Microchimerism.
Authors: Busch Michael P. , Reed William 
Published: October 2019

Abstract
Abstract SCI-46
Microchimerism (MC) is the long-term persistence of an allogeneic cell population of <5% relative to host cells. MC may result from various allogeneic exposures, including transplantation, pregnancy, twinning and blood transfusion. Advances in PCR, particularly development of allele-specific, real-time PCR in closed systems, have facilitated detection/quantitation of MC. Though conceptually related to fetal-maternal MC, transfusion-associated MC (TA-MC) is distinct. Transient chimerism has been found in patients transfused for elective surgery, hemoglobinopathies, congenital heart disease and advanced HIV infection. In contrast, persistent TA-MC occurs frequently among trauma patients who received cellular blood products shortly after massive injury and hemorrhage. At hospital discharge, TA-MC is present in about half of severe trauma patients; most loose detectable chimeric cells, but approximately 1 in 5 (10% overall) develop persistent TA-MC which may approach 5% of all circulating leukocytes and persist for years. While TA-MC has been primarily studied in civilian trauma populations, recent studies of soldiers transfused from World War II to the Iraq war have confirmed its occurrence in military trauma settings. The severity of injury and freshness of blood are prominent determinants of the incidence and persistence of TA-MC. Of note, leukoreduction of blood products, widely implemented in the 1990s, did not affect the incidence of TA-MC. TA-MC appears to represent engraftment at the level of the hematopoietic stem cell (HSC), given long-term persistence of multiple lineages of donor leukocytes in humans and in murine models of TA-MC. As with multiple cord blood transplantation, in most cases, leukocytes from only a single donor persist. The presence of a focal deficit in the cellular immunologic repertoire following injury but prior to transfusion that matches a blood donor's HLA type appears to be an important predisposing factor. This focal deficit is superimposed on a generalized immune suppression that occurs following severe injury. Preliminary studies have also documented allelic-polymorphisms in immune response genes that predispose some patients to development of TA-MC. Transfusion studies using knock-out mice have demonstrated innate and adaptive immune functions that predispose to TA-MC, supporting these human data. In addition to ongoing studies of degree of engraftment and cellular immunity, we recently analyzed 41 soluble immune mediators in 56 trauma patients, both transfused (n = 39) and non-transfused (n = 17), and healthy blood donor controls. A number of these proteins fluctuate in response to trauma and transfusion, including those involved in immune modulation, inflammation, lymphocyte homeostasis, lymphocyte homing, and wound healing. Preliminary data suggest that failure to upregulate IL-10 immediately following trauma may be associated with the development of TA-MC. The phenomenon of TA-MC presents an opportunity to study the immunobiology of trauma, transfusion, tolerance, engraftment and alloresponsiveness. Our studies are now expanding to other populations (burn and peripartum recipients), and addressing clinical manifestations of TA-MC that may be either pathologic (autoimmunity, GVHD) or therapeutic (tolerance induction, cell therapies).

Disclosures
No relevant conflicts of interest to declare.