Transfusion-associated microchimerism: the hybrid within

Abstract

Microchimerism, the coexistence of genetically disparate populations of cells in a receptive host, is well described in both clinical and physiological settings, including transplantation and pregnancy. Microchimerism can also occur after allogeneic blood transfusion in traumatically injured patients, where donor cells have been observed decades after transfusion. To date, transfusion-associated microchimerism (TA-MC) appears confined to this clinical subset, most likely due to the immune perturbations that occur after severe trauma that allow foreign donor cells to survive. Transfusion-associated microchimerism appears to be unaffected by leukoreduction and has been documented after transfusion with an array of blood products. The only significant predictor of TA-MC to date is the age of red cells, with fresher units associated with higher risk. Thus far, no adverse clinical effect has been observed in limited studies of TA-MC. There are, however, hypothesized links to transfusion-associated graft vs host disease that may be unrecognized and consequently underreported. Microchimerism in other settings has gained increasing attention owing to a plausible link to autoimmune diseases, as well as its diagnostic and therapeutic potential vis-a-vis antenatal testing and adoptive immunotherapy, respectively. Furthermore, microchimerism provides a tool to further our understanding of immune tolerance and regulation.

Figure 1. Real time PCR and Detection of Microchimerism

Fluorescence intensity is plotted on the y-axis while cycles are plotted on the x-axis. Cycle threshold (C_T) is defined as the cycle where the fluorescence intensity of amplified DNA crosses a background threshold. Lower cycle thresholds indicate presence of more DNA compared to samples with higher C_T s. The patient pre-transfusion sample was typed as HLA DR1*4 and HLA DR1*8, with cycle thresholds for the major types of 27.8 and 28.6 cycles, respectively. Following identification of the subject type, the post-transfusion sample was probed for microchimerism by amplifying for HLA-DR1*1, 3, 4, 7, 8, 9, 10, 11, 12,13, 15 and 16. The cycle threshold for the post-transfusion minor population of DR1*1 is 33.3 cycles.

Figure 2. Kinetics of immune response to trauma

Blood samples were collected from trauma patients beginning with arrival to the emergency room and up to 1 year after injury. Multiplexing techniques were used to measure the levels of 41 immunomodulatory proteins in the plasma. Multivariable generalized estimating equations models were generated using the natural log of the concentration of each protein as the dependent variable and time since trauma, injury severity score, injury type, size of transfusion, age, sex, and microchimerism as the independent variables. Overlays of the models’ prediction of the influence of time since trauma controlling for the other covariates are plotted by protein type. Predicted values at 1 year after trauma are set as the baseline (0) for each cytokine to show elevation or depression relative to this value. The inflammation plot includes the pro-inflammatory cytokines interleukin (IL)-1α, IL-5, IL-9, IL-17, tumor necrosis factor α, tumor necrosis factor β, and macrophage migration inhibitory factor, the anti-inflammatory cytokines IL-1 Receptor a and IL-10, and IL-6, which has both pro- and anti-inflammatory properties. The healing plot includes the wound healing proteins epidermal growth factor, fibroblast growth factor-2, vascular endothelial growth factor, matrix metallopeptidase 9, and total plasminogen activator inhibitor-1, the activated endothelial markers soluble E-Selectin, soluble inter-cellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1, and the homeostasis cytokines IL-7 and IL-15. The apoptosis plot includes the pro-apoptotic soluble FasL and the anti-apoptotic soluble Fas. The chemokine plot includes interferon gamma-induced protein-10, IL-8, macrophage inflammatory protein 1 α, monocyte chemotactic protein-1, eotaxin, fractalkine, and macrophage derived chemokine. (Adapted from Jackman, R. P., et al. 2012, Transfusion. doi: 10.1111/j.1537-2995.2012.03618.x, with permission) [120]