Alloimmunity

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Alloimmunity (sometimes called 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 antigens [1] 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.

Contents

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. [2]

Transplant rejection

Acute rejection

Acute rejection is caused by antigen-specific Th1 and cytotoxic T-lymphocytes. They recognize transplanted tissue because of expression of alloantigens. A transplant is rejected during first several days or weeks after transplantation. [3]

Hyperacute and accelerated rejection

Hyperacute and accelerated rejection is antibody-mediated immune response to the allograft. Recipient's blood already contains circulating antibodies before the transplantation [3] – 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). [4] It takes two months at least to reject the graft in this way.

Mechanisms of rejection

CD4+ and CD8+ T-lymphocytes along with other mononuclear leukocytes (their exact function regarding the topic is not known) participate in the rejection. [3] B-lymphocytes, NK cells and cytokines also play a role in it.

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. [5] 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. Mechanism of humoral rejection is relevant for hyperacute, accelerated and chronic rejection. Alloimmunity can be also regulated by neonatal B cells. [6]

Cytokines

Cytokine microenvironment where CD4 + T-lymphocytes recognize alloantigens significantly influences polarization of the immune response.

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" [9] 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 [10] 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 [9] 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 [11] or by anti-inflammatory cytokine IL-10 and TGF-β secretion. [12] However it is important to note that 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. [9]

T-lymphocytes

Alloantigen recognition

Alloantigen on APC surface can be recognized by recipient's T-lymphocytes through two different pathways: [13]

Activation of T-lymphocytes

T-lymphocytes are fully activated under two conditions:

Alloimmune response can be enhanced by proinflammatory cytokines and by CD4+ T-lymphocytes [20] that are responsible for APC maturation and IL-2 production. IL-2 is crucial for memory CD8+ T cell development. [21] These cells may represent a serious problem after the transplantation. As the effect of being exposed to various infections in the past, antigen-specific T-lymphocytes have developed in patient's body. Part of them is kept in organism as memory cells and these cells could be a reason for "cross-reactivity" – immune response against unrelated but similar graft alloantigens. [22] This immune response is called secondary and is faster, more efficient and more robust.

Graft tolerance

Transplanted tissue is accepted by immunocompetent recipient if it is functional in the absence of immunosuppressive drugs and without histologic signs of rejection. Host can accept another graft from the same donor but reject graft from different donor. [23] Graft acceptance depends on the balance of proinflammatory Th1, Th17 lymphocytes and anti-inflammatory regulatory T cells. [3] This is influenced by cytokine microenvironment, as mentioned before, where CD4+ T-lymphocytes are activated and also by inflammation level (because pathogens invading organism activate the immune system to various degrees and causing proinflammatory cytokine secretion, therefore they support the rejection). [24] Immunosuppressive drugs are used to suppress the immune response, but the effect is not specific. Therefore, organism can be affected by the infection much more easily. The goal of the future therapies is to suppress the alloimmune response specifically to prevent these risks. The tolerance could be achieved by elimination of most or all alloreactive T cells and by influencing alloreactive effector-regulatory T-lymphocytes ratio in favor of regulatory cells which could inhibit alloreactive effector cells. [3] Another method would be based on costimulatory signal blockade during alloreactive T-lymphocytes activation. [25]

See also

Literature

Related Research Articles

Antigen Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. The term antigen originally referred to a substance that is an antibody generator. Antigens can be proteins, peptides, polysaccharides, lipids, or nucleic acids.

T cell White blood cells of the immune system

A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

T helper cell Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4.

Natural killer cell Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal immune response against a specific antigen, usually a self-antigen. Lymphocytes are said to be anergic when they fail to respond to their specific antigen. Anergy is one of three processes that induce tolerance, modifying the immune system to prevent self-destruction.

Transplant rejection Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

Superantigen

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically it causes non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

Fc receptor Protein

A Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell. In the case of T cells, two stimuli are required to fully activate their immune response. During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

The following are notable events in the Timeline of immunology:

The following outline is provided as an overview of and topical guide to immunology:

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

Alloantigen recognition refers to immune system recognition of genetically encoded polymorphisms among the genetically distinguishable members of same species. Post-transplant recognition of alloantigens occurs in secondary lymphoid organs. Donor specific antigens are recognized by recipient’s T lymphocytes and triggers adaptive pro-inflammatory response which consequently leads to rejection of allogenic transplants. Allospecific T lymphocytes may be stimulated by three major pathways: direct recognition, indirect recognition or semidirect recognition. The pathway involved in specific cases is dictated by intrinsic and extrinsic factors of allograft and directly influence nature and magnitude of T lymphocytes mediated immune response. Furthermore, variant tissues and organs such as skin or cornea or solid organ transplants can be recognized in different pathways and therefore are rejected in different fashion.

Danger model

The danger model is a theory of how the immune system works. It is based on the idea that the immune system does not distinguish between self and non-self, but rather between things that might cause damage and things that will not.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.

<span class="mw-page-title-main">Adaptive NK cell</span> Specialized subtype of cytotoxic lymphocyte

An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses.

<span class="mw-page-title-main">CD28 family receptor</span>

CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.

References

  1. ↑ Isoantigen Archived 2016-10-09 at the Wayback Machine at eMedicine Dictionary
  2. ↑ "Home". allaboutantibodies.com.
  3. 1 2 3 4 5 6 7 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
  4. ↑ Seetharam A, Tiriveedhi V, Mohanakumar T (2010), Alloimmunity and autoimmunity in chronic rejection. Curr Opin Organ Transplant 15(4):531-536
  5. ↑ 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
  6. ↑ Walker WE, Goldstein DR (August 2007). "Neonatal B cells suppress innate toll-like receptor immune responses and modulate alloimmunity". J. Immunol. 179 (3): 1700–10. doi: 10.4049/jimmunol.179.3.1700 . PMID   17641036.
  7. ↑ Walsh PT, Strom TB, Turka LA (2004), Routes to transplant tolerance versus rejection: the role of cytokines. Immunity (20):121-131
  8. ↑ 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
  9. 1 2 3 Villard J. (2011), The role of natural killer cells in human solid organ and tissue transplantation. J Innate Immun. 3(4): 395-402
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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):1521-9
  15. ↑ Gould DS, Auchincloss H Jr (1999), Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol Today. 20(2):77-82
  16. ↑ Li XC, Rothstein DM, Sayegh MH (2009), Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev. 229(1):271-93
  17. ↑ Jenkins MK, Taylor PS, Norton SD, Urdahl KB (1991), CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 147(8):2461-6 – according to Priyadharshini B, Greiner DL, Brehm MA (2012), T-cell activation and transplantation tolerance. Transplant Rev (Orlando). 26(3):212-22
  18. ↑ Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA (1994), CTLA-4 can function as a negative regulator of T cell activation. Immunity. ;1(5):405-13 – according to Priyadharshini B, Greiner DL, Brehm MA (2012), T-cell activation and transplantation tolerance. Transplant Rev (Orlando). 26(3):212-22
  19. ↑ Jenkins MK, Schwartz RH (1987), Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 165(2):302-19
  20. ↑ Curtsinger JM, Mescher MF (2010), Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 22(3):333-40
  21. ↑ Williams MA, Tyznik AJ, Bevan MJ (2006), Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 441(7095):890-3
  22. ↑ Welsh RM, Selin LK (2002), No one is naive: the significance of heterologous T-cell immunity. Nat Rev Immunol. 2(6):417-26
  23. ↑ Ashton-Chess J, Giral M, Brouard S, Soulillou JP (2007), Spontaneous operational tolerance after immunosuppressive drug withdrawal in clinical renal allotransplantation. Transplantation. 84(10):1215-9 – according to 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
  24. ↑ Ahmed EB, Daniels M, Alegre ML, Chong AS (2011), Bacterial infections, alloimmunity, and transplantation tolerance. Transplant Rev (Orlando). 25(1):27-35
  25. ↑ Ford ML, Larsen CP (2009), Translating costimulation blockade to the clinic - lessons learned from three pathways. Immunol Rev. 229(1):294-306
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