Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction?

Allogeneic blood transfusion results in the infusion into the recipient of large amounts of foreign antigens in both soluble and cell-associated forms. The persistence of these antigens in the circulation of the recipient may create conditions that allow the development of immune down-regulation. Evidence from a variety of sources indicates that allogeneic blood transfusion enhances the survival of renal allografts1 and may increase the recurrence rate of resected malignancies2 and the incidence of postoperative bacterial infections,3-7 as well as reduce the recurrence rate of Crohn disease8 and/or activate infections with cytomegalovirus9 or human immunodeficiency virus.10 This clinical syndrome, the mechanisms of which remain to be defined, has been referred to in the transfusion medicine literature as allogeneic blood transfusion–associated immunomodulation (TRIM).11 Clinical evidence for the existence of TRIM has been available since 1973. In their seminal study, Opelz et al1 provided evidence, counterintuitive at the time, that recipients of allogeneic blood transfusion had improved renal allograft survival. Subsequent clinical studies and studies in experimental animals corroborated the results of Opelz et al,1 and allogeneic blood transfusions were used deliberately in the early 1980s to prevent rejection of renal allografts.12 The beneficial effect of TRIM was obscured following the introduction of immunosuppression with cyclosporine, but it was recently reported to persist even in renal allograft recipients receiving modern immunosuppressive therapy.13 On the basis of the immunomodulatory effect of allogeneic blood transfusion in renal allograft recipients, Gantt14 raised the question in 1981 whether the TRIM effect might also be associated with an increased risk of cancer recurrence in patients undergoing resection of a malignancy. Gantt’s hypothesis was based on the premise that, if allogeneic blood transfusion down-regulated the host’s immune surveillance mechanism that targets malignant cells, the receipt of allogeneic blood transfusion could enhance tumor growth. A subsequent hypothesis proposed that, if allogeneic blood transfusion causes immunosuppression, then recipients of perioperative allogeneic blood transfusion could be at increased risk for postoperative bacterial infection. Since 1981, more than 150 clinical studies have examined the association of perioperative allogeneic blood transfusion with cancer recurrence and/or postoperative bacterial infection. Most of these are observational cohort studies comparing patients who had or did not have transfusion.15-20 In addition, 7 randomized controlled trials (RCTs) have compared the risk of cancer recurrence2,21,22 and/or postoperative infection3-7,21-23 between a treatment arm receiving standard7 or buffy-coat–reduced red blood cells (RBCs)2,4-6,21,22 or whole blood3 and a control arm receiving autologous or white blood cell (WBC)-reduced RBCs or whole blood.24,25 These studies are based on the assumption that the transfusion of autologous2,4,21,23 or WBC-reduced3,5-7,22 RBCs, or whole blood, is immunologically neutral. Both the earlier observational cohort studies and the recent RCTs have produced contradictory findings, and—because of the discrepancies among the published studies—the long-standing hypothesis of the potentially deleterious immunomodulatory effect of perioperative allogeneic blood transfusion remains unresolved.11,26,27 The mechanism(s) of the TRIM effect(s) also remains elusive, and it is possible that a large number of biologic mechanisms may underlie the effect(s).28-31 The infusion of foreign antigen in either a soluble31-36 or cell-associated37-43 form has been shown to induce immune suppression, anergy, and clonal deletion in studies in experimental animals. However, most studies evaluating proposed mechanisms have been done in rodents, and these findings may not be applicable to the human immune system.44 Caution should be exercised, therefore, when findings from experimental animals are extrapolated to humans. Moreover, different biologic mechanisms may be involved in each reported clinical manifestation of TRIM,1-10 and the clinical evidence supporting each of the aforementioned hypotheses1-10 should be examined on its own merits. The specific constituent(s) of allogeneic blood that mediates the TRIM effect1-10 remains unclear. Allogeneic plasma,31-36 allogeneic WBCs,30,37-43 and substances that accumulate in blood components during storage39 have been implicated in the pathogenesis of TRIM. However, both the animal and human data suggest that the TRIM effects are most likely mediated by transfused allogeneic WBCs.45,46 Lee et al47 reported persistence of donor WBCs in humans for up to 1.5 years after an allogeneic blood transfusion. In murine and rabbit experimental models, Blajchman et al37,38 and Bordin et al39 demonstrated a tumor growth–promoting effect of allogeneic blood transfusion that appeared to be associated with transfusion of allogeneic WBCs. The findings of these experiments support the hypothesis that allogeneic WBCs actively induce immune suppression in transfusion recipients. In another relevant study, Kao40 induced immune suppression in mice receiving donor WBCs free of plasma and platelets. These and several other investigators41,42 also attributed an induction of TH2 cells in transfusion recipients to the allogeneic donor WBCs, showing that TH2 cells can produce immunosuppression in transfusion recipients by down-regulating the activity of TH1 cells. Mincheff et al43 implicated the antigen-presenting cells of the allogeneic donor in the induction of a state of anergy in the recipient and proposed that, during refrigeration, antigen-presenting cells lose their ability to deliver costimulation. These investigators hypothesized that after an allogeneic transfusion, the recipient’s T cells are stimulated by