Blood Transfusion-Induced Immunomodulation

Blood transfusion therapy is associated with many risks, including major or minor blood transfusion reaction, non-A non-B hepatitis, hepatitis B, and HIV infection. Blood transfusion may result in immunologic changes (immunomodulation) that are beneficial in some patients but harmful in others. After reports of increased renal allograft survival in patients receiving pretransplant transfusion 1, Gantt 2 questioned whether transfusion might diminish or retard the immune response. Clinical studies have shown a beneficial effect of blood transfusion on graft survival 3,4, but an adverse effect on cancer recurrence 5-10 and postoperative infection 10-14. Approximately two thirds of 11,000 transfusions 15,16 given perioperatively are administered by anesthesiologists 17, and 26% are given inappropriately 18,19. This review will focus on the immunomodulatory effects of transfusion therapy. It will begin with a brief review of the immune system and then discuss 1) the effect of transfusion therapy on modulating the immune system, and 2) transfusion-induced immunomodulatory effects on vascularized graft survival, cancer recurrence, and postoperative infections. Immune System Overview The major function of the immune system is to recognize various pathogens and respond to them. Although the immune system evolved to inactivate pathogens, it is now known that it also protects the body against the development of tumors and the rejection of foreign tissue. The immune system consists of an afferent (recognition) limb and an efferent (response) limb. The afferent limb is involved with alerting the host against the entry of foreign pathogens or foreign alloantigens. The afferent (response) limb may respond by cellular and/or humoral immunity and by secretion of lymphokines that modulate the immune response 20. Human Lymphoid System The lymphoid tissue is responsible for most of the body's immune response and contains about 1012 lymphocytes, which produce approximately 1020 antibody molecules 21. The mature lymphocytes circulate to lymph nodes, spleen, or tonsils and remain in these secondary locations until they are activated by antigens and antigen-presenting cells 20. T Lymphocytes T lymphocytes (T cells) are so named because they are matured by the thymus. T cells become activated by antigens and by antigen-presenting cells (APCs) and are characterized by an antigen-binding molecule or T-cell receptor (TCR) on their surface. TCRs react with antigens that have been processed and presented by major histocompatibility complex (MHC) molecules on the surface of macrophages or APCs. The TCR and the CD3 chain form a complex that functions as the primary antigen recognition site on the cell surface Figure 1. In addition to the TCR/CD3 molecules, numerous accessory surface molecules are present Figure 2. They include the CD8 and CD4 molecules, which bind to MHC class I and class II molecules on the APCs Figure 122.Figure 1: Interaction of a peptide-major histocompatibility complex (MHC) complex on a presenting cell with a receptor on a T cell. The presenting cell can be a macrophage using a class II MHC or any tissue cell using a class I MHC. The T cells can be helper T lymphocytes carrying CD4 or cytotoxic T lymphocytes carrying CD8. The class I MHC binds CD8; class II binds CD4. The T-cell receptor not only has CD8 or CD4 molecules as components of its interaction system, it also has four different proteins that make up the CD3 complex; their role is uncertain. Also, bound to the CD4 or CD8 proteins is the lck protein tyrosine kinase, which can phosphorylate a CD3 component on tyrosine in response to an interaction of the T-cell receptor with MHC-peptide complex. The CD3 and lck proteins are apparently part of the response system used by T cells after encounters with an MHC-peptide complex antigen. (From Darnell J, Lodish H, and Baltimore D. Molecular cell biology. 2nd ed. Copyright (c) 1990 by Scientific American Books, Inc., New York, NY. Used with permission of W. H. Freeman and Company.)Figure 2: Cell surface markers involved in T-cell activation and adhesion. Depicted are a number of T-cell surface molecules and their known ligands on the surface of antigen-presenting cells and/or the extracellular matrix. Many of these molecules are also known to deliver intracellular signals capable of interacting with the activation signal delivered through the T-cell receptor (TCR). HA, hyaluronic acid; FN, fibronectin; LN, laminin; Ag, antigen; PTP prime ase, protein tyrosine phosphatase; circles with dots represent phosphotyrosine residues; fyn (p59fyn) and lck (p56lck), protein tyrosine kinases. (Adapted with permission from Rothstein DM. The cellular immune response. In: Anderson KC, Ness PM, eds. Scientific basis of transfusion medicine--implications for clinical practice. Philadelphia: WB Saunders, 1994;124-46.)MHC I and MHC II antigens are cell surface glycoproteins that are responsible for alloreactivity and therefore rejection. The gene complex for human MHC is known as the human leukocyte antigen (HLA) complex. MHC genes that encode the targets for cytotoxic T lymphocytes' (CTLs') self-recognition are called class I MHC genes. These genes code for class I antigens at HLA A, B, and C loci Table 1. Several thousand molecules of each HLA A, B, and C antigen are expressed on every nucleated cell in the body.Table 1: Class I and Class II Antigens: Structure and FunctionThe receptors on T cells recognize peptide fragments of antigens that are linear sequences of eight to 15 amino acids Figure 1. These peptides bind to MHC molecules on the cell's surface. The MHC molecules then present the peptides to a TCR. Class I MHC expresses peptides synthesized by the cell itself. These may be derived from normal self-proteins or from peptides from viral proteins made in a virusinfected cell Figure 3. Class II MHC binds exogenous protein which is endocytosed and broken down into peptide fragments.Figure 3: Antigen processing and presentation. Endogenously synthesized or intracellular proteins (e.g., viral gene products) are degraded into peptides that are transported to the endoplasmic reticulum. These peptides bind to class I major histocompatibility complex (MHC) molecules and are transported to the surface of the antigen-presenting cell. CD8+ T cells recognize the foreign peptide bound to class I MHC by way of the T-cell receptor complex. Extrogenous antigen (e.g., bacterial) is endocytosed and broken down into peptide fragments in endosomes. Class II molecules are transported to the endosome in association with the invariant chain, bind the peptide, and are delivered to the surface of the antigen-presenting cell, where they are recognized by CD4+ cells. (Adapted with permission from Hanto DW, Mohanakumar T. Transplant immunology. In: Greenfield LJ, Mulholland MW, Oldham KT, Zelenock GB, eds. Surgery--scientific principles and practice. Philadelphia: JB Lippincott, 1993;461-500.)T cells are divided into at least two subpopulations: CD-4 (helper) and CD-8 (killer) T-cells. The helper T lymphocytes, or TH cells, utilize the CD-4 molecules to bind the class II MHC-peptide complexes that have been presented by macrophage APCs. The TH cells recognize the antigen presented by the class II MHCs. The TH cells then secrete lymphokines that stimulate other cells involved in the immune response 23. Cytokines are nonantibody mediators of cellular immunity produced by activated lymphocytes 24,25. As shown by Table 2, an individual lymphokine or cytokine may have multiple actions, with effect on immunomodulation, angiogenesis, hematopoiesis, septic shock, or antiproliferative activity against tumor cells 20. Cytokines are known to have multiple effects on both T cells and B cells. Cytokines stimulate TH cells through specific receptors on their surfaces. Activation of a TH cell by an encounter with peptide-MHC complex induces formation of an IL-2 receptor, which responds to the IL-2 it secretes by activating autocrine growth 25.Table 2: Partial List of Cytokines Secreted by TH Cells or Macrophages in Response to AntigenaAs B cells are maturing, they develop surface receptors for T-cell derived IL-2 and IL-4-6. These cytokines find receptors on activated B cells and stimulate growth of the B cells and their maturation to plasma cells. In summary, cytokines secreted by TH cells promote antibody production from B cells and stimulate both T- and B-cell growth and maturation. TH cell loss after HIV infection causes failure of the immune system in AIDS 26. CTLs can be distinguished from TH cells because they express the CD8 surface protein. CTLs recognize foreign antigens in the context of class I MHC and the CD8 molecule. Antibodies deal with intact foreign materials, whereas CTLs deal with cell-bound peptides. A classic CTL target is a virus-infected cell that displays fragments of viral glycoproteins on its surface bound to class I MHC. CTLs attach to the target cell and secrete proteases that form ion channels that depolarize the cell, thereby destroying its ionic and osmotic balance, resulting in cell death 20. A third T cell, the suppressor T cell (TS), suppresses B-cell activity and inhibits lymphocytotoxicity. The TS cell appears to be associated with a CD8 surface protein that is different from the CD8 protein associated with CTL cells 20. B Lymphocytes B lymphocytes (B cells) originate in the bone marrow, mature into plasma cells, and are specialized for antibody production. During development, B cells pass through successive stages characterized by different patterns of cell surface marker expression and immunoglobulin (Ig) production. B lymphocytes express many different cell surface antigens Figure 4 as they pass from the pre-B cell to become activated B cells and then functional plasma cells 27. These shortlived, noncirculating plasma cells are capable of producing 10 million antibody molecules an hour 28. B-cell activation and response to antigen is directed by TH cells and their secreted cytokines. The B cell can decompose a protein into peptides in association with MHC class II molecules and display them in a manner similar to the way an APC displays peptides in association with MHC class I or II molecules Figure 5.Figure 4: Cell surface antigen expression. The stages of expression of some B-cell antigens are indicated by a solid line. Cytoplasmic but not surface expression is indicated by a dashed line. (Adapted with permission from Ord DC, Tedder TF. The humoral immune response. In: Anderson KC, Ness PM, eds. Scientific basis of transfusion medicine--implications for clinical practice. Philadelphia: WB Saunders, 1994;124-46.)Figure 5: The hapten-carrier complex activates B cells by first stimulating helper T (TH) cells. The hapten-carrier complex is a protein to which several hapten molecules have been covalently coupled. The hapten portion binds to a B cell but cannot by itself initiate B-cell proliferation. The B cell internalizes and digests the hapten-carrier complex, and portions of the carrier peptide are displayed on the B-cell surface as a complex with class II major histocompatibility complex (MHC) protein. A macrophage cell also internalizes carrier protein and displays peptide fragments on its surface in association with class II MHC. Then TH cells with appropriate receptors bind to the peptide-MHC complex displayed on the macrophage surface. Binding stimulates the TH cells, which then proliferate, recognize the identical peptide-MHC complex on the B cell, and secrete factors that stimulate the B cell to grow. (From Darnell J, Lodish H, Baltimore D. Molecular cell biology. 2nd ed. Copyright (c) 1990 by Scientific American Books, Inc., New York, NY. Used with permission of W. H. Freeman and Company).Antibody secretion by plasma cells requires a B lymphocyte to bind an antigen and then receive costimulation from TH cells in order to differentiate and become an active plasma cell. IL-2, IL-4, and IL-5 stimulate B-cell maturation into plasma cells. After the B lymphocyte binds an antigen to its receptor, it differentiates and secretes antibody molecules 20,29. IgA-producing plasma cells are located in the gut and bronchial mucosa; IgG-producing plasma cells are located in bone marrow, spleen, and lymph nodes; IgM-producing plasma cells are located in the spleen and lymph nodes; and IgE plasma cells are found in gut, mesenteric, and bronchus lymphoid tissue. Each antibody molecule consists of two classes of polypeptide chains, light and heavy. Another type of activated B lymphocytes are memory B cells, which retain, for the life of the organism, a record of the antigens previously encountered so that a second encounter with the antigen can elicit a rapid, highly avid response 20. Transfusion-Induced Immunomodulation Mechanism Exposure to allogenic tissue, including blood, can cause both allosensitization and immunosuppression 30,31. The development of tolerance can be specific to the tissue donor; however, immune responses can be characterized in varying degrees by cross-reactivity or cross-specificity 32. The best characterized clinical effect of transfusion-induced modulation is survival of renal in previously patients may be as a of immunologic cells or as a of immunologic suppressor cells transfusion-induced immune functions include cytokine TH cells, cells, and lymphocyte function and and increased cell number and function cells are cytotoxic lymphocytes, their activity is by IL-2, and they are a against virus-infected cells In order to the transfusion will first discuss immune and immune after The of blood responsible for these immunomodulatory effects is however, are to that cells or plasma are in the host immune to cells in the cells of the plasma and of the cells The of plasma and cells present in blood cells may be responsible for the in the of cells to a modulating Immune after Blood The by which transfusions produce is is that transfusions the system and that cause the changes production and IL-2 also a role in immune production by is increased after transfusions is known to macrophage class II antigen expression and IL-2 production and target cell response to IL-2 IL-2 production by TH lymphocytes is known to after transfusion As IL-2 is for the activation and of B cells and for the of cytotoxic T a in IL-2 production will result in a in B-cell antibody and activity These immunomodulatory effects after transfusion to be after but they become and after multiple patients increased immune up to after transfusion In a that the of transfusion to patients and not to or to as a that transfusions however, they receiving the the of lymphocytes which by the the the as a secondary and immunosuppression at the of or of cells. 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