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. 2022 May 23:13:874499.
doi: 10.3389/fimmu.2022.874499. eCollection 2022.

"VSports" Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach

Friedrich Wittenbecher  1   2 , Stella Lesch  1 , Stefan Kolling  1 , Igor-Wolfgang Blau  1 , Lam Vuong  1 , Franziska Borchert  1 , Kamran Movasshagi  1 , Carola Tietze-Bürger  1 , Olaf Penack  1   2 , Johann Ahn  1 , Lars Bullinger  1   3   4 , Marco Frentsch  1   2 , Il-Kang Na  1   2   3   4
Affiliations

Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach

"VSports手机版" Friedrich Wittenbecher et al. Front Immunol. .

"V体育ios版" Abstract

Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point VSports手机版. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT. .

Keywords: allogeneic hematopoietic stem cell transplantation (HSCT); granulocyte-colony stimulating factor (G-CSF); immune cell network; immune subsets; mobilization; reconstitution V体育安卓版. .

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Conflict of interest statement

The authors declare that the research for this study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest VSports最新版本. The reviewer HTG declared past co-authorships with the author OP to the handling editor.

Figures

Figure 1
Figure 1
Methodological set-up. Flow cytometric evaluation of the depicted cell types from 100µl heparinized whole blood. Treg, Regulatory CD4 T-cells; Tcon, conventional CD4 T-cells; TEMRA, Terminally differentiated effector memory T-cells; DC, Dendritic cells; NK cells, Natural killer cells. Created with Biorender.
Figure 2
Figure 2
Donor cell counts before and after G-CSF mobilization. (A) Median cell counts per µl whole blood with 25th and 75th percentiles before and after G-CSF treatment. (B) Log2 fold changes of the median cell counts before and after G-CSF stimulation. Significance levels were calculated with the Wilcoxon signed rank test with *p < 0.05 **p < 0.01 ***p < 0.001 ****p < 0.0001; T_cells, T cells; CD8_T, CD8 T cytotoxic cells; CD8_TEMRA, CD8 terminally differentiated memory T cells; CD4_T, CD4 T helper cells; CD4_Treg, Regulatory CD4 T cells; CD4_Tcon, Conventional CD4 T cells; CD4_TEMRA, CD4 terminally differentiated memory T cells; CD4CD8_T, CD4CD8 double positive T cells; gd_T, gamma-delta T cells; B_cells, B cells; Naive_B, Naive B cells; NonSwitch_B, Non-switched memory B cells; Mem_B, Memory B cells; Plasmablasts, Plasmablasts; NK_cells, NK cells; brightNK, CD56 bright NK cells; dimNK, CD56 dim NK cells; Mono, Monocytes; cMono, Classical monocytes; ncMono, Non-classical monocytes; DC, Dendritic cells; pDC, Plasmacytoid dendritic cells; mDC, Myeloid dendritic cells; Neutro, Neutrophils; Eosino, Eosinophils; Baso, Basophils.
Figure 3
Figure 3
Recipient immune cell reconstitution until day +360. Cell counts per µl whole blood post transplantation with fitted polynomial surface; using local fitting. T_cells, T cells; CD8_T, CD8 T cytotoxic cells; CD8_TEMRA, CD8 terminally differentiated memory T cells; CD4_T, CD4 T helper cells; CD4_Treg, Regulatory CD4 T cells; CD4_Tcon, Conventional CD4 T cells; CD4_TEMRA, CD4 terminally differentiated memory T cells; CD4CD8_T, CD4CD8 double positive T cells; gd_T, gamma-delta T cells; B_cells, B cells; Naive_B, Naive B cells; NonSwitch_B, Non-switched memory B cells; Mem_B, Memory B cells; Plasmablasts, Plasmablasts; NK_cells, NK cells; brightNK, CD56 bright NK cells; dimNK, CD56 dim NK cells; Mono, Monocytes; cMono, Classical monocytes; ncMono, Non-classical monocytes; DC, Dendritic cells; pDC, Plasmacytoid dendritic cells; mDC, Myeloid dendritic cells; Neutro, Neutrophils; Eosino, Eosinophils; Baso, Basophils.
Figure 4
Figure 4
Subset distribution approaches that of healthy donors on day +180 post transplantation. (A) Representative t-sne plot of measured subsets of a healthy donor before G-CSF stimulation. (B) Spearman correlation of cell counts of healthy donors before G-CSF stimulation (n=18) with those after G-CSF stimulation (n=21) and days +7 (n=20), +28 (n=21) and +180 (n=19) after transplantation. Correlation coefficients and p-values are shown in the graphs. Positive correlation indicates similar subset distribution as that of reference timepoint (healthy donors before stimulation). T_cells, T cells; CD8_T, CD8 T cytotoxic cells; CD8_TEMRA, CD8 terminally differentiated memory T cells; CD4_T, CD4 T helper cells; CD4_Treg, Regulatory CD4 T cells; CD4_Tcon, Conventional CD4 T cells; CD4_TEMRA, CD4 terminally differentiated memory T cells; CD4CD8_T, CD4CD8 double positive T cells; gd_T, gamma-delta T cells; B_cells, B cells; Naive_B, Naive B cells; NonSwitch_B, Non-switched memory B cells; Mem_B, Memory B cells; Plasmablasts, Plasmablasts; NK_cells, NK cells; brightNK, CD56 bright NK cells; dimNK, CD56 dim NK cells; Mono, Monocytes; cMono, Classical monocytes; ncMono, Non-classical monocytes; DC, Dendritic cells; pDC, Plasmacytoid dendritic cells; mDC, Myeloid dendritic cells; Neutro, Neutrophils; Eosino, Eosinophils; Baso, Basophils.
Figure 5
Figure 5
Correlation heatmaps of selected immune cell populations and on selected time points. Unclustered correlation (Spearman) of selected immune cell populations between donors and recipients identifies strong positive association of donor B-cell counts with early timepoints post transplantation, negative association of donor plasmacytoid dendritic cell (pDC) counts and donor CD8 T cell counts with early immune reconstitution, and positive association of early recipient CD4 T cell counts with later recipient CD4 T cell counts. CD4 T, CD4 T helper cells; CD8 T, CD8 T cytotoxic cells; pDC, Plasmacytoid dendritic cells; Memory B, Memory B cells. Timepoint (n): preGCSF (18), postGCSF (21), d3 (20), d7 (20), d14 (21), d28 (21), d60 (20), d90 (20), d180 (19), d360 (15).
Figure 6
Figure 6
Unsupervised hierarchical clustering of recipients according to cell counts on early time points. Unsupervised hierarchical clustering (ward.D) of Z-transformed cell count values for different time points reveals distinct reconstitution groups on days +14 and +28 post alloHSCT. T_cells, T cells; CD8_T, CD8 T cytotoxic cells; CD8_TEMRA, CD8 terminally differentiated memory T cells; CD4_T, CD4 T helper cells; CD4_Treg, Regulatory CD4 T cells; CD4_Tcon, Conventional CD4 T cells; CD4_TEMRA, CD4 terminally differentiated memory T cells; CD4CD8_T, CD4CD8 double positive T cells; gd_T, gamma-delta T cells; B_cells, B cells; Naive_B, Naive B cells; NonSwitch_B, Non-switched memory B cells; Mem_B, Memory B cells; Plasmablasts, Plasmablasts; NK_cells, NK cells; brightNK, CD56 bright NK cells; dimNK, CD56 dim NK cells; Mono, Monocytes; cMono, Classical monocytes; ncMono, Non-classical monocytes; DC, Dendritic cells; pDC, Plasmacytoid dendritic cells; mDC, Myeloid dendritic cells; Neutro, Neutrophils; Eosino, Eosinophils; Baso, Basophils; aGvHD, acute GvHD; cGvHD, chronic GvHD; CR, complete response; MRD+, minimal residual disease positive; PR, partial response. For GvHD prophylaxis; “none” depicts patients who received neither ATG nor post transplantation cyclophosphamide; these patients may still have received ciclosporin A; MTX; mycophenolat mofetil.
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