Transfusion-related Immunomodulation Effect Research Articles

Implications of perioperative allogeneic red blood cell transfusion on the immune-inflammatory response.

BackgroundThe allogeneic transfusion-related immunomodulation (TRIM) may be responsible for an increase in survival of renal transplants but in contrast it could increase the rate of bacterial infections or the recurrence rate of tumors post-operatively.ObjectiveThis review focuses in the implications of perioperative allogeneic transfusions on the immune-inflammatory response of surgical transfused patients.ResultsABTs modify immune functions in recipients including decrease of the number of lymphocytes; decrease the CD4 cells; decrease the CD4/CD8 T-cell ratio; decrease NK cells; and decrease the lymphocyte response to mitogens. TRIM effects may be mediated by allogeneic white cells present in blood products; soluble peptides present in transfused plasma; and/or biologic mediators released into the supernatant of blood units. A recent systematic review and meta-analysis including 36 clinical observational studies (n = 174,036) concluded that perioperative ABTs not only decreased overall survival and reduced colorectal cancer-specific survival. Furthermore ABTs increased the rate of infectious, cardiac, pulmonary and anastomotic complications in colorectal cancer patients undergoing surgery.ConclusionsIt has been demonstrated by laboratory tests that TRIM is associated with transfusion recipient immune alterations but its influence in colorectal cancer recurrence after resection remains controversial though may exist. Surgical techniques reducing intraoperative blood loss have limited the number of ABTs perioperatively, however increase in mortality continues to be reported in literature after ABT in colorectal cancer surgery. Poor survival associated to TRIM in colorectal cancer might be due to higher number of allogeneic transfused units and/or prolonged length of blood storage.

The abandoned controversy surrounding universal white blood cell reduction.

The abandoned controversy surrounding universal white blood cell reduction.

Regulation of immune responses by RBC transfusion

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.

Is the number of blood products transfused associated with lower survival in children with acute lymphoblastic leukemia?

Blood transfusion during acute lymphoblastic leukemia (ALL) of childhood is scarcely documented. Children with ALL are immunosuppressed by both the disease and its therapy. Transfusion may contribute to the course of ALL through its transfusion-related immunomodulation (TRIM) effect. Blood transfusion history and response to therapy for 108 children <16 years of age at the time of ALL diagnosis was documented. Clinical files, electronic records, and blood bank registries were scrutinized. Overall survival (OS) and event-free survival (EFS) in relation to blood product type and number of transfusions was determined. Hazard ratios (HR) for death and relapse were estimated through uni- and multivariate Cox regression analysis. One hundred eight ALL patients were included. Median age was 6 years (range: 0-15 years). Ninety-seven patients (89.8%) were transfused. Median number of transfused products was seven (range: 0-345). After multivariate analysis, transfusion of >5 packed red blood cells (PRBC) remained a significant predictor for death (P = 0.003) and relapse (P = 0.011). For platelets, maximal significance was observed when >30 platelet concentrates (PC) were transfused (P < 0.001). When both, PRBC and PC were considered, maximal significance for predicting death was observed with transfusion of >30 blood products (P < 0.001). The number of blood products transfused to children with ALL appears to be significantly associated with lower survival rates. This may reflect both the severity of the disease and the TRIM effect, which may decrease immune surveillance capacity and the probability of leukemic clone eradication.

Transfusion‐related immunomodulation by platelets is dependent on their expression of MHC Class I molecules and is independent of white cells

Transfusion-related immunomodulation (TRIM) has been correlated with the presence of white cells (WBCs) in blood transfusions, but the role of components such as platelets (PLTs) in mediating TRIM has not been extensively examined. We designed a murine PLT transfusion model to study whether leukoreduced PLTs mediate TRIM effects. CBA recipient mice were administered four weekly transfusions of either fresh (4 hr) or aged (24 and 72 hr) donor leukoreduced PLTs from allogeneic BALB/c mice and then transplanted with skin grafts from donor-matched mice. TRIM was measured by comparing the times to graft rejection and these were correlated with immunoglobulin G (IgG) antibody development measured by flow cytometry. Compared with nontransfused control recipients, four transfusions of fresh, extremely leukoreduced (<0.05 WBCs/mL), allogeneic PLTs significantly (p < 0.002) reduced the recipient's ability to reject donor-matched skin grafts (survival >49 days compared with <14 days in nontransfused controls) despite the presence of high-titered serum IgG donor antibodies. In contrast, however, aged PLTs or fresh PLTs devoid of MHC Class I molecules were unable to affect skin graft survival nor stimulate antibody production. The PLT age-related inability to induce TRIM was shown to be due to loss of PLT-associated MHC Class I molecules; soluble supernatant MHC molecules that were transfused were unable to induce TRIM. These results suggest that fresh PLTs can induce TRIM independently of WBCs due to their MHC antigen expression whereas aging results in loss of MHC and ability to mediate TRIM. The findings support the concept that either active MHC removal from fresh PLTs or passive removal by, for example, storage, may reduce any deleterious effects of TRIM in transfusion recipients.

Pneumonia as a complication of blood product transfusion in the critically ill: Transfusion-related immunomodulation (TRIM)

An increased risk of postoperative infection (including pneumonia) attributable to the receipt of allogeneic blood transfusion has been investigated as a possible manifestation of transfusion-related immunomodulation (TRIM) in 16 randomized controlled trials (RCTs) and approximately 40 observational studies. This review categorizes RCTs and observational studies with regard to the inference that they permit about possible mediators of TRIM-allogeneic white cells (WBCs), WBC-derived soluble mediators, and/or allogeneic plasma-and examines whether the totality of the clinical evidence supports an association between allogeneic blood transfusion and postoperative infection. When all available studies are considered together in meta-analyses, three types of studies show no increased risk of postoperative infection in association with allogeneic blood transfusion: a) RCTs comparing recipients of buffy-coat-reduced and prestorage-filtered, WBC-reduced allogeneic red cells; b) RCTs comparing recipients of allogeneic and autologous blood; and c) observational studies comparing patients transfused before and after implementation of WBC reduction. RCTs comparing recipients of nonbuffy-coat-reduced and WBC-reduced red blood cells may point to a TRIM effect, but they cannot yet be subjected to formal meta-analysis. No overwhelming clinical evidence has been presented to establish the existence of a TRIM effect that relates allogeneic blood transfusion to postoperative infection.

The Mechanism of Transfusion-Related Immunomodulation Is Related to the Transfusion of Dendritic Cells Expressing the CD200 (OX-2) Tolerance Signal and Alloantigen: Evidence from a Murine Tumor Model.

Background: The transfusion of blood products containing allogeneic leukocytes can alter recipient resistance to infection and stimulate the growth of some types of tumors in animal models of transfusion-induced tumor growth. Transfusion related immunomodulation (TRIM) represents a credible mechanism for the altered resistance to infection seen clinically, but cannot explain the growth of non-immunogenic tumors in syngeneic hosts seen regularly in the various transfusion-related animal models of tumor growth.Methods and Results: In this study the transfusion of 50–200 μL of unmodified anticoagulated allogeneic BALB/c (H-2d) mouse blood into C57B1/6 (H-2b) mice, four days before being intravenously injected with syngeneic (H-2b) FSL10 fibrosarcoma cells (1–2 x 106 cells per mouse) resulted in a significant increase in the number of pulmonary nodules observed at 3 weeks compared to that seen in control mice. The median number of pulmonary nodules increased in an allogeneic blood transfusion dose-dependent manner, as did the proportion of mice without pulmonary nodules. This tumor growth-promoting effect of the allogeneic blood transfusions required the presence in the transfused blood of allogeneic CD11c+ dendritic cells bearing the CD200 co-stimulatory tolerance signal. This tumor growth-promoting effect of allogeneic blood could be blocked by specific monoclonal antibodies to either CD11c or to CD200. CD200 receptor-mediated signaling alone, in the absence of alloantigen, failed to augment the number of TRIM-induced pulmonary tumor nodules. Physiological concentrations of TGFβ, but not IL-10, were shown to stimulate proliferation of FSL10 cells in vitro in these studies. In this context, it is known that CD200 together with alloantigens are known to stimulate development of suppressor cells acting via IL-10 and TGFβ in vivo. Allogeneic blood also caused a significant CD200-dependent accumulation of TGFβ+ suppressor cells in the spleen, 12 days after transfusion, when the spleen cells could be shown to adoptively transfer the TRIM effect to naive animals.Conclusions: These data support the hypothesis that allogeneic transfusions in an allogeneic blood transfusion mouse tumor model results in tumor growth promotion in recipient mice. This effect appears to result in both the induction of TGFβ-producing suppressor cells as well as requiring the transfusion of allogeneic CD11c+ dendritic cells, bearing both CD200 tolerance signaling molecules and alloantigens.