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Allogeneic red blood cell transfusion impairs antigen presentation and stimulates inflammatory response

ABSTRACT: Allogeneic red blood cell transfusion increases risk of infection and organ injury, which we here attempted to explain by analyzing gene expression in various types of immune cells. We prospectively compared adverse events and transcriptomic profiles in immune cells between patients who received transfusion of red blood cells (not plasma or platelets) during or after on-pump cardiac surgery and patients who did not. The composite rate of adverse events was significantly more frequent among patients who received transfusions (4 of 16, 25%) than among those who did not (3 of 60, 5%, p = 0.03). Transfusion downregulated in monocytes several genes involved in antigen presentation, such as HLA-DQA2 and HLA-DPB1, as well as several ligand-receptor pairs linking monocytes to natural killer cells (HLA-C-KIR2DL1, HLA-E-CD94:NKG2A) and T cells (CD28-CD86, CD2-CD58) for antigen presentation. Transfusion upregulated the early activation marker CD69 and pro-inflammatory and chemotactic factors (IL-6, TNFR1, TNFR2, CXCL9 and CCL3) in T, B and natural killer cells. Transfusion volume correlated positively with the percentage of CD69+ CD8+ T cells, which in turn correlated positively with composite risk of adverse events. Our findings may help explain how transfusion causes immunosuppression and systemic inflammation, thereby increasing risk of adverse events. Our work may provide clues to developing preventive or mitigating measures in order to optimize prognosis of patients who receive blood cell transfusions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251696 | GEO | 2025/03/19

REPOSITORIES: GEO

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Project description:Measurement of specific gene expression in clinical samples is a promising approach for monitoring the recipient immune status to the graft in organ transplantation. Identification of biomarker genes closely associated with tolerance or rejection is critical for this monitoring protocol. Unlike previous studies, our microarray analysis focused on donor antigen-reactive T cells, which were prepared by collecting CD69+ T cells from cocultures of recipient peripheral T cells and donor antigen-presenting cells. A comparison of different recipient groups enabled us to identify several tolerance- and rejection-correlated biomarker genes, including previously unknown genes. By measuring biomarker gene expression in the CD69+ T cell fraction using quantitative reverse-transcription polymerase chain reaction, we were able to precisely detect the immune status of recipients relative to their graft. Full-thickness donor (BDF1; C57BL/6 x DBA/2) tail skin was grafted onto recipient (C57BL/6) mice. Tolerance to the graft was induced by donor specific transfusion combined with administration of anti-CD40L Ab (MR-1). Total T lymphocytes were prepared from spleen and lymph nodes of tolerant recipient mice on day 100 after skin transplantation, untreated recipient mice on day 7, and ungrafted, healthy C57BL/6 mice and used as tolerant, rejecting and naïve T lymphocyte samples, respectively. In order to isolate alloantigen-reactive cells, T lymphocytes were cocultured with donor T cell-depleted splenocytes for 20-21 hours and then separated into two subpopulations based on CD69 expression using fluorescence cell sorter. Total RNA was extracted from these CD69+ and CD69- T cells and subjected to microarray using Illunima MouseWG-6 Expression BeadChip. All data analysis and visualization of differentially expressed genes was conducted using Illumina GenomeStudio v2009.2 (Gene Expression Module v1.5.4) and R statistical language v2.6.1. Candidate tolerance genes were defined as the common genes satisfying the following criteria; 1) 1.5 fold or higher expression in CD69+ T cells isolated from tolerant recipients than those from naïve mice, 2) 1.5 fold or higher expression in CD69+ T cells than CD69- T cells from tolerant mice, 3) 500 or higher average signal measured in CD69+ T cells from tolerant mice. The criteria for candidate rejection genes were 1) 1.5 fold or higher expression in CD69+ T cells isolated from rejecting recipients than those from tolerant mice, 2) 1.5 fold or higher expression in CD69+ T cells than CD69- T cells from rejecting mice, 3) 500 or higher average signal measured in CD69+ T cells from rejecting mice.

Project description:Measurement of specific gene expression in clinical samples is a promising approach for monitoring the recipient immune status to the graft in organ transplantation. Identification of biomarker genes closely associated with tolerance or rejection is critical for this monitoring protocol. Unlike previous studies, our microarray analysis focused on donor antigen-reactive T cells, which were prepared by collecting CD69+ T cells from cocultures of recipient peripheral T cells and donor antigen-presenting cells. A comparison of different recipient groups enabled us to identify several tolerance- and rejection-correlated biomarker genes, including previously unknown genes. By measuring biomarker gene expression in the CD69+ T cell fraction using quantitative reverse-transcription polymerase chain reaction, we were able to precisely detect the immune status of recipients relative to their graft. Full-thickness donor (BDF1; C57BL/6 x DBA/2) tail skin was grafted onto recipient (C57BL/6) mice. Tolerance to the graft was induced by donor specific transfusion combined with administration of anti-CD40L Ab (MR-1). Total T lymphocytes were prepared from spleen and lymph nodes of tolerant recipient mice on day 21 and 100 after skin transplantation, untreated recipient mice on day 7, and ungrafted, healthy C57BL/6 mice and used as early tolerant, tolerant, rejecting and naïve T lymphocyte samples, respectively. In order to isolate alloantigen-reactive cells, T lymphocytes were cocultured with donor BM-DCs for 20-21 hours and then separated into two subpopulations based on CD69 expression using fluorescence cell sorter. Total RNA was extracted from these CD69+ and CD69- T cells and subjected to microarray using Illunima MouseRef-8 Expression BeadChip. All data analysis and visualization of differentially expressed genes was conducted using Illumina BeadStudio v3.1.3 (Gene Expression Module v3.3.8), Array Assist 5.5.1 (Stratagene) and R 2.4.1(www.r-project.org). Candidate tolerance genes were defined as the common genes satisfying the following criteria; 1) 1.5 fold or higher expression in CD69+ T cells isolated from tolerant recipients than those from naïve mice, 2) 1.5 fold or higher expression in CD69+ T cells than CD69- T cells from tolerant mice, 3) 500 or higher average signal measured in CD69+ T cells from tolerant mice. The criteria for candidate rejection genes were 1) 1.5 fold or higher expression in CD69+ T cells isolated from rejecting recipients than those from tolerant mice, 2) 1.5 fold or higher expression in CD69+ T cells than CD69- T cells from rejecting mice, 3) 500 or higher average signal measured in CD69+ T cells from rejecting mice.

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Allogeneic red blood cell transfusion impairs antigen presentation and stimulates inflammatory response

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