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The microchimerism puzzle

T he recent study of transfusion-associated microchimerism (TA-MC)—the persistence of allogeneic donor white blood cells (WBCs) for unexpectedly long periods in transfusion recipients—sprang from the serendipitous finding by Lee and colleagues, that transfused trauma patients harbored donor WBCs for unexpectedly long periods. In many ways, the unfolding story of TA-MC since that finding is akin to a jigsaw puzzle whose size and complexity are yet unknown. To understand the role of the current article in this issue by Sanchez and coworkers in this puzzle, it is worth briefly recapping progress on this topic to date. Although findings by investigators in the 1960s and 1970s began to suggest that donor WBCs could survive and remain immunologically active in transfusion recipients, further study of the topic did not gain steam until the advent of polymerase chain reaction (PCR)-based techniques for detecting the donor WBCs. Important advances—largely from the laboratory of Lee and Busch—improved the capabilities of the PCR assays, which isolate cellular DNA only, for detecting and characterizing TA-MC. The use of allelespecific primers that recognize at least a 2to 3-bp difference in the minor population (rather than just a single-base-pair difference) meant that the PCR primer would not get consumed by the closely related major population (i.e., recipient) DNA. Also, while initial primers were limited to detection of Y-chromosome sequences, subsequent primers allowed detection of differences between HLA alleles, in addition to a variety of insertiondeletion polymorphisms across a number of different chromosomes. Real-time PCR allowed quantitation of these sequences, with the copy number inversely related to the cycle at which the reaction became positive. Together, these advances resulted in extraordinary sensitivity of TA-MC assays applicable to most donor-recipient pairs (i.e., independent of gender or HLA relationship), probably capable of detecting single cells in aliquots and quantifying the proportion of donor WBCs relative to all WBCs. After the initial study by Lee and coworkers demonstrating TA-MC in trauma patients persisting at least 18 months in some cases, subsequent studies confirmed that TA-MC occurred in additional populations of trauma patients, that TA-MC occurred despite leukoreduction of blood units, and that PCR evidence consistent with TA-MC could be observed decades after transfusion. Although these studies consistently demonstrated TA-MC for only one or two nonrecipient alleles in most cases, much work remains to determine why a transfusion recipient typically develops TA-MC for presumably only one donor. Donor-recipient pairs that subsequently develop TA-MC clearly have a unique relationship in that their lymphocytes are mutually hyporesponsive in mixed WBC cultures that use pretransfusion specimens. Additional factors which might contribute to the development of TA-MC require further detailed study, a complicated endeavor given the practical difficulties of obtaining additional blood samples from all donors for a particular recipient to definitively determine the donor(s) responsible for TA-MC and to characterize their immunologic state vis-à-vis the recipient. Among the many donor, blood component, and recipient factors that may be important to the development of TA-MC, the recipient condition and the viability of the donor WBCs are of paramount interest. To date, durable TA-MC has not been observed in groups of patients other than those with acute traumatic injuries; negative results have been found in human immunodeficiency virus–positive patients, patients with hemoglobinopathies, pediatric patients who underwent cardiac surgery, and adult elective surgery patients. However, study of these other groups has been limited in some cases by modest numbers of subjects and techniques that might not have been sufficiently sensitive—for example, the PCR assay predated the use of the panel of insertion-deletion polymorphisms. Thus, more information is desirable before we conclude that TA-MC outside of the trauma setting categorically does not occur. Elucidating the role of donor WBC viability in the development of TA-MC is important to understand exactly both what TA-MC is and, if necessary some day, how to prevent its occurrence. Because durable TA-MC involves the observation of donorWBCs many months or years after transfusion, it seems the only plausible explanations are that either a population of donor lymphocytes has persisted or, more dramatically, that some degree of engraftment with hematopoietic cells, however modest, has occurred. In theory, engraftment might result from the inclusion of circulating donor pluripotent precursor cells in blood units. Preliminary evidence for such engraftment comes from the study by Lee and colleagues This article was supported by Grant HL083388 from the National Heart, Lung, and Blood Institute. doi: 10.1111/j.1537-2995.2012.03645.x TRANSFUSION 2012;52:926-928.