Molecular Therapy - Methods & Clinical Development

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Molecular Therapy - Methods & Clinical Development Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety Joni Keto, Tanja Kaartinen, Urpu Salmenniemi, Johanna Castrén, Jukka Partanen, Arno Hänninen, Matti Korhonen, Kaarina Lähteenmäki, Maija Itälä-Remes, Johanna Nystedt Molecular Therapy - Methods & Clinical Development Volume 9, Pages 109-118 (June 2018) DOI: 10.1016/j.omtm.2018.02.001 Copyright © 2018 The Author(s) Terms and Conditions

Molecular Therapy - Methods & Clinical Development 2018 9, 109-118DOI: (10.1016/j.omtm.2018.02.001) Copyright © 2018 The Author(s) Terms and Conditions

Figure 1 Lymphocyte Counts in Patients Treated with MSCs Numbers of T cells (CD3+, CD4+, CD8+), NK cells (CD16+CD56+), and B cells (CD19+) in samples collected from patients before the MSC treatment (day 0) and approximately 1 week and 1 month after the first MSC dose are shown. The shaded area represents the current reference interval (range of cell numbers) for a healthy population. (A) Individual lymphocyte numbers in each patient, with mean values and 95% confidence intervals. The numbers of CD3+, CD4+, and CD19+ lymphocytes were very low throughout the follow-up period. (B) Lymphocyte numbers in patients grouped according to the day 28 response to MSCs. Cell numbers are shown as a whisker plot showing the mean value and range. The Kruskal-Wallis test was used to calculate statistical significance. There was no statistically significant difference between the lymphocyte numbers of responding (n = 4) and non-responding (n = 7) patients or between different sample collection time points. Molecular Therapy - Methods & Clinical Development 2018 9, 109-118DOI: (10.1016/j.omtm.2018.02.001) Copyright © 2018 The Author(s) Terms and Conditions

Figure 2 Relative Amounts of CD4+ T Helper Cell Subsets The relative proportion (out of CD4+ gated cells) of circulating Th1, Th2, Th17, and FOXP3-expressing Tregs, measured from patient samples collected before the MSC treatment (day 0) and approximately 1 week and 1 month after the first MSC dose, as well from healthy volunteer samples, are shown. Closed circles represent samples from patients responding and open circles not responding to MSCs. Dashed line represents the lower limit of quantification of the method; inverted triangles are measured samples that could not be reliably quantified. Results are plotted as individual dots and means with 95% confidence intervals. The Kruskal-Wallis test was used to calculate statistical significance. All differences between the groups were statistically non-significant. Molecular Therapy - Methods & Clinical Development 2018 9, 109-118DOI: (10.1016/j.omtm.2018.02.001) Copyright © 2018 The Author(s) Terms and Conditions

Figure 3 Concentrations of GvHD-Related Serum Protein Markers prior to the MSC Treatment (A) Concentrations of Reg3α, CK18F, and elafin in patient samples (day 0) shown in comparison with samples collected from healthy blood donors (n = 108). Results are shown as individual dots and mean values, with error bars indicating 95% confidence intervals. (B) Concentrations of the proteins in samples grouped according to the GvHD organ involvement of the patient. Patients are divided into groups based on the GI GvHD severity and liver and skin involvement at the time of GvHD diagnosis (−, no involvement of an organ; +, involvement of an organ; GI +, stage 1–2 gastrointestinal GvHD; GI ++, stage 3–4 gastrointestinal GvHD). Results are shown as individual dots and mean values, with error bars indicating SD. The Mann-Whitney test was used to calculate statistical significance (*p < 0.05; **p < 0.01; ***p < 0.001). Concentrations of all serum proteins were significantly higher in the patients than in the healthy controls; an elevated CK18F concentration was noted in the patients with liver GvHD, and a trend of higher elafin concentrations in the patients with skin GvHD. Molecular Therapy - Methods & Clinical Development 2018 9, 109-118DOI: (10.1016/j.omtm.2018.02.001) Copyright © 2018 The Author(s) Terms and Conditions

Figure 4 Concentrations of GvHD-Related Serum Protein Markers in the Patients Responding and Not Responding to MSC Therapy (A) Concentrations of Reg3α, CK18F, and elafin in serum samples collected from patients before the MSC treatment (day 0) and approximately 1 week and 1 month after the first MSC dose are shown. Results are shown as individual dots and mean values, with error bars indicating 95% confidence intervals. (B) Heatmaps showing the individual kinetics of the proteins during the follow-up period were created using log2 transformed concentrations. Patients are grouped according to the day 28 response to MSCs (A and B) and the GvHD target organ (B). The Kruskal-Wallis test was used to calculate statistical significance. All differences between the groups were statistically non-significant. Molecular Therapy - Methods & Clinical Development 2018 9, 109-118DOI: (10.1016/j.omtm.2018.02.001) Copyright © 2018 The Author(s) Terms and Conditions