Abstract

Abstract Transfusion Related Immunomodulation (TRIM) is a phenomenon that was first described over 30 years ago when it was reported that patients receiving blood transfusions prior to renal transplants had improved graft survival rates. The prevailing hypothesis for these observations at the time was that donor leukocytes were responsible for the effects; however, transfusion of leukoreduced and irradiated blood products still resulted in TRIM, suggesting that another component of the blood products, such as red blood cells (RBCs), might mediate the immunosuppressive effects. RBCs have been shown to affect the activation of immune cells and immune responses. For example, monocytes co-cultured with RBCs and stimulated with LPS produce lower levels of TNF-a than those that are not co-cultured. This suggests that RBCs can shape the immune response that develops during antigen presentation. Splenic red pulp macrophages are critical for clearance of both RBCs and heme, and these processes are essential for maintaining RBC homeostasis and preventing heme-mediated toxicity. Inside macrophages, heme is degraded by the enzyme Heme Oxygenase-1 (HO-1) and HO-1 activity leads to increased IL-10 and decreased TNF-a secretion. We hypothesized that erythrophagocytosis by macrophages during RBC transfusion may result in the activation of a heme-mediated HO-1 dependent signaling pathway that causes immunosuppressive effects. We used the robust TLR stimulation models of LPS and CpG challenge, and tested whether RBC transfusion or heme signaling could modulate the resulting macrophage cytokine response. We found that CORM-2 (a synthetic CO releasing molecule) downregulates the macrophage pro-inflammatory cytokine profile.

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