated rejection in nonprimed mice took more than 6 days. Antibody-mediated BM rejection was not due to a defect in BM homing as rejection occurred despite direct intra-BM infusion of donor BM. Rejection was dependent upon host FcR+ cells. BM cells incubated with serum from primed mice were eliminated in nonprimed recipients, indicating that persistent exposure to high-titer antibody was not essential for rejection. High donor engraftment was achieved in a proportion of primed mice by mega-BM cell dose, in vivo T-cell depletion, and high-dose immunoglobulin infusion. The addition of splenectomy to this protocol only modestly added to the efficacy of this combination strategy. These data demonstrate both rapid alloantibody-mediated elimination of BM by host FcR+ cells and priming of host antidonor T cells and suggest a practical strategy to overcome engraftment barriers in primed individuals.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 May 2016
                2016
                : 11
                : 5
                : e0154682
                Affiliations
                [1 ]Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany
                [2 ]Klinik und Poliklinik für Chirurgie, Klinikum der Universität Regensburg, Regensburg, Germany
                Emory University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MDJ HJS KT. Performed the experiments: MDJ WR TR KT. Analyzed the data: MDJ FWRV TR HJS HB JK KT. Contributed reagents/materials/analysis tools: MDJ WR TR HJS KT. Wrote the paper: MDJ FWRV WR TR HJS HB JK KT.

                Article
                PONE-D-15-44667
                10.1371/journal.pone.0154682
                4854389
                27139494
                5e9e410f-c3ad-4704-aeaf-24da4242b432
                © 2016 Jäger et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 October 2015
                : 18 April 2016
                Page count
                Figures: 7, Tables: 4, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: Sonderforschungsbereich 265, Projekt B5
                Award Recipient :
                This work was supported by the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 265, Projekt B5.
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