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. 2019 Aug 13;3(15):2250-2263.
doi: 10.1182/bloodadvances.2018029892.

Kinetics of immune cell reconstitution predict survival in allogeneic bone marrow and G-CSF-mobilized stem cell transplantation

Edmund K Waller  1 , Brent R Logan  2 , Mingwei Fei  2 , Stephanie J Lee  3 , Dennis Confer  4 , Alan Howard  4 , Shanmuganathan Chandrakasan  5 , Claudio Anasetti  6 , Shanelle M Fernando  7 , Cynthia R Giver  1
Affiliations

Kinetics of immune cell reconstitution predict survival in allogeneic bone marrow and G-CSF-mobilized stem cell transplantation

Edmund K Waller et al. Blood Adv. .

Abstract

The clinical utility of monitoring immune reconstitution after allotransplant was evaluated using data from Blood and Marrow Transplant Clinical Trials Network BMT CTN 0201 (NCT00075816), a multicenter randomized study of unrelated donor bone marrow (BM) vs granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cell (G-PB) grafts. Among 410 patients with posttransplant flow cytometry measurements of immune cell subsets, recipients of G-PB grafts had faster T-cell reconstitution than BM recipients, including more naive CD4+ T cells and T-cell receptor excision circle-positive CD4+ and CD8+ T cells at 3 months, consistent with better thymic function. Faster reconstitution of CD4+ T cells and naive CD4+ T cells at 1 month and CD8+ T cells at 3 months predicted more chronic graft-versus-host disease (GVHD) but better survival in G-PB recipients, but consistent associations of T-cell amounts with GVHD or survival were not seen in BM recipients. In contrast, a higher number of classical dendritic cells (cDCs) in blood samples at 3 months predicted better survival in BM recipients. Functional T-cell immunity measured in vitro by cytokine secretion in response to stimulation with cytomegalovirus peptides was similar when comparing blood samples from BM and G-PB recipients, but the degree to which acute GVHD suppressed immune reconstitution varied according to graft source. BM, but not G-PB, recipients with a history of grades 2-4 acute GVHD had lower numbers of B cells, plasmacytoid dendritic cells, and cDCs at 3 months. Thus, early measurements of T-cell reconstitution are predictive cellular biomarkers for long-term survival and response to GVHD therapy in G-PB recipients, whereas more robust DC reconstitution predicted better survival in BM recipients VSports手机版. .

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Conflict of interest statement

Conflict-of-interest disclosure: E. K. W. has received payments and other support from Cambium Medical Technologies, grants from Celldex Therapeutics, payments from Kalytera Therapeutics, grants and payments from Novartis, grants and nonfinancial support from Pharmacyclics, has equity ownership in Cerus Corporation and Chimerix that is outside the scope of this study, and has intellectual property related to the immune-modulatory effects of vasoactive intestinal polypeptide that have been licensed to Cambium Oncology LLC, a biotechnology company in which he holds equity V体育ios版. The remaining authors declare no competing financial interests.

Figures

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Graphical abstract
Figure 1.
Figure 1.
Recipients of G-PB grafts from unrelated donors have faster T-cell reconstitution than recipients of BM grafts. Mean numbers of immune cells in the blood are shown with the 25th and 75th percentiles at the upper and lower limits of the “box” and 95% confidence intervals (“whiskers”) at 1, 3, 6, 12, and 24 months posttransplant for recipients of BM (blue) or G-PB (red) grafts for total T cells (A), CD4+ T cells (B), CD8+ T cells (C), CD4+ Tregs (D), γδ T cells (E), B cells (F), cDCs (G), pDCs (H), CD56+ CD16+ NK cells (I), and CD56+ CD16− NK cells (J). ***P < .001, **P < .01.
Figure 2.
Figure 2.
Recipients of G-PB grafts have faster T-cell reconstitution and thymopoiesis than BM graft recipients with more naive and TREC+ T cells. The proportions of CD4+ (A) and CD8+ (B) T cells with naive, central memory, effector memory, and terminal effector memory phenotype were determined by flow cytometry, as previously described, in blood samples obtained at 1, 3, 6, 12, and 24 months posttransplant from recipients of BM or G-PB grafts. Numbers of TREC+ CD4+ T cells (C) and TREC+ CD8+ T cells (D) per milliliter. (E) Percentages of TREC+ CD4+ naive T cells and TREC+ CD8+ naive T cells among recipients of BM or G-PB grafts. ***P < .001.
Figure 3.
Figure 3.
The amount of cDCs in the blood at 3 months posttransplant predicts survival after allogeneic HSCT from unrelated donors. (A) Multivariate analysis showing the hazard ratios (HRs) for the numbers of viable T cells, T-cell subsets, B cells, NK cells, DC subsets (cDCs/myeloid DCs and pDCs), CD4+ and CD8+ TREC, and plasma IL-2 and IL-7 levels with OS for recipients of G-PB grafts. (B) Multivariate analysis showing HRs for the numbers of immune cells and plasma cytokine levels with OS for recipients of BM grafts. (C) Estimated probability of 3-year OS, stratifying 291 evaluable recipients of BM and G-PB grafts by the median number of cDCs in blood samples at 3 months posttransplant. (D) Estimated probability of 3-year OS by the median number of pDCs in blood samples at 3 months posttransplant.
Figure 4.
Figure 4.
Posttransplant numbers of blood lymphocytes and DCs are suppressed by the occurrence of grade 2-4 aGVHD in BM recipients, whereas functional immunity is similar in BM and G-PB graft recipients. (A) Serial measurements of T-cell, B-cell, and DC subsets in blood samples from patients stratified by whether they had a previous diagnosis of grade 2-4 aGVHD (orange lines) or grade 0-1 aGVHD (blue lines) (upper panels). Reconstitution kinetics for mean values of B cells (far left and near left lower panels) and pDCs (far right and near right lower panels) stratified by a prior diagnosis of grade 2-4 aGVHD among BM or G-PB transplant recipients. (B) Intracellular expression of IL-2, IFN-γ, and TNF-α in CD4+ and CD8+ T cells from recipients of BM and G-PB grafts. Percentages of CD4+ and CD8+ T cells that synthesized IL-2 in response to antigenic nonspecific activation with PMA/ionomycin (top row). Percentages of CD4+ and CD8+ T cells that expressed IL-2 (second row), IFN-γ (third row), or TNF-α (bottom row) following overnight coculture with CMV lysate. pts, patients.
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