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Immunologic Tolerance
- State of unresponsiveness to antigens (self Ags especially)
- Central tolerance: Central thymic tolerance to self antigens (autoantigens)
- Peripheral tolerance in lymphoid organs:
- 1. Self-reactive T cells ignore self-antigens (sequestered from circulation)
- 2. Self antigens present in privileged sites ignored
- 3. Self-reactive T & B cells deleted
- 4. Self-reactive T cells rendered anergic (unresponsive)
- 5. Self antigens kept in check by T regulatory cells
- Failure of self-tolerance leads to autoimmunity: The immune system attacks the body’s own cells and tissues
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Central Tolerance
- Gene rearrangements (such as VDJ recombinations) in the central lymphoid organs (e.g. thymus & BM) inevitably generate lymphocytes that have affinity for self-antigens. These are normally removed or kept in check by self-tolerance, in which an individual’s immune system does not attack the normal tissues of the body.
- Failure of tolerance mechanisms leads to autoimmunity
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Role of Autoimmune regulator (AIRE) gene in thymic tolerance
- - Aire gene in the thymic medulla turns on ectopic (outside) expression of self Ag, peptides to be tested against thymocyte being presented by MHC
- - Tolerance through anergy or deletion. The ones fail the test, either don't bind, or bind too vigorously, are removed. Positive/negative selection
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Layers of self-tolerance - mechanism @ site of action
- central tolerance - deletion (apoptosis), editing (receptor; B cells), development of Treg @ thymus, BM
- Ag segregation - physical barrier to self-Ag access to lymphoid system @ peripheral organs (e.g. thyroid, pancreas)
- Peripheral anergy - cellular inactivation by weak signaling w/o costimulus @ secondary lymphoid tissue
- Regulatory cells - suppression by cytokines, intercellular signals @ secondary lymphoid tissue and sites of inflammation
- Cytokine deviation - differentiation to TH2 cells, limiting inflammatory cytokine secretion @ secondary lymphoid tissue and sites of inflammation
- Clonal deletion - apoptosis post-activation @ secondary lymphoid tissue and sites of inflammation
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Fates of lymphocytes after encounter of antigens
- Normal immune response to pathogenic Ag - proliferation and differentiation
- Self-tolerance to self Ag - Anergy (unresponsive); Deletion (cell death); Change in specificity (receptor editing)
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Mechanisms of T cell anergy
- In normal responses: recognition of foreign antigen with costimulation by T cell and APC expressing costimulators, activation, effector T cell proliferation and differentiation.
- In T cell anergy: recognition of self Ag leads to either signaling block (costimulator lacking) or engagement of inhibitory receptors (e.g. CTLA-4), resulting in unresponsive T cell (anergic)
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The correlation between avidity and thymocyte selection
- avidity too low: apoptosis
- avidity intermediate: positive selection; at the highest end is the selection of CD25+ Treg
- avidity high: negative selection; apoptosis
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Treg cells (FoxP3+, CD4+, CD25+; TGF-β, IL-10)
- moderately autoreactive that escaped deletion in the thymus
- When activated by self antigen, they cannot initiate an autoimmune response; instead, they differentiate into powerful suppressor cells that inhibit other selfreactive T cells that recognize Ags on the same tissue
- Therapeutic intervention of colitis (inflammation of the colon), diabetes, SLE (EAE in mouse model)
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Self Ag-induced death of peripheral T lymphocytes
- Normal immune response: expression of anti-apoptotic (survival) proteins, induced by IL-2 (T cell growth factor), which is released by activated T cell -> T cell proliferation and differentiation
- Self Ag recognifition: induction of pro-apoptotic proteins (e.g. Bim) -> apoptosis
- Self Ag recognifition: expression and engagement of death receptors, Fas:FasL -> apoptosis
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Role of regulatory T cells in T cell-mediated suppression
- Differentiated in thymus (main site) and lymph node w/ the help of IL-2 when avidity is medium high.
- Inhibit peripheral (self-Ag responsive) T cell activation or function via TGF-beta.
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Central deletion or inactivation of newly formed lymphocytes is the first check point of self-tolerance
- 1. Organs express tissue-specific Ags
- 2. In thymus, T cells recognizing those Ags arise
- 3. Under control of AIRE protein, thymic medullary cells express tissue-specific proteins, deleting tissue-reactive T cells.
- 4. In the absence of AIRE, T cells reactive to tissue-specific Ags mature and leave thymus
- - AIRE (auto-immune regulator) gene promotes expression of many tissue-specific antigens in the thymic medullar cells.
- - Rare inherited deficiency of AIRE leads to APECED (auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy) – autoimmune destruction of multiple endocrine tissues, such as insulin producing pancreatic cells
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Self Ags recognized by TLRs can ___________.
- activate autoreactive B cells by providing co-stimulation
- B cells w/ specificity for DNA bind soluble fragments of DNA, sending a signal through BCR
- The cross-linked B-cell receptor is internalized w/ bound DNA
- GC-rich fragments of the internalized DNA bind to TLR-9 in an endosomal compartment, sending a co-stimulatory signal
- - Unmethylated CpG DNA (common in bacteria) is produced in mammalian cells undergoing apoptosis (possibly as result of infection)
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Factors that Determine the Tolerogenicity of Self Ags: favoring immune response vs favoring tolerance
- - optimal doses vs. high doses
- - short-lived vs. prolonged
- - subcu, intradermal, absence from generative organs vs. intravenous, oral, presence in generative organs
- - Ag w/ adjuvants (stim TH cells) vs. Ag w/o adjuvants
- - APC w/ high levels of costimulators vs. APC w/ low levels of costimulators and cytokines
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Immunologic privileged sites
- Brain
- Eye
- Testis
- Uterus (fetus)
- Hamster cheek pouch
- - Tissue grafts placed in these sites often last indefinitely
- - The Ags sequestered at these sites are often targets of autoimmune attack.
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Infectious agents could break self tolerance in different ways
- Disruption of barrier - release sequestered self Ag; activate nontolerized cells. E.g. sympathetic ophthalmia
- Molecular mimicry - produce cross-reactive Ab or T cells. E.g. rheumatic fever, reactive arthritis, lyme arthritis
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Damage to immunologically privileged site can induce autoimmunity
- Trauma to one eye releases sequested intraocular protein Ags
- Released Ags are carried to lymph nodes and activate T cells
- Effector T cells return via bloodstream and encounter Ag in both eyes - sympathetic ophthalmia
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Tolerance mediated by regulatory T cells can inhibit multiple autoreactive T cells that all recognize the same tissue
- T-cell specific for self Ag in thymus becomes a natural Treg
- T cell in peripheral specifc for self or commensal microbiota Ag recognized in presence of TGF-beta becomes an induced Treg
- IL-10 and TGF-beta released by Treg inhibit other self-reactive T cells in periphery
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Autoimmunity:
- The response of the immune system against the body’s own tissues (i.e. response to self). This often leads to Autoimmune Disease
- - “Horror autotoxicus” – Paul Ehlich (“The Body turns against itself”)
- Autoantigens: are self molecules recognized as Ags
- Autoantibodies: are Abs that react against self Ags
- Autoreactive cells: are lymphocytes with receptors for self Ags
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Why does autoimmunity develop?
- Failed central tolerance
- - Flawed thymic selection
- - Failure in deletion of autorective lymphocytes
- - Failure in activation-induced cell death (AICD)
- Defects in peripheral tolerance
- - Hyper-immune stimulation (e.g. unregulated costimulation)
- - Cytokine imbalance
- - T cell bypass: Most self-reactive T cells are deleted or anergized, but autoreactive B cells may become activated by a mechanism that bypasses the tolerant T cell. A cross-reactive exogenous Ag taken up by an autoreactive B cell could be presented to a T cell recognizing a non-self epitope, which then helps the B cell.
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Requirements for development of autoimmune disease
- Failure of intrinsic tolerance mechanisms and/or environmental triggers such as infection, may lead to autoimmunity in genetically predisposed individuals.
- Genetic factors and infection & environmental exposure act together on immune regulation -> autoimmunity
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Autoimmune diseases may be classified as organ-specific or non-organ-specific depending on whether the response is primarily against antigens localized to particular organs or against widespread antigens.
Not all autoimmune diseases fit the classification - autoimmune hemolytic anemia can occur in isolation or with SLE.
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Organ specific autoimmune disease
- M.S. - CNS, myelin
- Goodpasture's syndrome - lungs and kidneys; collagen IV
- insulin-dependent diabetes mellitus - pancreatic beta cells
- Crohn's disease - Mucosa (GI, mouth, anus) - NOD2 (non-obese diabetes II; F=M)
- Psoriasis - skin plaques, discolored nails
- Graves’ disease - anti-TSHR-hyperthyroidism
- Hasimoto thyroiditis - Thyroid gland-hypothyroidism
- Autoimmune hemolytic anemia - RBC destruction
- Autoimmune Addison's disease - Adrenal insufficiency
- Vitiligo - skin depigmentation; melanocyte death
- Myasthenia gravis - muscle; Ach receptors
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Non-organ-specific (systemic) autoimmune disease
- Rheumatoid arthritis (RA) - IgM anti-IgG (RF in joints)
- Scleroderma - arteriole hardening (ANAs -skin, heart, kidney, lung)
- SLE - various tissues (skin, heart, lung, kidney, intestine, CNS)
- Primary Sjogren's syndrome - anti-nuclear Abs, anti-Ach receptor Abs, dry mouth
- Polymyositis - inflammation of muscle fibers
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Rheumatoid factors:
Anti-IgG Abs produced to immune complex of IgG, as a result of infection. These are usually of IgM isotype, and are normally short-lived, and are cleared, but become immunogenic if uncleared. E.g. Rheumatoid arthritis
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_________ in germinal centers can produce self-reactive B cells. These are normally removed by _______.
- Somatic hypermutation
- apoptosis
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Sex difference of autoimmune diseases
- Many are more common in females than males
- frequently X-linked
- double dosage
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Inflammatory bowel disease and colitis
- - result from autoreactive T cells in the lamina propria
- - Can be treated by transfer of CD4 CD25 Treg cells, which home to the colon and mesenteric lymph nodes
- - They proliferate and inhibit the pathogenic effector T cells
- - After inflammation resolves, CD4 CD25 Treg cells remain in clusters w/ DC and pathogenic effector T cells
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myasthenia gravis
- Auto-Abs inhibit receptor function
- Ach receptors are internalized and degraded
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Graves Disease:
- Ab-mediated autoimmune diseases; can appear in the infants of affected mothers as a consequence of transplacental anti-TSHR Ab (IgG) xxtransfer
- plasmapheresis removes maternal anti-TSHR Ab and cures the disease in newborn.
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Experimental Allergic Encephalomyelitis (EAE) mouse model for ___________.
multiple sclerosis
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Pathogenesis of multiple sclerosis
- - Unknown trigger sets up initial focus of inflammation in brain and blood-brain barrier becomes locally permeable to leukocytes and blood proteins
- - T cells specific for CNS Ag and activated in peripheral lymphoid tissues reencounter Ag presented on microglia or DC in brain
- - Inflammatory reaction in brain due to mast-cell activation, complement activation, Ab, and cytokines
- - Demyelination of neurons
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T cells specific for ________ mediate ________ of the brain in experimental autoimmune encephalomyelitis (EAE).
- myelin basic protein
- inflammation
- - Mice injected w/ myelin basic protein and complete Freund's adjuvant develop EAE and are paralyzed
- - The disease is mediated by TH1 specific cells (IFN-gamma and TFN-a released) for myelin basic protein
- - disease can be transmitted by transfer of T cells from affected animal
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Autoimmune hemolytic anemia
- - RBCs coated with IgG auto-Abs are readily cleared by FcR+ macrophages; RBCs coated with IgM auto-Abs fix C3 and are cleared by CR1+ and C3+ macrophages. Both mainly occur in the spleen
- - Binding of rare auto-Abs that fix complement avidly cause formation of membrane-attack complex, resulting in intravascular hemolysis
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Sjogren's syndrome:
- - An autoimmune disease characterized by inflammation of the glands of the eyes and mouth (lachrymal and salivary), which can lead to severe eye and mouth dryness
- - 9-10x more in women; usually in late 40s
- - Can occur alone (primary Sjogren's syndrome) or later in association with rheumatoid arthritis, SLE, scleroderma, primary biliary cirrhosis, etc. (Secondary Sjögren's syndrome).
- - Characterized by presence of anti-nuclear Ab (ANA; directed against contents of the cell nucleus) and rheumatoid factor in serum. The rheumatoid factor is usually antibody against the Fc portion of IgG.
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Autoantibodies in Sjogren’s syndrome
- Anti-nuclear antibodies:
- - Anti-Ro/SSA- Most prevalent (e.g. SLE, SLE/SS); 52 & 60 kD protein + small RNA particles
- - Anti-LA/SSB- more associated with SS; 48-52 kD protein + small RNA particles
- Rheumatoid factors
- - IgM anti-IgG Fc (30% rheumatoid arthritis patients do not have RF)
- - IgA RF in pSS
- Anti-M3, acetylcholine (muscarinic) receptor
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Immunologic cascade in Sjogren's syndrome pathogenesis
- - Genes and environment produce auto Ags, carried by DCs, go to lymph nodes and spleen
- - Ags go into glands, complements are produced and inflammation starts
- - Chemokine, CXCL13 is produced and is a chemoattractant for B and T cell, go from lymph nodes into glands, then initiate ectopic germinal centers and reaction occurs in the glands
- - These cells are vigorously reactive can get out and cause lymphoma
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Transfer of Autoantibodies to infants
- Mother with SLE or Sjogren’s syndrome
- Placental transmission of IgG autoantibodies
- Failure of infant to catabolize autoantibodies early leads to Chronic organ damage of infant – heart
- Plasmapheresis
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Animal models of Sjogren’s syndrome
- Ovariectomized Non-obese diabetic (NOD) mice
- Increased cytokine/chemokine secretion in lacrimal glands - IL-1, TNF-α, IL-17, CXCL13
- Damage to lacrimal gland like in human SS
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Autoimmune diseases transferred across the placenta to the fetus and newborn infant
- Myasthenia gravis: Anti-acetylcholine receptor -> Muscle weakness
- Graves' disease: Anti-thyroid-stimulating-hormone (TSH) receptor -> Hyperthyroidism
- Thrombocytopenic purpura: Anti-platelet antibodies -> Bruising and hemorrhage
- Neonatal lupus rash and/or congenital heart block: Anti-Ro/La antibodies -> Photosensitive rash and/or bradycardia
- Pemphigus vulgaris: Anti-desmoglein-3 -> Blistering rash
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Autoimmune diseases involve all aspects of the immune response
- SLE: T - pathogenic or help for Ab; B - AP to T; Ab - pathogenic
- Type 1 diabetes: T - pathogenic; B - AP to T; Ab - unclear
- Myasthenia gravis: T - help for Ab; B - Ab secretion; Ab - pathogenic
- M.S.: T - pathogenic; B - AP to T; Ab - unclear
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Auto-Ab-mediated diseases
- Graves' disease -> TSHR
- Myasthenia gravis -> AchR
- Insulin-resistant diabetes (2) -> insulin receptor (antagonist)
- Hypoglycemia -> insulin receptor (agonist)
- Chronic utricaria -> receptor-bound IgE or IgE receptor (agonist)
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Therapeutic Management of autoimmune Diseases
- - Anti-inflammatory drugs - corticosteroids
- - Antagonists to pro-inflammatory cytokines and their receptors
- - Antagonists to costimulatory molecules – CTLA4-hIg blocks B7
- - Plasmapheresis -> Ab IgG
- - Ab-dependent cell-mediated cytotoxicity (ADCC): Anti-CD20 mAb (with human Fc), anti-CD40 mAb
- - Intravenous IgG
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Transplatation
The process of taking cells, tissues, or organs, called a graft, from one individual and placing them into a (usually) different individual
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Autograft
graft transplanted from one site to another in the same individual. eg. skin grafts – autologous graft
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Isograft (syngraft) /syngeneic transplantation
graft transplanted between two genetically identical or syngeneic individuals, i.e. identical (homozygotic) twins
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Allograft
graft transplanted between two genetically different individuals of the same species– most common type of graft
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Alloantigens
molecules that are recognized by T cells as foreign on allografts
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Orthotopic (homotopic) transplantation
The graft is placed into its normal anatomic location
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Heterotopic transplantation
transplantation of tissue typical of one area to a different site in a recipient.
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Xenograft
between members of different species
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Transplantation and Rejection
- The barrier to transplantation is the genetic disparity between donor and recipient.
- The immune response in transplantation depends on a variety of factors:
- - Host versus graft responses cause transplant rejection.
- - Histocompatibility Ags are the targets for rejection.
- - Minor Ags can be targets of rejection even when donor and recipient MHC are identical.
- - Graft versus host reactions result when donor lymphocytes attack the graft recipient (i.e. host).
- Rejection results from a variety of different immune effector mechanisms:
- - Hyperacute rejection is immediate and caused by antibody.
- - Acute rejection occurs days to weeks after transplantation
- - Chronic rejection is seen months or years after transplantation.
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Testing for donor-recipient compatibility in transplantation
- ABO matching
- HLA matching: HLA-A, HLA-B, HLA-DR
- Preformed Abs
- Cross matching - see if the Abs recognize
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The initiation of graft rejection normally involves the migration of donor APC from the graft to local lymph nodes, activation of effector T cells, and T cells' migration back to graft via blood to destroy graft.
- Depletion of passenger leukocytes extends grafting
- If site of grafting lacks lymphatic drainage, no response to graft occurs.
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Skin graft rejection is the result of T cell-mediated anti-graft response
- Syngeneic -> same MHC, tolerated
- Allogeneic -> different MHC, rejected
- For naive recipient, rejection happens quickly
- For second-time recipient (same host/donor), rejection happens even faster
- For naive host, if T cell from sensitized host is injected, rejection happens as faster as second-time receiver
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Even complete matching at the MHC locus does not ensure graft survival
if the minor H antigen is incompatible
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Minor H antigens are peptides derived from polymorphic cellular proteins bound to MHC class I molecules
- polymorphic self proteins that differ in AA sequence between individuals give rise to minor H Ag differences between donor and recipient
- TAP (transporters associated with antigen processing) is involved in taking the peptide into ER before it is attached to MHC and presented on cell surface.
- Targeted by CD8 T cells
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Alloantigens in grafted organs are recognized in two different ways
- Direct recognition - Donor APCs migrate to secondary lymphoid tissue (LN or spleen) and stim alloreactive recipient T cells
- Indirect recognition - Recipient APCs process proteins and present peptides derived from the graft
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Preexisting Ab against donor graft Ags (e.g. blood group antigens) can cause _______ rejection within _____.
- Hyperacute
- minutes
- preexisting Ab bind vascular endothlium of graft, initiating inflammation, occluding blood vessels, killing the graft.
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Among commonly transplanted organs, _____ has the highest 5-yr survival rate, _____ is most frequently transplanted.
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Hyperacute rejection
- circulating allo-Ag specific Ab binding, complement activation, endothelial damage, inflammation and thrombosis.
- - Minutes after transplant
- - Ab & C’
- - Typical in ABO incompatibility & xenografts
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Acute rejection
- parenchymal cell damage, interstitial inflammation, endothelialitis
- - Days to weeks after transplant
- - Alloreactive CD8 CTL
- - CD4 T cell cytokines recruit inflammatory cells: DTH (Delayed type hypersensitivity)-like
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Chronic rejection
- chronic DTH in vessel wall, intimal smooth muscle cell proliferation, vessel occlusion
- - Months to years after transplant
- - accelerated arteriosclerosis
- - Specialized DTH – lymphocytes induce macrophages to secrete smooth muscle growth factors
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Mixed lymphocyte reaction (MLR) used for detection of histocompatibility
- - Lymphocytes from two individuals to be tested for compatibility are isolated from peripheral blood and mixed.
- - Stimiulator cells - including APCs; from one person, either irradiated or treated with mitomycin C, can't respond by DNA synthesis and cell division to antigenic stimulation
- - Responders cells, the unirradiated lymphocytes, if contain alloreactive T cells, will be stimulated to proliferate and differentiate to effector cells between 3 and 7 days after mixing.
- - Assessed for T-cell (CD4) proliferation, recognizing differences in MHC class II molecules, measuring H3-thymidine incorporated in DNA.
- - Or assessed for the generation of activated cytotoxic T cells (51Cr-labeled), responding to differences in MHC class I molecules.
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Structures of the ABO blood group antigens
- - All have a common structure: ceramide, Glu, Gal, GalNac, Gal, Fuc
- - A antigen: extra GalNAc
- - B antigen: extra Gal
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Donors and recipients for blood transfusion must be matched for the ABO system of blood group antigens
- A: RBC has A-Ag, plasma contains Anti-B Ab -> A, AB
- B: B-Ag, Anti-A Ab -> B, AB
- O: Anti-A and B Abs -> A, B, AB, O
- AB: A- and B-Ags, no Ab against A or B -> AB
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Matching the ABO and rhesus erythrocyte antigens in blood transfusion
- A/B/AB/O - RhD+/-
- blood type w/ highest frequency in US population is O+ and A+
- AB- being the lowest
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Graft-versus-host Disease, GVHD (converse of graft rejection)
- - Major complication of allogeneic bone marrow transplantation:
- - Donor T cells recognize host tissues as foreign, causing severe inflammatory disease.
- - Particularly violent when there is mismatch of MHC class I and II Ags
- - Occurs even in disparities in minor histocompatibility Ags.
- - Occurs if the host is severly immunocompromised and cannot reject the alloreactive T cells
- - Sometimes seen in solid organ transplants such as lung or small bowel
- - Classified into Acute or Chronic GvHD
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Recipient type APCs are required for the efficient initiation of GVHD
- Donor T cells can recognize minor histocompatibility Ags of the recipient and start an immune response against the recipient's tissues.
- In stem-cell transplantation, minor Ags could be presented by either recipient- or donor-derived APCs.
- Cross-presentation of the recipient's minor histocompatibility Ags on donor APCs is not sufficient to stimulate GVHD; Ags endogenously synthesized and presented by the recipient's APCs are required.
- Mice w/ host APCs knocked out were entirely resistant to GVHD mediated by donor CD8 T cells.
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BONE MARROW TRANSPLANTATION
- Pluripotent hematopoietic stem cell (CD34+) of donor - cord or peripheral blood; donor cells mobilized into circulation by treatment with GM-CSF
- Since allogeneic stem cells are readily rejected by minimally immunocompetent host, host immune system is ablated by radiation and chemotherapy prior to transplantation.
- Used to treat hematological malignancies, anemias, immune deficiency disorders and some solid tumors.
- In addition to alloreative T cells, NK cells also play a role in BM rejection
- GVHD is common in BM transplants and the principal limitation to successful BM transplantation.
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Alloreactions in transplant rejection and graft versus host reaction
- host T cell vs graft
- graft T cell vs recipient
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Histopathology of acute GVHD in the skin
- Apoptotic cells seen
- Destruction due to apoptosis
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Methods of Immunosuppression to prevent or treat allograft rejection
- Anti-CD3 monoclonal Ab: Depletes T cells (any type) by binding to CD3 and promoting phagocytosis or complement-mediated lysis (used to treat acute rejection)
- CTLA-4-Ig: Inhibits T cell activation by blocking B7 costimulator binding to T cell CD28; in clinical trials
- Anti-CD40 ligand: Inhibits macrophage and endothelial activation by blocking T cell CD40 ligand binding to CD40; in clinical trials
- Anti-IL-2 receptor (CD25) antibody: Inhibits T cell proliferation by blocking IL-2 binding and depletes activated T cells that express CD25
- Rapamycin: inhibiting IL-2 signaling (important to T activation) -| proliferation
- Azathioprine: Blocks proliferation of lymphocyte precursors
- Mycophenolate mofetil (MMF): inhibiting guanine nucleotide synthesis in lymphocytes -| proliferation
- Cyclosporine and FK-506: inhibiting activation of the NFAT transcription factor -| T cell cytokine production
- Corticosteroids: inhibiting macrophage cytokine secretion -| inflammation
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Regulatory T cells in future GVHD therapy
- - Recipient CD4+CD25+ Treg cells activated and expanded ex vivo and injected into recipient prior to BM transplant
- - Recipient CD8+CD28- Treg cells, with anergic phenotype are thought to maintain T-cell tolerance by inhibiting the capacity of APCs to activate helper T cells
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Setbacks to sustained immunosuppression
- • opportunistic viral infections with CMV and HSV
- • B cell lymphomas (EBV) and squamous cell carcinomas of the skin (HPV)
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The fetus is an allograft that is not rejected (tolerance!) - Hypotheses:
- - Trophoblast (separates fetal and maternal tissues) does not express MHC class I or II. Vulnerable to attack by NK cells.
- - Protection from NK killing by expression of non-classical MHC class I (HLA-G) which binds the
- two major inhibitory NK receptors (KIR1 and KIR2), and prevents killing.
- - Uterine epithelium and trophoblast secrete TGF-β, IL-4, and IL-10 which suppresses TH1 response.
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The favored animal for xenotransplantation is the pig
- Advantages:
- - physiological and anatomical compatibility
- - ability to breed large numbers of animals rapidly
- Barriers :
- - public acceptability
- - safety (transmission of viruses from pigs- not major concern)
- - scientific issues - preventing graft rejection (genetically engineered/humanized pig)
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Basic principles of tissue engineering
- take cells from a biopsy
- culture in the lab
- make a scaffold - artificial matrix w/ recipients cells or biological matrix from pigs
- generate a graft
- implant back to the person
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Skin cell spray - transplantation device
culture stem cells w/ cytokines, GF, spray on to burn site
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