Volume 95, Issue 3, Pages (March 2019)

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Volume 95, Issue 3, Pages 693-707 (March 2019) Infusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I- II, open-label, clinical study Pauline Erpicum, Laurent Weekers, Olivier Detry, Catherine Bonvoisin, Marie-Hélène Delbouille, Céline Grégoire, Etienne Baudoux, Alexandra Briquet, Chantal Lechanteur, Gianni Maggipinto, Joan Somja, Hans Pottel, Frédéric Baron, François Jouret, Yves Beguin Kidney International Volume 95, Issue 3, Pages 693-707 (March 2019) DOI: 10.1016/j.kint.2018.08.046 Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 1 Design of the study. Analysis 1 refers to comparisons between the 10 MSC-treated vs. the 10 MSC-non-treated patients, whereas analysis 2 refers to comparisons between the 10 MSC-treated patients and the whole KTR cohort. DBD, donor after brain death; DCD, donor after circulatory death; EBV, Epstein-Barr virus; HCV, hepatitis C virus; KTR, kidney transplant recipient; KTx, kidney transplantation; MSC, mesenchymal stromal cell; PNF, primary nonfunction; PRA, panel-reactive antibody. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 2 Evolution of glomerular filtration rate (eGFR) after kidney transplantation. eGFR was estimated using the Modification of Diet in Renal Disease equation. eGFR was significantly higher at day 7 in the mesenchymal stromal cell (MSC) group than in the whole cohort, with a similar nonsignificant trend for the control group. eGFR at 12 months after kidney transplantation was similar in all groups. Statistical analyses were performed using the Mann-Whitney U test. Repeated measures of eGFR were evaluated using linear mixed models with fixed effects on group, day, age, and sex and patient as a random effect. P1 refers to comparisons between MSC and control groups, whereas P2 refers to comparisons between the MSC group and the whole cohort. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 3 Kinetics of T-cell populations in peripheral blood after kidney transplantation (KTx). Mesenchymal stromal cell (MSC)–treated patients are indicated by dark blue boxes, whereas controls are indicated by light blue boxes. Absolute numbers of (a) CD4+ T cells (CD3+CD4+ lymphocytes), (b) naive CD4+ T cells (CD4+CD45RAhigh lymphocytes), (c) natural killer cells (CD3−CD56+ lymphocytes), and (d) memory CD4+ T cells (CD4+CD45RO+ lymphocytes) at days 0, 30, and 180 after kidney transplantation. Plots display the median (25th and 75th percentiles) of the distributions (boxes), and whiskers extend to the 10th and 90th percentiles. Arrowheads indicate significant longitudinal statistical analyses between day 30 and the indicated time point in the control group. Bold lines represent differences between MSC and control groups at the indicated time point. *P ≤ 0.05, ∗∗ P ≤ 0.01. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 4 Evolution of regulatory T cells (Tregs) in mesenchymal stromal cell (MSC)–treated versus control kidney transplant recipients. MSC-treated patients are indicated by dark blue boxes, whereas controls are indicated by light blue boxes. (a) Percentage of Tregs. (b) Absolute number of Tregs. (c) Treg interleukin-2 signaling (assessed by phosphorylated signal transducer and activator of transcription 5 [pSTAT5] expression levels). (d) Treg proliferation (assessed by Ki-67 expression levels). (e) HLA-DR mean fluorescence intensity (MFI) of activated effector Tregs. (f) Treg subsets. Tregs were divided into naive HLA-DR−CD45RA+ (DR−, RA+), resting HLA-DR−CD45RA− (DR−, RA−), and activated effector HLA-DR+CD45RA− (DR+, RA−) cells. Plots display the median (25th and 75th percentiles) of the distributions (boxes), and whiskers extend to the 10th and 90th percentiles. Arrowheads indicate significant longitudinal statistical analyses within MSC or control groups. Bold lines represent differences between MSC and control groups at the indicated time point. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. D0, day 0; D30, day 30; D180, day 180; D365, day 365; KTx, kidney transplantation. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 5 Evolution of B-cell subsets in mesenchymal stromal cell (MSC)–treated versus control kidney transplant recipients. MSC-treated patients are indicated by dark blue boxes, whereas controls are indicated by light blue boxes. (a) Percentage of CD19+ B cells, (b) absolute numbers of CD19+ B cells, (c) percentage of naive B cells, (d) marginal zone B cells, (e) transitional B cells, (f) plasmablasts, (g) class switched memory B cells, (h) class nonswitched memory B cells, and (i) CD21lowCD38low B cells in MSC-treated and control patients at 30, 180, and 365 days after kidney transplantation (KTx). Plots display the median (25th and 75th percentiles) of the distributions (boxes), and whiskers extend to the 10th and 90th percentiles. Arrowheads indicate significant longitudinal statistical analyses in the MSC group. Bold lines represent differences between MSC and control groups at the indicated time point. *P ≤ 0.05, **P ≤ 0.01. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 6 Serum levels of Igs in mesenchymal stromal cell (MSC)–treated versus control kidney transplant recipients. MSC-treated patients are indicated by dark blue boxes, whereas controls are indicated by light blue boxes. (a) IgG, (b) IgM, (c) IgA levels before kidney transplantation (KTx) at days 14, 90, 180, and 365. Plots display the median (25th and 75th percentiles) of the distributions (boxes), and whiskers extend to the 10th and 90th percentiles. Arrowheads indicate significant longitudinal statistical analyses between pretransplant values and the values at indicated time point within MSC or control groups. Bold lines represent differences between MSC and control groups at the indicated time point. Gray zones depict the normal range. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S1 Individual evolution of mesenchymal stromal cell (MSC)–treated kidney transplant recipients over 1-year follow-up. CMV, cytomegalovirus; D2, day 2; D4, day 4; D5, day 5; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; KTx, kidney transplantation; MSC-DSA, mesenchymal stromal cell–donor-specific antibody; NSTEMI, non–ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S1 Individual evolution of mesenchymal stromal cell (MSC)–treated kidney transplant recipients over 1-year follow-up. CMV, cytomegalovirus; D2, day 2; D4, day 4; D5, day 5; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; KTx, kidney transplantation; MSC-DSA, mesenchymal stromal cell–donor-specific antibody; NSTEMI, non–ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S2 Individual evolution of control kidney transplant recipients over 1-year follow-up. DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; KTx, kidney transplantation. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S2 Individual evolution of control kidney transplant recipients over 1-year follow-up. DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; KTx, kidney transplantation. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S3 Gating strategy for the identification of regulatory T cells (Tregs). Tregs were defined as CD4+CD25+CD127lowFoxp3+ lymphocytes. The gating strategy for CD25 was permissive, excluding only the negative fraction, because the anti-CD25 antibody (CD25-PeCy7 [BC96, Sony]) shares a common epitope (BC96) with basiliximab.99 From this CD25+CD127low population, we selected the Foxp3-positive fraction. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S4 Flow cytometry of the intracellular expression of Foxp3 and Ki-67 within each regulatory T-cell (Treg) subsets. Tregs were defined as CD4+CD25+CD127lowFoxp3+. Tregs were divided into naive (CD45RA+HLA-DR), resting (CD45RA−HLA-DR−), and activated effector (CD45RA−HLA-DR+) cells. (A) Expression of Foxp3 in Treg subpopulations. The left axis represents the mean fluorescence intensity (MFI) of Foxp3. (B) Expression of Ki-67 in Treg subpopulations. **P ≤ 0.01, ***P ≤ 0.001. Kidney International 2019 95, 693-707DOI: (10.1016/j.kint.2018.08.046) Copyright © 2018 International Society of Nephrology Terms and Conditions