Regulation of immune responses by RBC transfusion

Abstract

It has long been appreciated that transferring allogeneic tissues between members of the same species can have complicated effects upon the recipient immune system. Transfusion represents the most common exposure to large quantities of alloantigen, which unlike solid organ transplant, occurs in the absence of pharmacological immunosuppression. Transfused products constitute a complex cellular entity, with multiple potential pathways of affecting recipient immunity. In many ways, transfusion is a complex and variable cellular therapy, the broad effects of which are poorly understood. In addition to the well‐described phenomenon of direct alloimmunization, multiple transfusion induced alterations of the immune response to third party alloantigens or to antigens in general have also been described, the biology of which has been named ‘Transfusion Related Immunomodulation (TRIM)’. Early observations of TRIM effects most famously included the striking observation that transfusing red blood cells (RBCs) prior to renal transplant, substantially delayed organ rejection. This phenomenon, which was named ‘The Transfusion Effect’, was interpreted by some as evidence that transfusion tolerized to alloantigen, whereas others regarded this as a reflection of a general immunosuppressant property of transfused blood. This latter interpretation was bolstered by subsequent observations that increased frequency of transfusion correlated with increased rates of infection, neoplastic metastases, and decreases in symptoms of autoimmune disorders. In aggregate, the above observations have led to a general belief, across multiple fields and medical specialties, that transfused blood products are immunosuppressive. However, such understanding has evolved in the context of the clear demonstration that transfused blood can induce a primary immune response in the form of alloantibodies. This leads to the apparently paradoxical landscape of transfusions being simultaneously ‘immunosuppressive’ and ‘immunogenic’. The proposed solution to the apparently conflicting observations is a widely stated paradigm that transfusions stimulate humoral immunity whilst simultaneously inhibiting cellular immunity. Such could certainly be the case, and is consistent with more general understandings of mutually antagonistic arms of the immune system (e.g. Th1 that favors cellular immunity and Th2 that favors humoral immunity). However, it must be emphasized in the strongest possible terms that the vast majority of studies that describe TRIM effects do not in fact measure immunity. Rather, they measure biological outcomes that may be affected by immunity, but may just as likely be affected by processes independent of the immune system. In support of this notion, recent reports have indicated that transfused blood can have growth factors that directly stimulate bacterial growth and tumor expansion, bringing previous interpretations of immunosuppression, based upon infections and metastasis, into question. However, recent studies on TRIM effects have indeed focused on innate immunity and inflammation, and in doing so have started to tackle the direct issue of measuring the immune response itself; however, the absence of detailed and specific analysis of adaptive immunity remains an impediment to understanding how transfused blood products regulate long‐term immune effects.