Mechanisms and clinical effects of microchimerism in transfused trauma patients

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DESCRIPTION (provided by applicant): Microchimerism (MC), the stable persistence of cells or tissues from one individual within another, has been described in association with pregnancy, twinning, transplantation, and, most recently, routine blood transfusion. Long-term MC has recently been implicated in the development of a variety of chronic autoimmune diseases. We have reported and confirmed the surprising finding that, in the clinical setting of traumatic injury, leukocytes from a single blood donor can persist in a transfusion recipient for at least three years at a level which rises over time to as much as 3-4% of the recipient's total circulating leukocytes. In our preliminary studies, this transfusion-associated MC (TA-MC) affected 10% of transfused trauma patients long-term and occurred at a similar rate even when all transfused blood products were leukocyte-reduced (LR). Multiple lineages of leukocytes appear to be involved in TA-MC, including B- and T-lymphocytes as well as myelomonocytes. The broad hypothesis behind this proposed research is that TA-MC is a prevalent complication of blood transfusion in patients with severe tissue injury having both adverse and therapeutic implications. To investigate this hypothesis, we propose a set of closely related Specific Aims to determine: 1a) the prevalence of TA-MC in two additional clinical populations in which its occurrence is plausible, burn and orthopedic surgery patients, relative to trauma patients; 1b) the recognizable health problems associated with long-term TA-MC; 2) the kinetics and immunologic mechanisms of TA-MC; and 3) the extent of donor hematopoietic stem cell engraftment and donor lymphocyte clonality in transfusion recipients with long-term high level TA-MC. The epidemiologic aims 1a and 1b will be addressed through a retrospective cohort study (n=600), and the immunologic mechanisms of TA-MC will be investigated in detail in a prospective study of transfused trauma patients (n=360). These studies will identify selected subjects with high-level long-term TA-MC for investigation of engraftment and clonality in aim 3 (n=10). LAY LANGUAGE DESCRIPTION OF THE RESEARCH: From the standpoint of blood use policy, we believe that it is now critical to determine the prevalence of transfusion-associated microchimerism and whether it represents a harmful consequence of transfusion. TA-MC also offers an opportunity to better understand, and potentially exploit, injury-induced tolerance for future therapeutic purposes.