In immunology, alloimmunity or isoimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigensIsoantigen at eMedicine Dictionary and histocompatibility antigens. In alloimmunity, the body creates antibodies (called alloantibodies) against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. (The allo- prefix means "other", whereas the auto- prefix means "self".) Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.
Alloimmunity is caused by the difference between products of highly polymorphic genes, primarily genes of the major histocompatibility complex, of the donor and graft recipient. These products are recognized by T-lymphocytes and other mononuclear leukocytes which infiltrate the graft and damage it.
Types of the rejection
Transfusion reaction Blood transfusion can result in alloantibodies reacting towards the transfused cells, resulting in a transfusion reaction. Even with standard blood compatibility testing, there is a risk of reaction against human blood group systems other than ABO and Rh.
Hemolytic disease of the fetus and newborn Hemolytic disease of the fetus and newborn is similar to a transfusion reaction in that the mother's antibodies cannot tolerate the fetus's antigens, which happens when the immune tolerance of pregnancy is impaired. In many instances the maternal immune system attacks the fetal blood cells, resulting in fetal anemia. HDN ranges from mild to severe. Severe cases require intrauterine transfusions or early delivery to survive, while mild cases may only require phototherapy at birth.
Transplant rejection Acute rejection Acute rejection is subsequent to the recipient's immune system identifies a graft organ as foreign. This results in the mounting of an immune response, leading to organ rejection and destruction. Acute rejection is caused by antigen-specific Th1 and cytotoxic T-lymphocytes. They recognize transplanted tissue because of expression of alloantigens. When a genetic difference between the donor and recipient is detected, the immune system of the recipient identifies MHC I and MHC II as foreign. Subsequently, CD4+ T-cells react to these alloantigens presented by antigen-presenting cells (APCs), resulting in the release of cytokines which stimulate immune reactivity. A transplant is rejected during first several days or weeks after transplantation.Sánchez-Fueyo A, Strom TB (2011), Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology 140(1):51-64
Hyperacute and accelerated rejection Hyperacute and accelerated rejection is antibody-mediated immune response to the allograft. The difference between hyperacute and acute rejection lies in the presence of preformed antibodies that cause an instantaneous rejection. Recipient's blood already contains circulating antibodies before the transplantation – either IgM or antibodies incurred by previous immunization (e.g. by repeated blood transfusion). In case of hyperacute rejection, antibodies activate complement; moreover, the reaction can be enhanced by neutrophils. This type of rejection is very fast, the graft is rejected in a few minutes or hours after the transplantation. Accelerated rejection leads to phagocyte and NK cell activation (not of the complement) through their Fc receptors that bind Fc parts of antibodies. Graft rejection occurs within 3 to 5 days. This type of rejection is a typical response to xenotransplants.
Chronic rejection Chronic rejection is not yet fully understood, but it is known that it is associated with alloantibody and cytokine production. Endothelium of the blood vessels is being damaged, therefore the graft is not sufficiently supplied with blood and is replaced with fibrous tissue (fibrosis).Seetharam A, Tiriveedhi V, Mohanakumar T (2010), Alloimmunity and autoimmunity in chronic rejection. Curr Opin Organ Transplant 15(4):531-536 It takes two months at least to reject the graft in this way.
Mechanisms of rejection Unlimited graft acceptance is hindered by allogenic immune responses. CD4+ and CD8+ T-lymphocytes along with other mononuclear leukocytes (their exact function regarding the topic is not known) participate in the rejection. B-lymphocytes, NK cells and cytokines also play a role in it. Cellular rejection – CD4+ and CD8+ T-lymphocytes, NK cells Humoral rejection – B-lymphocytes Cytokines
B-lymphocytes
Humoral (antibody-mediated) type of rejection is caused by recipient's B-lymphocytes which produce alloantibodies against donor MHC class I and II molecules.Fang Li, Mary E. Atz, Elaine F. Reed (2009), Human leukocyte antigen antibodies in chronic transplant vasculopathy-mechanisms and pathways. Curr Opin Immunol. 21(5): 557–562 These alloantibodies can activate the complement – this leads to target cell lysis. Alternatively, donor cells are coated with alloantibodies that initiate phagocytosis through Fc receptors of mononuclear leukocytes. The mechanism of humoral rejection is relevant for hyperacute, accelerated and chronic rejection. Alloimmunity can be also regulated by neonatal B cells.
In addition to humoral immune responses, B-lymphocytes aid in T-cell activation by acting as antigen-presenting cells (APCs). This is activation by indirect allorecognition is crucial, as these T-cells are able to translocate the follicular border to retrieve a T-follicular helper cell (Tfh). This will then lead to an induced B-cellular response. They are important for lymphoid neogenesis (de novo formation of lymphoid tissues during transplant rejection) and forming in-graft tertiary lymphoid organs (TLOs). TLOs also encourage a local alloimmune response needed for recovery and long-term health outcomes.
Cytokines
Cytokine microenvironment where CD4+ T-lymphocytes recognize alloantigens significantly influences polarization of the immune response. CD4+ T-lymphocytes differentiate into Th1 helper cells in the presence of IL-12 (which is usually secreted by mature dendritic cells). Th1 cells produce proinflammatory cytokine IFN-γ and destroy the allograft tissue. If there is IL-4, CD4+ T-lymphocytes become Th2 cells secreting IL-4 and IL-5. Then allograft tolerance is mostly observed.Walsh PT, Strom TB, Turka LA (2004), Routes to transplant tolerance versus rejection: the role of cytokines. Immunity (20):121-131 TGF-β induces expression of Foxp3 gene in the absence of proinflammatory cytokines and thus differentiation of CD4+ T-lymphocytes into regulatory T cells (Treg). Regulatory T cells produce anti-inflammatory cytokines IL-10 and TGF-β which ensures the allograft tolerance. However, in the presence of IL-6 or IL-21 along with TGF-β, CD4+ T-lymphocytes acquire tissue-destructive Th17 phenotype and secrete IL-17.Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK (2007), IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484-7
NK cells
NK cells can also directly target the transplanted tissue. It depends on the balance of activating and inhibitory NK cell receptors and on their ligands expressed by the graft. Receptors of KIR (Killer-cell immunoglobulin-like receptor) family bind concrete MHC class I molecules. If the graft has these ligands on its surface, NK cell cannot be activated (KIR receptors provide inhibitory signal). So if these ligands are missing, there is no inhibitory signal and NK cell becomes activated. It recognizes target cells by "missing-self strategy" Villard J. (2011), The role of natural killer cells in human solid organ and tissue transplantation. J Innate Immun. 3(4): 395-402 and induces their apoptosis by enzymes perforin and granzymes released from its cytotoxic granules. Alloreactive NK cells also secrete proinflammatory cytokines IFN-γ and TNF-α to increase expression of MHC molecules and costimulatory receptors on the surface of APCs (antigen-presenting cells). This promotes APC maturation McNerney ME, Lee KM, Zhou P, Molinero L, Mashayekhi M, Guzior D, Sattar H, Kuppireddi S, Wang CR, Kumar V, Alegre ML (2006), Role of natural killer cell subsets in cardiac allograft rejection. Am J Transplant. 6(3):505-13 which leads to amplification of T-cell alloreactivity by means of direct and also indirect pathway of alloantigen recognition (as described below). NK cells are able to kill Foxp3+ regulatory T-lymphocytes as well and shift the immune response from graft tolerance toward its rejection. Besides the ability of NK cells to influence APC maturation and T cell development, they can probably reduce or even prevent alloimmune response to transplanted tissue – either by killing the Donor APCs Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC (2006), NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med. 203(8):1851-8 or by anti-inflammatory cytokine IL-10 and TGF-β secretion.De Maria A, Fogli M, Mazza S, Basso M, Picciotto A, Costa P, Congia S, Mingari MC, Moretta L (2007), Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patiens. Eur J Immunol. 37(2):445-55 NK cell sub-populations differ in alloreactivity rate and in their immunomodulatory potential. Concerning immunosuppressive drugs, the effects on NK cells are milder in comparison to T cells.
T-lymphocytes
Alloantigen recognition
Alloantigen on APC surface can be recognized by recipient's T-lymphocytes through two different pathways:Lafferty KJ, Prowse SJ, Simeonovic CJ, Warren HS (1983), Immunobiology of tissue transplantation: a return to the passenger leukocyte concept. Annu Rev Immunol.1:143-73 – according to Archbold JK, Ely LK, Kjer-Nielsen L, Burrows SR, Rossjohn J, McCluskey J, Macdonald WA (2008), T-cell allorecognition and MHC-restriction – A case of Jekyll and Hyde? Mol Immunol. 45(3):583-98 Direct allorecognition – occurs when donor's APCs are presenting graft antigens. Recipient's T-lymphocytes can identify either MHC molecules alone or complex MHC molecule-foreign peptide as alloantigens. Specific T-cell receptors (TCR) of CD8+ T-lymphocytes recognize these peptides when form the complex with MHC class I molecules and TCR of CD4+ T-lymphocytes recognize a complex with MHC class II molecules. Indirect allorecognition – recipient's APCs infiltrate transplanted tissue, then they process and present, as any other foreign peptides, donor's MHC glycoproteins by MHC class II molecules. Mechanism of indirect allorecognition and therefore the involvement of CD4+ T-lymphocytes is the main cause of graft rejection.Fangmann J, Dalchau R, Fabre JW (1992), Rejection of skin allografts by indirect allorecognition of donor class I major histocompatibility complex peptides. J Exp Med. 175(6):1521-9Gould DS, Auchincloss H Jr (1999), Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol Today. 20(2):77-82 That is why the compatibility between donor and recipient MHC class II molecules is the most important factor concerning transplantation.
Activation of T-lymphocytes
T-lymphocytes are fully activated under two conditions: T-lymphocytes must recognize complex MHC-alloantigen presented by APC through direct or indirect allorecognition pathway.