Immunologic Tolerance and Autoimmunity Review PDF

Immunologic Tolerance and Autoimmunity Central and peripheral tolerance to self antigens  In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central organs in the context of tolerance...

Immunologic Tolerance and Autoimmunity Central and peripheral tolerance to self antigens  In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central organs in the context of tolerance induction) and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (Tregs).  In peripheral tolerance, some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by an encounter with self antigens in these tissues or are suppressed by the regulatory T cells (Tregs, peripheral tolerance). 1 Central T cell tolerance  Many immature T cells that recognize antigens with high avidity die, and some of the surviving cells in the CD4+ lineage develop into Tregs.  Death of immature T cells as a result of recognition of antigens in the thymus is known as deletion, or negative selection 2  The function of AIRE in deletion of T cells in the thymus  The antigens that are present in the thymus include many circulating and cell-associated proteins that are widely distributed in most tissues.  The thymus also has a special mechanism for expressing numerous protein antigens that are not ubiquitously expressed but rather are limited to certain peripheral tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire.  These peripheral tissue antigens are produced in medullary thymic epithelial cells (MTECs) under the control of the autoimmune regulator (AIRE) protein. 3 Mechanisms of peripheral T cell tolerance  The mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression by Tregs, and deletion (cell death).  These mechanisms may be responsible for T cell tolerance to tissue-specific self antigens, especially those that are not abundant in the thymus.  The same mechanisms may also induce unresponsiveness to foreign antigens that are presented to the immune system under tolerogenic conditions. 4  Mechanisms of T cell anergy Several mechanisms may function to induce and maintain the anergic state:  TCR-induced signal transduction is blocked in anergic cells  Self antigen recognition without costimulation may activate cellular ubiquitin ligases, which ubiquitinate TCR-associated proteins and target them for proteolytic degradation in proteasomes or lysosomes.  When T cells recognize self antigens in the absence of innate immune responses, they may engage inhibitory receptors of the CD28 family, whose function is to terminate T cell responses 5  Mechanisms of action of CTLA-4  CTLA-4 functions as a competitive inhibitor of CD28 and reduces the availability of B7 for the CD28 receptor.  CTLA-4 has an unusual mechanism of action. It is expressed constitutively at high levels on Tregs and transiently on recently activated T cells, and it prevents the activation of responding T cells.  In other words, CTLA-4 on one T cell (a Treg) can inhibit responses of other T cells. Recall that CD28 and CTLA-4 recognize the same ligands, B7-1 (CD80) and B7-2 (CD86) 6 Mechanisms of action of CTLA-4 7 Actions and Functions of CTLA-4 and PD-1 8 Regulatory T cells 9 Role of interleukin-2 in the maintenance of regulatory T cells Tregs appear to suppress immune responses at multiple Steps:  Production of the immunosuppressive cytokines IL-10 and TGF-β.  Reduced ability of APCs to stimulate T cells.  Consumption of IL-2 10  Inhibitory Cytokines Produced by Regulatory T Cells Transforming Growth Factor-β.  TGF-β1 is produced by CD4+ Tregs, activated macrophages, and many other cell types.  TGF-β1 inhibits the proliferation and effector functions of T cells and the activation of macrophages.  TGF-β1 regulates the differentiation of functionally distinct subsets of T cells, FoxP3+ Tregs.  TGF-β1 stimulates production of immunoglobulin A (IgA) antibodies by inducing B cells to switch to this isotype.  TGF-β promotes tissue repair after local immune and inflammatory reactions subside. Interleukin-10  IL-10 is an inhibitor of activated macrophages and dendritic cells and is thus involved in the control of innate immune reactions and cell-mediated immunity.  IL-10 inhibits the production of IL-12 by activated dendritic cells and macrophages.  IL-10 inhibits the expression of co-stimulators and class II MHC molecules on dendritic cells and macrophages.  IL-10 inhibits T cell activation and terminates cell-mediated immune reactions. 11 Factors That Determine the Immunogenicity and Tolerogenicity of Protein Antigens  Tolerogenic antigens are expressed in generative lymphoid organs, where they are recognized by immature lymphocytes. In peripheral tissues, self antigens engage antigen receptors of specific lymphocytes for prolonged periods and without inflammation or innate immunity.  The nature of the dendritic cell that displays antigens to T lymphocytes is an important determinant of the subsequent response. 12  Summary  Immunologic tolerance is unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen.  Tolerance to self antigens is a fundamental property of the normal immune system, and the failure of self-tolerance leads to autoimmune diseases.  Central tolerance is induced in the generative lymphoid organs (thymus and bone marrow) when immature lymphocytes encounter self antigens present in these organs.  Peripheral tolerance occurs when mature lymphocytes recognize self antigens in peripheral tissues under particular conditions.  Some immature T cells that encounter self antigens in the thymus die (negative selection), and others develop into FoxP3+regulatory T lymphocytes (Tregs) that function to control responses to self antigens in peripheral tissues.  Anergy is induced by antigen recognition without adequate costimulation or by engagement of inhibitory receptors such as CTLA-4 and PD-1.  In B lymphocytes, central tolerance is induced when immature B cells recognize multivalent self antigens in the bone marrow, resulting in the acquisition of a new specificity (receptor editing), or apoptotic death.  Mature B cells that recognize self antigens in the periphery in the absence of T cell help may be rendered anergic and ultimately die by apoptosis or become functionally unresponsive because of the engagement of inhibitory receptors. 13 Postulated mechanisms of autoimmunity  The factors that contribute to the development of autoimmunity are genetic susceptibility and environmental  triggers, such as infections and local tissue injury.  Autoimmune diseases may be systemic or organ specific, depending on the distribution of the autoantigens that are recognized.  Various effector mechanisms are responsible for tissue injury in different autoimmune diseases including: immune complexes, circulating autoantibodies, and autoreactive T lymphocytes  Autoimmune diseases tend to be chronic, progressive, and self-perpetuating. 14  Immunologic Abnormalities Leading to Autoimmunity  Defective self-tolerance. Inadequate elimination or regulation of T or B cells, leading to an imbalance between lymphocyte activation and control, is the underlying cause of all autoimmune diseases.  Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs.  Defective numbers or functions of regulatory T lymphocytes.  Defective apoptosis of mature self-reactive lymphocytes.  Inadequate function of inhibitory receptors.  Abnormal display of self antigens. Abnormalities may include increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury, “neoantigens”.  Inflammation or an initial innate immune response may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcome regulatory mechanisms and result in excessive T cell activation 15  Selected Non-HLA Genes Associated With Autoimmune Diseases Genetic Basis of Autoimmunity Association of HLA Alleles With Autoimmune Disease  Helper T cells are the key regulators of all immune responses to proteins, and most self antigens implicated in autoimmune diseases are proteins 16 Examples of Single-Gene Mutations That Cause Autoimmune Diseases Antiphospholipid syndrome (APS), Systemic lupus erythematosus (SLE), Autoimmune lymphoproliferative syndrome (ALPS), Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. 17 Role of infections in the development of autoimmunity 18 Summary  Autoimmunity results from inadequate self-tolerance or regulation of lymphocytes. Autoimmune reactions may be triggered by environmental stimuli, such as infections, in genetically susceptible individuals.  Most autoimmune diseases are polygenic, and numerous susceptibility genes contribute to disease development. The greatest contribution is from MHC genes.  Additional genes are believed to influence the selection or regulation of self-reactive lymphocytes.  Infections may predispose to autoimmunity by several mechanisms, including enhanced expression of costimulators in tissues and cross reactions between microbial antigens and self antigens.  Some infections may protect individuals from autoimmunity, by unknown mechanisms. 19 EVOLUTION OF THERAPIES FOR AUTOIMMUNE DISORDERS Characterized by a loss or failure of self- tolerance  More than 80 known autoimmune disorders  May affect a wide range of organ systems  Both cellular and humoral components of the immune system may be implicated  COMMON AUTOIMMUNE MECHANISMS  Each autoimmune disease likely has specific triggers and pathogenesis  Common mechanisms include development of autoantibodies and aberrant cytokine signaling  Therapeutic strategies focus on dampening the aberrant immune response JM Anaya. Autoimmunity Rev. 11(11);781-784 (2012).  EARLY TREATMENT STRATEGIES Dr. Kersley recommended the following: 1. Complete physical and mental rest (bed rest), good nourishing diet with plenty of vitamins and iron, and live under best hygienic conditions 2. Eliminate any sepsis that is found in the body 3. Physical and orthopedic treatment: balancing of rest and exercise, re-education of capillary circulation (contrast heat and cold followed by rub-down), counter- irritation, X-ray therapy, correction of deformity 4. Analgesics to promote sleep and relieve pain: aspirin, phenacetin, caffeine GD Kersley. Bristol Med Chir J (1883). 63(225);11-15 (1945).  THERAPEUTIC TARGETS IN AUTOIMMUNITY  Many potential therapeutic targets for autoimmune disorders  Targets include cell surface markers, cytokines, and autoantibodies  Selection of optimal target will depend on the disease pathology IB McInnes, EM Gravallese. Nat Rev Immunol. 21;680-686 (2021).  EVOLUTION OF RHEUMATOID ARTHRITIS TREATMENT  Therapies have evolved from broadly acting drugs (e.g., NSAIDs, steroids) to specific inhibitors  Diagnostic tools have improved in parallel with treatment strategies G Burmester, J Bijlsma et al. Nat Rev Rheumatol. 13;443-448 (2017). DISEASE MODIFYING AGENTS  Frequently referred to as ‘disease modifying anti-rheumatic drugs’  Synthetic agents (sDMARD)  Conventional: Methotrexate, Sulfasalazine, Leflunomide, etc.  Targeted: Tofacitinib, etc.  Biological (bDMARD)  Original: Anti-TNF mAbs, anti-CD20 mAbs, anti-IL-6R mAbs, IL-1 inhibitor, etc.  Biosimilars: Generic versions of original bDMARD  These act to slow disease progression (hence the name!)  Drugs such as NSAIDs and steroids treat symptoms but do not slow disease progression  Wide range of therapies give providers many options to treat patients if they relapse or are refractory to a given therapy  ROLE OF CYTOKINES IN AUTOIMMUNITY Pro-inflammatory cytokines contribute to pathogenesis and Numerous cytokine blocking mAbs propagation of disease have been approved to treat autoimmune conditions Y Lai, C Dong. Int Immunol. 28(4);181-188 (2015).  THERAPEUTIC TARGETS IN AUTOIMMUNITY  Many potential therapeutic targets for autoimmune disorders  Targets include cell surface markers, cytokines, and autoantibodies  Selection of optimal target will depend on the disease pathology IB McInnes, EM Gravallese. Nat Rev Immunol. 21;680-686 (2021).  ROLE OF CYTOKINES IN AUTOIMMUNITY Pro-inflammatory cytokines contribute to pathogenesis and Numerous cytokine blocking mAbs propagation of disease have been approved to treat autoimmune conditions Y Lai, C Dong. Int Immunol. 28(4);181-188 (2015).  HOW DO B CELL DEPLETING MABS WORK?  Rituximab leads to death of CD20-expressing B cells by 3 mechanisms  Direct lysis  Antibody-dependent cellular cytotoxicity  Complement-dependent cytotoxicity  This significantly reduces circulating B cells and therefore reduces B cell-dependent autoimmunity RP Taylor, MA Lindorfer. Nat Rev Rheumatol. 3;86-95 (2007). JCW Edwards, L Szczepanski et al. N Engl J Med. 350;2572-2581 (2004).  HOW DOES IVIG WORK IN AUTOIMMUNITY?  IVIG has many likely mechanisms by which it acts in autoimmune conditions  Direct neutralization of autoantibodies and cytokines is possible  Altered function of effector mechanisms (FcR) – biased towards anti-inflammatory  Accelerated elimination of pathogenic antibodies N Nikolov, J Reisinger et al. Immunotherapy. 8(8);923-940 (2016).  IMPACTS OF IVIG ON ‘AUTOANTIBODY’ ELIMINATION  In rodents, increasing doses of IVIG leads to accelerated elimination of a tracer antibody  Tracer antibody used to understand effects on endogenous IgG concentrations  IVIG only affected tracer antibody elimination in mice where FcRn function was intact  Compare open vs. closed symbols to see this!  Saturation of FcRn function by IVIG is the likely mechanism underlying accelerated elimination of autoantibodies by IVIG  Suggested direct inhibition of FcRn as a RJ Hansen, JP Balthasar. Thromb Haemost. 88;898-899 (2002). novel strategy SUMMARY  Disease modifying treatments for autoimmune disorders often rely on modulating cytokine signaling and/or cell functions  These include kinase inhibitors, cytokine inhibitor mAbs, and B cell depleting mAbs  One mechanism of IVIG efficacy in autoimmune disorders is saturation of FcRn  This led to the development of FcRn inhibitors as a therapeutic class  Next generation agents for autoimmune disorders may include cell therapies Hypersensitivity Disorders The Coombs and Gell classification of the four types of hypersensitivity reaction Hypersensitivity refers to harmful immune responses against foreign antigens:  Environmental antigens,  Drugs,  Microbes. 33 Hypersensitivity reactions may be specific for different types of antigens: Reactions against Reactions against self nonmicrobial Reactions against antigens: autoimmunity. microbes. environmental antigens. Immune responses Most healthy individuals do Failure of the normal mechanisms of self- against microbial antigens not react against common, tolerance results in T cell may cause disease if the generally harmless and B cell reactions reactions are excessive or environmental substances, against one’s own cells the microbes are but 20% or more of the and tissues that are called unusually resistant to population is abnormally autoimmunity eradication and thus the infections are persistent. responsive to one or more of these substances. These individuals produce IgE (immunoglobulin E) antibodies that cause allergic diseases 34  Classification of Hypersensitivity Diseases  Hypersensitivity diseases are commonly classified according to the type of immune response and the effector mechanism responsible for cell and tissue.  These mechanisms include some that are predominantly dependent on antibodies and others predominantly dependent on T cells, although humoral and cell-mediated immunities often coexist, and both contribute to tissue injury in many hypersensitivity diseases. 35 Comparison of allergy, transplantation, and Autoimmunity  Allergic diseases, the diseases arising from transplantation, and autoimmune diseases all involve effector mechanisms that correspond to the type II, III, and IV hypersensitivity reactions.  Unique to allergic disease is the type I hypersensitivity reaction mediated by IgE. 36  Abs against streptococcal cell-wall Ags cross-react with Ags on heart tissue (rheumatic fever) The immune response to the bacteria produces antibodies against various epitopes of the bacterial cell surface. Some of these antibodies (yellow) cross-react with the heart, whereas others (blue) do not. An epitope in the heart (orange) is structurally similar, but not identical, to a bacterial epitope (red). 37 Infections associated with the start of autoimmunity. 38 Types of antibodies that cause disease 39  Effector mechanisms of antibody-mediated disease  Auto Abs that are receptor agonists mimic the natural ligand of the receptor and cause the receptor to transduce activating signals in the absence of its ligand.  In contrast, autoAbs that are receptor antagonists do not activate signaling on binding to the receptor and they block the natural ligand from binding to the receptor and activating its signaling function. 40 AutoAbs (agonist) against the TSH receptor cause overproduction of thyroid hormones and Graves’ disease. Thyroid epithelial cells make thyroglobulin. Iodide (green) is taken up and used to iodinate and cross-link tyrosine residues of thyroglobulin (left half of the figure). TSH from the pituitary gland binds to the TSH receptor on thyroid cells, inducing the endocytosis and breakdown of iodinated thyroglobulin, with release of the thyroid hormones T3 and T4. T3 and T4 signal the pituitary to stop releasing TSH (upper right panel). In Graves’ disease, autoAbs bind to the TSH receptor of thyroid cells, mimicking TSH and inducing the continuous synthesis and release of thyroid hormones. In patients with Graves’ disease, the production of thyroid hormones becomes independent of the presence of TSH and of the body’s requirements for thyroid hormones (lower right panel). 41 AutoAbs (antagonist) against the acetylcholine receptor cause myasthenia gravis. In a healthy neuromuscular junction, signals generated in nerves cause the release of acetylcholine, which binds to the acetylcholine receptors of the muscle cells, causing an inflow of sodium ions that indirectly causes muscle contraction (upper panel). In patients with myasthenia gravis, autoAbs specific for the acetylcholine receptor reduce the number of receptors on the muscle-cell surface by binding to the receptors and causing their endocytosis and degradation (lower panel). Consequently, the efficiency of the neuromuscular junction is reduced, which is manifested as muscle weakening. 42 Diseases mediated by Abs against cell-surface receptors.  Antibodies act as agonists when they stimulate a receptor on binding it, and as antagonists when they block a receptor’s function on binding it. 43 Diseases Caused by Cell- or Tissue-Specific Antibodies Antibodies that cause cell- or tissue-specific diseases are usually autoantibodies produced as part of an autoimmune reaction, but sometimes the antibodies are specific for microbes. 44 Three mechanisms destroy RBCs in autoimmune hemolytic anemia. RBCs opsonized with IgG can be bound and engulfed by phagocytes in the spleen that bear an Fcγ receptor (lower left panel) a complement receptor (lower middle panel) or both types of receptor (not shown). Complement fixation on the RBC surface can also lead to complement-mediated lysis of the opsonized erythrocyte. 45  Sequence of immunologic responses in experimental acute serum sickness Immune Complex- Mediated Disease The major mechanism of tissue injury in ICMD is inflammation within the walls of blood vessels, resulting from complement activation and binding of leukocyte Fc receptors to antibodies in the deposited complexes. 46 Human Immune Complex–Mediated Diseases  Glomerulus of a patient with SLE.  Deposition of immune complexes causes thickening of the basement membrane.  Neutrophils (N) are also present, attracted by the deposited immune complexes. 47  Human Immune Complex–Mediated Diseases  Immune complex-mediated diseases are usually caused by antigen-antibody complexes that form in the circulation and are deposited in multiple tissues, producing systemic disorders.  The immune complexes that cause disease may be composed of antibodies bound to either self antigens or foreign antigens.  Almost all of these diseases are systemic, but a few are restricted to kidneys, perhaps because, in those cases, complexes are formed only in the glomerular basement membrane. 48 Mechanisms of T cell–mediated diseases  T lymphocytes injure tissues by either producing cytokines that induce inflammation or directly killing target cells.  Inflammatory reactions are elicited mainly by CD4+ T cells of the Th1 and Th17 subsets. In some T cell–mediated disorders, the principal mechanism of tissue injury is killing of cells by CD8+ CTLs.  The T cells that cause tissue injury may be autoreactive, or they may be specific for foreign protein antigens that are present in or bound to cells or tissues.  T lymphocyte–mediated tissue injury may also accompany strong protective immune responses against persistent microbes, especially intracellular microbes that resist eradication by phagocytes and antibodies. 49 T Cell–Mediated Diseases  Many organ-specific autoimmune diseases are caused by activation of autoreactive T cells by self antigens, leading to cytokine release and inflammation.  This is thought to be the major mechanism underlying rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes, psoriasis, and other autoimmune diseases  Type 1 diabetes, also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes, is caused by the selective autoimmune destruction of the insulin-producing cells of the pancreas. 50  Comparison of histological sections of a pancreas from a healthy person and a patient with type 1 diabetes. Panel a is a micrograph of healthy human pancreas, showing a single islet. The islet is the discrete light-staining area in the center of the photograph. It is composed of hormone-producing cells, including the β cells that produce insulin. Panel b shows a micrograph of an islet from a patient with acute onset of type 1 diabetes. The islet shows insulitis, an infiltration of lymphocytes from the islet periphery toward the center. The lymphocytes are the clusters of cells with darkly staining nuclei. 51  Granulomatous inflammation  A, Lymph node from a patient with tuberculosis containing granulomas with activated macrophages, multinucleate giant cells, and lymphocytes. In some granulomas, there may be a central area of necrosis (not shown). Immunohistochemical studies would identify the lymphocytes as T cells. B, Mechanisms of granuloma formation.  Cytokines are involved in the generation of Th1 cells, activation of macrophages, and recruitment of leukocytes. Prolonged reactions of this type lead to the formation of granulomas. APC, Antigen-presenting cell; IFN-γ, interferon-γ; TNF, tumor necrosis factor. 52  Delayed-type hypersensitivity (DTH) reaction  In the classic animal model of DTH, a guinea pig was first immunized by the administration of a protein antigen in adjuvant; this step is called sensitization. About 2 weeks later, the animal was challenged subcutaneously with the same antigen, and the subsequent reaction was analyzed; this step is called the elicitation phase.  Humans may be sensitized for DTH reactions by microbial infection, by contact sensitization with chemicals and environmental antigens, or by intradermal or subcutaneous injection of protein antigens.  Subsequent exposure to the same antigen (called challenge) elicits the reaction. For example, purified protein derivative (PPD), a protein antigen of Mycobacterium tuberculosis, elicits a DTH reaction, called the tuberculin reaction, when it is injected into individuals who have been exposed to M. tuberculosis. A positive tuberculin skin test response is a widely used clinical indicator of previous or active tuberculosis infection. 53 Type 4 Hypersensitivity Reaction Mantoux Test = Purified Protein Derivative (PPD) = Tuberculin Skin Test (TST) (Tb) 0.1 mL intradermal Skin (dermis) Subcutan eous fat Prior TB Exposure? Type 4 NO YES Indurated Hypersensitivity Reaction flat chemokines T- T-Cell Cell Macrophage Sangnya A Upadhyaya PY4 54 Cytokine Antagonists in Clinical Use or Trials 55 Therapeutic Approaches for Immunologic Diseases 56 A model for the pathogenesis of systemic lupus erythematosus 57 A model for the pathogenesis of rheumatoid arthritis  Some 80% of patients with rheumatoid arthritis make IgM, IgG, and IgA Abs specific for the Fc region of human IgG. Rheumatoid factor is the name given to these anti-Ig autoAbs. 58  The effects of treatment of RA with anti-TNF-α  The current treatment of autoimmune diseases is targeted at reducing immune activation and the injurious consequences of the autoimmune reaction.  Agents include those that block inflammation, such as antibodies against cytokines and integrins, and those that block lymphocyte activation or destroy lymphocytes.  A future goal of therapy is to inhibit the responses of lymphocytes specific for self antigens and to induce tolerance in these cells. 59 A 31-year-old woman has had systemic inflammation consisting of peripheral edema, pleuritic chest pain, and facial erythematous rash for the past six months. Laboratory studies show compromised renal function and a renal biopsy shows inflammatory infiltration and complement activation. What immunologic disorder best describes the findings of this pathology? 60 Transplantation Immunology Carlos A. Barrero M.D. Assistant Professor School of Pharmacy-Temple University November 4th , 2024 Number of transplants by organ type Transplants By Organ Type January 1, 1988 - September 30, 2018 Based on OPTN data as of October 24, 2018 62  T Lymphocyte Maturation in the Thymus  Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens present in the generative lymphoid organs. The cell death (Apoptosis) is due to a combination of factors, including:  Failure to productively rearrange the TCR β chain gene and thus to fail the pre-TCR/β,  Failure to be positively selected by self MHC molecules in the thymus,  Self antigen–induced negative selection. 63  MHC Genes  The polymorphic class I and class II MHC molecules are the ones whose function is to display peptide antigens for recognition by CD8+ and CD4+ T cells, respectively.  The products of different MHC alleles bind and display different peptides, different individuals in a population may present different peptides even from the same protein antigen.  For a given MHC gene, each individual expresses the alleles that are inherited from both parents. For the individual, this maximizes the number of MHC molecules available to bind peptides for presentation to T cells. 64  Direct and indirect alloantigen recognition Allogeneic MHC molecules of a graft can be presented for recognition by the recipient’s T cells in two different ways, called direct and indirect. Initial studies showed that the T cells of a graft recipient recognize intact, unprocessed MHC molecules in the graft, and this is called direct presentation (or direct recognition) of alloantigens. Subsequent studies showed that sometimes the recipient T cells recognize graft (donor) MHC molecules only in the context of the recipient’s MHC molecules, implying that the recipient’s MHC molecules must be presenting peptides derived from allogeneic donor MHC proteins to recipient T cells. This process is called indirect presentation (or indirect recognition), and it is essentially the same as the recognition of any foreign (e.g., microbial) protein antigen 65  Activation of alloreactive T cells  The T cell response to an organ graft may be initiated in the lymph nodes that drain the graft.  Most organs contain resident APCs, such as DCs, and therefore transplanted organs carry with them APCs that express donor MHC molecules.  These donor APCs can migrate to regional lymph nodes and present, on their surface, unprocessed allogeneic class I or class II MHC molecules to the recipient’s CD8+ and CD4+ T cells, respectively (direct MHC allorecognition).  Host DCs from the recipient may also migrate into the graft, pick up graft alloantigens, and transport these back to the draining lymph nodes, where they are displayed (the indirect pathway). 66 Hyperacute rejection Hyperacute rejection is characterized by thrombotic occlusion of the graft vasculature that begins within minutes to hours after host blood vessels are anastomosed to graft vessels and is mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens 67 Acute cellular rejection The principal mechanisms of acute cellular rejection are CTL-mediated killing of graft parenchymal cells and endothelial cells and inflammation caused by cytokines produced by helper T cells 68  Acute antibody mediated rejection  Alloantibodies cause acute rejection by binding to alloantigens, mainly HLA molecules, on vascular endothelial cells, leading to endothelial injury and intravascular thrombosis that result in graft destruction.  The binding of the alloantibodies to the endothelial cell surface triggers local complement activation, which causes lysis of the cells, recruitment and activation of neutrophils, and thrombus formation.  Alloantibodies may also engage Fc receptors on neutrophils and NK cells, which then kill the endothelial cells. In addition, alloantibody binding to the endothelial surface may directly alter endothelial function by inducing intracellular signals that enhance surface expression of proinflammatory and procoagulant molecules. 69  Chronic rejection  A dominant lesion of chronic rejection in vascularized grafts is arterial occlusion as a result of the proliferation of intimal smooth muscle cells, and the grafts eventually fail mainly because of the resulting ischemic damage.  The arterial changes are called graft vasculopathy or accelerated graft arteriosclerosis.  Graft vasculopathy is frequently seen in failed cardiac and renal allografts and can develop in any vascularized organ transplant within 6 months to a year after transplantation.  The likely mechanisms underlying the occlusive vascular lesions of chronic rejection are activation of alloreactive T cells and secretion of IFN-γ and other cytokines that stimulate proliferation of vascular smooth muscle cells.  As the arterial lesions of graft arteriosclerosis progress, blood flow to the graft parenchyma is compromised, and the parenchyma is slowly replaced by nonfunctioning fibrous tissue 70 Influence of MHC matching on graft survival Matching of major histocompatibility complex (MHC) alleles between the donor and recipient significantly improves renal allograft survival. The data shown are for deceased donor (cadaver) grafts. Human leukocyte antigen (HLA) matching has less of an impact on survival of renal allografts from live donors, and some MHC alleles are more important than others in determining outcome. Histocompatibility Video 71 Biologic actions of IL-2 A, Interleukin-2 (IL-2) stimulates the survival, proliferation, and differentiation of T lymphocytes, acting as an autocrine growth factor, leading to the generation of effector and memory cells. B, IL-2 also promotes the survival of regulatory T cells and maintains their functional capability, and thus controls immune responses (e.g., against self antigens). TCR, T cell receptor.  Autocrine  Paracrine  Endocrine 72 The Immune Synapse 73  The Immune Synapse  The synapse forms a stable contact between an antigen- T Cell specific T cell and an APC displaying that antigen and becomes the site for assembly of the signaling machinery of the T cell, including the TCR complex, coreceptors, costimulatory receptors, and adaptors.  The immune synapse provides a unique interface for TCR triggering, thus facilitating prolonged and effective T cell signaling.  The synapse ensures the specific delivery of secretory granule contents and cytokines from a T cell to APCs or to targets that are in contact with the T cell.  The synapse, may also be an important site for the turnover of signaling molecules. This degradation of signaling proteins contributes to the termination of T cell activation. APC 74 T cell signaling 75 Mechanisms of action of immunosuppressive drugs 76 Mechanisms of action of immunosuppressive drugs 77 Mechanisms of action of immunosuppressive drugs 78  Corticosteroids switch on anti-inflammatory gene expression Corticosteroid activation of anti-inflammatory gene expression. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs) that translocate to the nucleus, where they bind to glucocorticoid response elements (GREs) in the promoter region of steroid- sensitive genes and also directly or indirectly to coactivator molecules such as cAMP-response-element-binding-protein-binding protein (CBP), p300/CBP-associated factor (pCAF) or steroid receptor coactivator (SRC)-2, which have intrinsic histone acetyltransferase (HAT) activity, causing acetylation of lysines on histone H4, which leads to activation of genes encoding anti- inflammatory proteins, such as secretory leukoprotease inhibitor (SLPI), mitogen-activated protein kinase phosphatase (MKP)-1, inhibitor of nuclear factor-κB (IκB-α) and glucocorticoid-induced leucine zipper protein (GILZ). ↑: increase. European Respiratory Journal 2006 79  Corticosteroids switch off inflammatory genes  Corticosteroid suppression of activated inflammatory genes. Inflammatory genes are activated by inflammatory stimuli, such as interleukin (IL)-1β or tumour necrosis factor (TNF)-α, resulting in activation of inhibitor of I-κB kinase (IKK)2, which activates the transcription factor nuclear factor (NF)-κB.  A dimer of p50 and p65 NF-κB translocates to the nucleus and binds to specific κB recognition sites and also to coactivators, such as cAMP-response-element-binding-protein-binding protein (CBP) or p300/CBP-associated factor (pCAF), which have intrinsic histone acetyltransferase (HAT) activity.  This results in acetylation of core histone H4, resulting in increased expression of genes encoding multiple inflammatory proteins. Glucocorticoid receptors (GRs), after activation by corticosteroids, translocate to the nucleus and bind to coactivators in order to inhibit HAT activity directly and recruiting histone deacetylase (HDAC)2, which reverses histone acetylation, leading to suppression of these activated European Respiratory Journal 2006 inflammatory genes. ↑: increase; -: suppression. 80 Immunosuppressive drugs 81  Immunologic Complication of Hematopoietic Stem Cell Transplantation Histopathology of acute GVHD  HSC transplantation is a clinical procedure to treat lethal diseases in the skin caused by intrinsic defects in one or more hema­topoietic lineages in a patient.  A patient’s own hemato­poietic cells are destroyed, and HSCs from a healthy  donor are then given to restore normal blood cell produc­tion in the patient.  HSC transplantation is most often used clinically in the treatment of leukemias and pre­leukemic conditions.  Allogeneic HSCs are rejected by even a minimally immunocompetent host, and therefore, the donor and recipient must be carefully matched at all MHC loci.  GVHD is caused by the reaction of grafted mature T cells in the HSC inoculum with alloantigens of the host.  The consequence of immunodeficiency is that HSC transplant recipients are susceptible to viral infections, especially cytomegalovirus, bacte­rial and fungal infections.  They are also susceptible to Epstein­Barr virus–provoked B cell lymphomas. 82  Induced Pluripotent Stem (iPS) cells  There is great interest in the use of pluripotent stem cells to repair tissues that have little natural regenerative capacity, such as cardiac muscle, brain, and spinal cord.  The major barrier to their successful grafting embryonic stem cells will be their alloantigenicity and rejection by the recipient’s immune system.  A possible solution to this may be to use induced pluripotent stem (iPS) cells, which can be derived from adult somatic tissues by transduction of certain genes.  The immunologic advantage of the iPS cell approach is that these cells can be derived from somatic cells har­- vested from the patient, and therefore they will not be rejected.  Another solution now being investigated is to remove MHC genes from allogeneic embryonic stem cells by CRISPR­- Cas9 genome editing technology. 83 Genetic modifications that have been made in pigs to facilitate pig-to-human organ transplantation 84 Pigs with a record number of modified genes will now provide organs for experimental transplants in nonhuman primates doi:10.1126/science.aba6487 85