Immunomodulatory and pro-inflammatory effects of allogeneic blood transfusion

Introduction The question we confront is whether observations of immunologic consequences of allogeneic blood transfusion (ABT) represent only laboratory curiosities or clinically relevant alterations in the recipient’s immune function—the so-called immunomodulatory effect of ABT. The constellation of all such ABT-associated laboratory and clinical findings is known as transfusion-related immunomodulation (TRIM). Initially, the term TRIM encompassed effects attributable to ABT by means of immunologic mechanisms only; however, more recently, the term has been used more broadly to encompass additional effects that could be related to ABT by means of both immunomodulatory and pro-inflammatory rather than only immunomodulatory mechanisms. ABTmay either cause alloimmunization or induce tolerance. ABT introduces a multitude of foreign antigens into the recipient, including human leukocyte antigen cell surface receptor (HLA-DR) antigens found on the donor’s dendritic antigen-presenting cells (APCs). The presence or absence of autologous HLA-DR antigens on the donor’s white blood cells (WBCs) plays a decisive role in whether alloimmunizationor immune suppressionwill ensue followingABT. Transfusions sharing at least oneHLA-DR antigen with the recipient will induce tolerance, whereas fully HLA-DR-mismatched transfusions lead to alloimmunization. In addition to thedegree ofHLA-DR compatibility between donor and recipient, the immunogenicity of cellular or soluble HLA antigens found in transfused blood components depends on the viability of the donor dendritic APCs and the presence of the required co-stimulatory signals for the presentation of the donor antigens to the recipient’s T cells. Nonviable APCs and/or absence of the requisite co-stimulatory signals result in T-cell unreponsiveness. Thus, when amultitude of antigens is introduced into the host by ABT, the host response to some of these antigens is often decreased, and immune tolerance (or TRIM) ensues. Several immune-function alterations have been documented in association with ABT (Table 62.1). All these ABT-related laboratory immune alterations could potentially be associated with clinical effects. Evidence from a variety of sources indicates that ABT enhances the survival of renal allogrants. In addition, other possible effects are increase of the recurrence rate of resected malignancies and the incidence of postoperative bacterial infections, reduction of the recurrence rate of Crohn’s disease and the risk of fetal loss in women with recurrent spontaneous abortions (RSAs), activation of infections with cytomegalovirus (CMV) or human immunodeficiency virus (HIV), and increased short-term (up to 3 months post transfusion) mortality from all causes. Different biologic mechanisms may be involved in each of these purported clinical manifestations of TRIM, and the clinical evidence supporting each of the aforementioned hypotheses must be examined on its own merits. The specific constituent(s) of allogeneic blood that mediate(s) the TRIM effect(s) also remain(s) unknown, and published literature has suggested that TRIM effects may be mediated by one or more of the following: (1) soluble HLA class I peptides that circulate in allogeneic plasma; (2) soluble biologic response modifiers released in a time-dependent manner from WBC granules or membranes into the supernatant fluid of redblood cell (RBC) or platelet concentrates during storage; and/or (3) allogeneic mononuclear cells (Figure 62.1).