Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide by Franco Aversa, Esther.

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Immune tolerance induction by nonmyeloablative haploidentical HSCT combining T-cell depletion and posttransplant cyclophosphamide by Franco Aversa, Esther Bachar-Lustig, Noga Or-Geva, Lucia Prezioso, Sabrina Bonomini, Ilenia Manfra, Alessandro Monti, Chiara Schifano, Yael Zlotnikov-Klionsky, Massimo F. Martelli, Gabriella Sammarelli, Maria Sassi, Maurizio Soli, Silvia Giuliodori, Magda Benecchi, Nicola Giuliani, Frank Lohr, Silvia Pratissoli, and Yair Reisner BloodAdv Volume 1(24):2166-2175 November 14, 2017 © 2017 by The American Society of Hematology

Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Marked enhancement of chimerism induction upon combining megadose TCD BM transplantation with PTCY. (A) Typical mixed chimerism detected by FACS analysis at day 180. Marked enhancement of chimerism induction upon combining megadose TCD BM transplantation with PTCY. (A) Typical mixed chimerism detected by FACS analysis at day 180. (B-C) Cumulative results of 9 experiments including a total of 66 recipient mice treated by megadose TCD BM plus PTCY, measured at 210 to 300 days posttransplant. Data are presented by violin plot representing the distribution of percent donor chimerism (B) and percent donor chimera (C). Statistical analysis was performed by χ2 analysis. (D) Chimeric mice exhibit multilineage chimerism (green bars, donor; purple bars, host). Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Chimerism induction following different doses of TBI or PTCY Chimerism induction following different doses of TBI or PTCY. The effect of different doses of irradiation (A) or increased doses of cyclophosphamide (B) on donor-type chimerism in recipients of megadose (25 × 106) TCD Nude-BM (Nu/BM) treated with high-dose PTCY. Statistical comparisons were performed using the Mann-Whitney U test. Chimerism induction following different doses of TBI or PTCY. The effect of different doses of irradiation (A) or increased doses of cyclophosphamide (B) on donor-type chimerism in recipients of megadose (25 × 106) TCD Nude-BM (Nu/BM) treated with high-dose PTCY. Statistical comparisons were performed using the Mann-Whitney U test. Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Tolerance induction of allogeneic TCD donor BM following transplantation of megadose BM and PTCY. (A) Limiting dilution analysis of CTL-p performed against donor (yellow) or third-party (green) splenocytes. Tolerance induction of allogeneic TCD donor BM following transplantation of megadose BM and PTCY. (A) Limiting dilution analysis of CTL-p performed against donor (yellow) or third-party (green) splenocytes. A typical experiment assessing 1 chimeric mouse out of 3 tested is shown. (B) Acceptance of donor-type (BALB/c, white fur, red arrows) skin implanted at 7 months after BM transplantation, with rejection of third-party grafts (C57BL/6, black fur, yellow arrows). Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Scheme summarizing the haploidentical transplantation protocol combining megadose TCD HSCT and high-dose PTCY in high-risk MM patients. Scheme summarizing the haploidentical transplantation protocol combining megadose TCD HSCT and high-dose PTCY in high-risk MM patients. ATG, antithymocyte globulin. Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Chimerism analysis at different time points (percentage of donor [D] cells out of total PBMCs and BM). Chimerism analysis at different time points (percentage of donor [D] cells out of total PBMCs and BM). Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

CMV reactivation following megadose haploidentical TCD (following CD3/CD19 depletion) HSCT. (A) Immune resolution of CMV reactivation as indicated by viral DNA titer at different time points. CMV reactivation following megadose haploidentical TCD (following CD3/CD19 depletion) HSCT. (A) Immune resolution of CMV reactivation as indicated by viral DNA titer at different time points. (B) Lymphocyte subset reconstitution in peripheral blood, and time points of FACS analysis of CMV-specific T cells. (C) Enumeration of CMV-specific CD8+ T cells with the Dextramer CMV kit 55 days posttransplant. The host-type anti-CMV CD3+/CD8+/HLA-A02 was present at 214 cells/µL (vs 0 for donor-type CD3+/CD8+/HLA-B35/µL). Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology

Tolerance induction of donor cells following haploidentical transplantation combining megadose TCD HSCT and high-dose PTCY. Analysis of CTL-p against donor and third-party target cells by IFN-γ ELISpot assay, which measures the frequency of IFN-γ–secreting cells following specific activation at the single-cell level, in PBMCs of patients 1 and 3 at 144 and 117 days following transplantation, respectively (for details, see Materials and methods). Tolerance induction of donor cells following haploidentical transplantation combining megadose TCD HSCT and high-dose PTCY. Analysis of CTL-p against donor and third-party target cells by IFN-γ ELISpot assay, which measures the frequency of IFN-γ–secreting cells following specific activation at the single-cell level, in PBMCs of patients 1 and 3 at 144 and 117 days following transplantation, respectively (for details, see Materials and methods). Franco Aversa et al. Blood Adv 2017;1:2166-2175 © 2017 by The American Society of Hematology