Autoimmunity and Transplantation PDF

Autoimmunity and Transplantation Autoimmune diseases Janeway’s Immunobiology, 9th edition This is an immune response against self natigens, bodies immune system will begin to attack itself because eof the breakdown of tolerance...

Autoimmunity and Transplantation Autoimmune diseases Janeway’s Immunobiology, 9th edition This is an immune response against self natigens, bodies immune system will begin to attack itself because eof the breakdown of tolerance 1  Multiple tolerance mechanisms normally prevent autoimmunity The ability to distinguish between ‘self’ and ‘non-self’ antigens is central to the normal functioning of the immune system. Tolerance to self antigens can be induced during immune cell development in the primary/central lymphoid organs and is called central tolerance. Tolerance induced after immune cells leave the primary/central lymphoid organs is known as peripheral tolerance. Undergo mechaims that will change their receptor sor not mak ethem recat to self antigens -tolernacemehcnaims that are central tolerance or peripheral tolerance --different mechnaims that contribute to this tolerance -in primary lymphoid tissues , immune cells are tested for their reactivity for their self natigens -rearrangege light chain to rescue that and if it cannot do that it will initiate apoptosis There are peripheral tolerance mechnaims as well -peripheral allergy and activation induced cell death , autreactivity T and B cells and recognize an antigen and receive a signal, then theuy will either rbecome allergic bc they do not receive eco-stimulatorty signal which are induced when there is an infection or inflammation that occurs, in the bascence of co-stimulatory signals they counte rtheir antigens; regulatory T cells are immunosuppressant and thei rfunction is to suppress the activity of immune cells which are important for mainting homeostasis , regulatory T cells are important for suppressing autrecative Functional deviation- the process in the intestine , cd4 helper t cells when tey recive a signal from pro inflammatory cytokines , instea dof pro inflammatory 2 T cell they differentiate into Treg cells Another mechanism that orevents autimmune reponse sis antigen segregation, proteinsof the eye, pancreas an dthryoid where there is a barrier so that antigens cannot leav ethe organs or have immune cells come into contact with antigens therefore prevent any autrecative T or B cells agaisn those antigen - 2  Central tolerance induced in the primary lymphoid organs is the first checkpoint of self-tolerance Developing thymocytes that recognize self antigens with high affinity in the thymus undergo apoptosis in a process called negative selection. Many (but not all) tissue-specific antigens are expressed in the thymus by thymic epithelial cells and DCs, and are presented to the developing thymocytes to facilitate negative selection of self-reactive thymocytes. The transcription factor, AIRE (autoimmune regulator) is responsible for turning on many peripheral genes in the thymus. Defects in AIRE function impair negative selection and allow self-reactive T cells to develop and move to the periphery, leading to an autoimmune disease known as autoimmune polyglandular syndrome type 1 (APS-1). Central tolerance in the tolerance which is mediated by negative selction but potential autoreactive T eclls Thymus is a unique organ if tehr eis expression of genes that code for antigens that are used for different organs or tissues, all those natigens are expressecd in the tissue so that developing T cells are exposed to those antigens ; autimmune regulator, APS-1 , transcirpton factor AIRE can transcribe all the egnes in the thymus so if tehre is a mutation of this gene thenT cells cannot get exposed to self antigens and some are self-autoreactive and then they are seen as harmless cells even when their not 3  Segregation of antigens in immunologically privileged sites Some sites in the body are off-limits for naïve lymphocytes. These are called immunologically privileged sites and antigens in these sites do not induce immune attack. Several characteristics of the immunologically privileged sites contribute to preventing immune responses in these sites under normal conditions: - Extracellular fluids do not pass through conventional lymphatics. - Privileged sites are surrounding by a barrier that exclude naïve lymphocytes; e.g. the blood-brain barrier. - Soluble factors, such as the anti-inflammatory TGF-β, are produced in the immunologically privileged sites to induce suppressive Treg cells instead of the inflammatory TH17 cells. - Expression of FasL in the immunologically privileged sites induce apoptotic cell death in Fas- expressing lymphocytes that enter these sites. Antigens sequestered in immunologically privileged sites can become targets of autoimmune attacks; for e.g. myelin basic protein of the brain and spinal cord is targeted in the autoimmune disease multiple sclerosis. -antigens are protected or prevented from coming in so that tehr eis no reaction, organs include eye, brain, testis and uterus -mother carrying fetus the mother willsee the fetus as foreign so the interal immune system will start attacking, fetus is protected byu thr barrier of immunologically privileged sites -inflammation in the brian is extremely dnagerou sos the brian is an immune privelige site top prevent inflmamtory reponses -these site have different emechnaims to suppress activation of immune cells of these sites including extracellular fluid (do npt pass through the lymphatic system so their fluiddoes not come into contact with immune cells or antigens) , or they could be surrounded by a barrier like the blood brain barrier which prevents the immune cells in the circulation to get our of the blood vessels into the brain tissues -blood brain brarrier makes it difficult to treat brain cancer bc durgs cannot eneter into the brain -soluble factors, is an antiinflmmatory cytokine, high concnetrationof these cytokines establish an immune tolerant eviornemnet -expression of FasLigands , this is the ligan that intercat with Fas and induces apoptosis (death receptor) when immune cells bceom activated they express Fas as a moral mechamins that is used for those cells 4  Peripheral tolerance induced by regulatory T cells Two subsets of regulatory T (Treg) cells: 1. Those committed to a regulatory fate during development in the thymus are called natural Treg (nTreg) cells. 2. Those which differentiate from naïve CD4 T cells under the influence of particular environmental conditions are called induced Treg (iTreg) cells. Antigen recognition by auto-reactive CD4 T cells in the presence of TGF-β induces differentiation into iTreg cells. When iTreg cells recognize their antigen, they produce inhibitory cytokines, TGF-β and IL-10, to supress other auto-reactive T cells. The transcription factor FoxP3 is essential for the development of both nTreg and iTreg cells. Humans and mice carrying mutation in the gene for FoxP3 develop severe autoimmune disease, demonstrating the importance of regulatory T cells in preventing autoimmune responses. Regulatory t cells, immune cell types that prevents uatimmune reponses and there are two type sthere is natural T reg and induced T reg -very important immune cells to regylatr the function of hyperactivation of immune cells cvausing excess ingmmatory reponses and are impotnat to prevent autimmune disease -tehre are soluble cytokine/chokines -Itreg can relase immune suppressant cytokines - Autoimmune disease that have muattaion in Fox 5  Autoimmune diseases: Genetic and environmental basis of autoimmunity Induction of autoimmune diseases: - Genetic predisposition – mutations that break down immune tolerance. - Accidental exposure of the immune system to autoantigens that are normally sequestered from immune cells (e.g., lens protein and myelin basic protein). - Inflammation-promoting environmental factors such as lifestyle (smoking), malnutrition, altered gut microflora, etc. - Infection – Certain pathogens express molecules that closely resemble self-antigens and may therefore induce autoimmunity; e.g., T cells reactive with mycobacterial heat shock antigens (hsp65) cross react with human heat shock antigen (hsp60) that is expressed on stressed cells, leading to autoimmune disease. These mechanisms are not mutually exclusive and that one or more of these mechanisms may contribute to the induction of a particular autoimmune disease. What cuases autimmune disease? What breaks the central or peripherla tolernaces? They can be genetic causes as well as environmental factors that can result in breakdown in immune tolerance and allows autoimmune cells to become activated -genetic predispotion , mutation in Fox , AIRE transcription factor these are genetic predispotions that can cause autimminue disease, other non-genetic are accidents that occur in the sites where immunological privlige is -lifetysle chocies that are made like malnutrition or smoking, all of which can have an impact of the immunity wheich can lead to autoimmune diseases -infections that can cuase uatimmune diseases and attacking the bdoy , lot of gene conservation between different species on of which is the mycobacterial heat shock protein so antibodies that are produced against the foreign antigen -autoimmune disease can have underlying mechaims that together can make an indivual more susceptible to immune auto dieases 6  Monogenic defects of immune tolerance Autoimmune polyglandular syndrome 1 Immune dysregulation, polyendocrinopathy, enerophathy, X-linked CTLA4 is an inhibitory receptor that is expressed after T cell activation and it competes with Cd28 for the ligand B7, this receptor prevents hyperactivation of T cells , FAS mutations death receptor which is required for homestatic purposes of immune cells after immune activation after clearance of antigens , if they do not have FAS they will not be cleared afte rthe immune recation efficiently and then those effector cells will cuase damage to the tissues -IL10 is immune suppresnat cytokine ar emuattions that are required for immune tolernaces when thosemechansimbreakdown autimmune disease breakthrough 7  Infectious agents can break immune tolerance and induce autoimmune diseases Mechanisms of breaking immune tolerance by pathogens Some pathogens express antigens that resemble host molecules, a phenomenon called molecular mimicry. Antibodies produced against a pathogen epitope may cross- react with a self molecule causing autoimmune tissue injury. Autoimmunity of this type can sometimes be transient and remits when the inciting pathogen is eliminated; e.g., autoimmune hemolytic anemia that follows mycoplasma infection. In other cases, the autoimmunity persists well beyond the initial infection; e.g., Rheumatic fever that sometimes follows streptococcal infection. Non-genetic factorsà infections Infections can induce immune reponses that can cause damage to the body and there are two mechaims that the pathogens can induce these breakdowsn and one of tehes is dispruptions of tissue barreiers and that camn relase antigens of the immune privilege site an dthose natigens are recognized as foreign bc they are neve ruspposed to be exposed even during thymus development , so when they are released the autrecative T cells will be actiaved and immune reponses against the natigens is created ex inb chart is antigens released form the eyes -molecular mimicry; some of the natigens in those pathogens will closely resemble self antigens ; antobpdies that can recognize ; this molecu;le can be seen for multiple other pathogens as well Rheumatic fever will cross recat with self antigens that are expressed in the hear, those antibodies while ar eproduced to fight infection they will also caus einflmmation to the heart and this is Rheumatic fever; some of tehse autimmune infections are tramnsisent and some willpersist and resolve after the infection is cleared like autimmune heolytic amenia which attacked red blood cells but once the infection is treated the new rbc will be generated an drepopulate, other ones that damage the heart like rheumatic fever will be more permenat and havce long term conseuqnces 8  Multiple components of the immune system are recruited in autoimmune disease Most autoimmune diseases are not caused solely by a single effector pathway. Similar to immune responses to pathogens, autoimmune diseases are caused by an integrated immune system involving both the adaptive (T and B cells) and the innate arms of the immune system. Both T and B cells, as well as effector cells of innate immune system, in particular the phagocytic myeloid cells, contribute to tissue damage in autoimmune diseases, even in cases where a particular type of response predominates. Based on the predominant immune mechanism, autoimmune diseases are classified into three groups: 1. Diseases caused by autoantibodies 2. Immune complex disease 3. T cell-mediated disease -very similar to regular immune recation with T and b cells and innate immunity, autimmuen didsease involve multiple components of the immune system some are main dirvers of the infection and other factors are playing accessory role, disease such as lupus the main antibody is pathogenic, contribution from T cells as well , autimmune can have T cells or B cells or a. combo of both -whether it is T cell mediated or humoral immunity these autimmune disease can be divided into three categories 1) Autoantibodies , 2) immune complex diseae 3)T cell-mediated disease- T cells directly are killing the cells or cuaisnginflammatory reponses that causes tissue damage in other organs 9  Autoimmune hemolytic anemia: autoantibodies against blood cells promote cell lysis Autoantibodies against antigens on the surface of red blood cells trigger their destruction of cells, leading to anemia. Both IgG and IgM antibodies are involved. RBCs with bound IgG and IgM are cleared from the circulation by interaction with the Fc or complement receptors on phagocytic cells. RBCs with bound antoantibodies can also be lysed by formation of the membrane attack complex of complement. Therapeutic approach: - Removal of spleen, the organ in which clearance of RBCs, platelets and leukocytes occur. - Intravenous administration of large quantities of nonspecific IgG (IVIG; intravenous immunoglobulin) to block Fc receptor- mediated phagocytosis of antibody-coated cells. Amenia is lack of rbc, hemolytciic is destruction of rbc and hemolytic amenia is both -autimmuen heolytic anemia; ther eis production of auto antibodies against antigens that are present on the surface of rbc, typically IgM or igG that can bind to rbc antigens, once binded they are opsonizing and recruit or actiovate colpliment factor sthat reusklt sin lyses of rbc or they can induce phagocytosis of those opsonized rbc -in the spleex for example when they run into oposnzied rbc they will pahgocytoiss and kill them -can induce destruction of rbcs and cuase anemia -removal of spleen, spleen is where rbc is removed, tehse cells that are opsonized the spleen is where they will be rempved or otherwise helathy rbc top prevent thjis pateints will ho through the removal of the spleen , the cell will tehrefor ebe healthy -another treatment of large quantites of immunoglubilins , if you infuse patients with large qunatites non-species ig those ig will go and bind to FC receptor of phagocytic cells and those receptors are occupied and that prvenets the Fc receptors to reocgnzie or bidn to the antibodies that are bound to the rbc , in a way you can interfere or block the inetrcation of ig recetpors ? 10  Graves’ disease: Autoantibodies against receptors cause disease by stimulating receptor function Absences pof the thyroid hormone can cuase or be associated with different pathologies -mechaims that control thyroid hormone , these organs hacve rceptors for another hormone called throid stimulatory hormone which can activate the gland to produce the thyroid hormone an dthat relase of TH will negatively effect the TSH and whne it reaches a threshold of it will negatively effect TSH an dstop producting TSH and the feedback suprresnat loop is important for mainting the right concentration of theyoid in the body and avoid hyper- thryopidism in the body -incase of diseae; there is autoantibodies against the TYSH receptors and these autoantibodies when bound to receptor will cause contiutive activation of the receptor, when the receptor is bund to the body the body think its TSH so it conutinously creates signals to produce more Thyrmoid hormones, even Th can ingibit TSH they will not effectuively repond bc the autoantibodies can bind to receptor to kepe the thyroid gland active this result in hyper-thryoidism 11  Myasthenia gravis: autoantibodies against receptors cause disease by blocking receptor function Myasthenia gravis results from the production of auto-antibodies directed against acetyl choline receptors (AChR) on the motor end plates of muscles. AChR blockade leads to progressive weakening of structural muscles and eventual death of AChR-bearing cells Patients with myasthenia gravis develop potentially fatal progressive muscle weakness. Removal of auto-antibodies by plasmapheresis, suppression of B cell activation with corticosteroids, and/or using cholinestease inhibitors to increase acetyl choline levels are used to treat the condition. -production of antibody agaisn a receptor present in a mcules tissue that result in neurotransmitters -neural msuclaulr junction, the info that is conveyed from neurons to meucles is through neurotranismmerts like acterylchloine ; regulate the iunfluc of Na and initaed contraction or rleaxtion of muscle ; antibodies gaianst tehse receptor scan block this cativity, they qre not causing activation in this case but here when tehese autoantibodies bind to receptors they will disprut the function an dcauses cells to interanalzie to endosomes and degrade the receptor sos ther eis loss of these receptors for neurotransmitters, preventing signmals form the neurons controlling the function of mcusles reuylsting in weakness of nmsucles and possible parlysis and fatal in some cases To treat this is to get rid of autoantibodies, filter plasma is through plasmaphereisi and the plasma will be fltered and returned bacl to pateinst and remove the autoantiboideis or corticalsterioids , immuospurresant drugs but reduces autoantibodies ; cholinstease inhibitors is another process that reduces produce of choline from nerves so you induc the neurons to produce more neurotransmitter swhich will ocmpoenate for the loss of receptors (like type 2 diabetes with insulin) and restore the function of the muscle 12  Goodpasture’s syndrome: autoantibodies against extracellular antigens cause inflammatory injury Autoantibodies are formed against IgG bound to glomerular basement the α3 chain of basement membrane membrane collagen. Autoantibodies cause glomerular damage in the kidney by binding to collagen in the basement membrane of the glomerular capillaries, causing activation of complement and recruitment of innate effector cells, such as monocytes and neutrophils. Influx of monocytes and neutrophil and their activation, as well as complement activation in the glomerulus cause tissue injury. G: glomerulus capillaries N: neutrophils M: monocytes Goodpastures effecst the function of kidneys and autoantibodies of collagene ? -collagen is one of the most abundant proteinin the body , major factor in the protein sthat are present in the extracellular matrix and helps with tissue intergrity and helaing and so in this case tehre are autoantibodie sthat are proecued agains the collagen of the glomeurla , which is the filtration unit in the kidney , glomerular is highly vascular and it is where you hace the filtration of blood , if you have damage to the glomueral you will have kidney damage, so in the case of goodpastrues sysndrome , tehse antibodies will bind to collagen and recuit activation compliment pathways which recruit other immune cells to the glomerular , in the purple picture it is a glomerular filled with immune cells and is not able to filter blood anymore hwihleads to kidney damage 13  Systemic lupus erythematosus (SLE): autoantibodies against soluble antigens Immune complexes are formed when there are antibodies against soluble antigens. Failure to clear immune complexes can cause tissue injuries. SLE is cause by either overproduction or defective clearance of immune complexes, or both. The main antigens are three types of intracellular nucleoprotein particles: (i) the chromatin, (ii) spliceosome, and (iii) small cytoplasmic ribonucleoprotein complex. SLE autoantigens are release due to extensive cell death coupled with inadequate clearance of apoptotic fragments. In such a scenario, B cells specific for chromatic components can internalize unmethylated CpG sequences, which are recognized by TLR-9, providing the co-stimulator signal for B cell activation and production of anti-chromatin autoantibodies. Deposition of large amounts of immune complexes in the walls of small blood vessels in the renal glomerular basement membrane, joints, and other organs, cause activation of phagocytic cells and tissue injury. Ig deposits in the basement membrane Systemic lupus ; antigen is the nuclear protein particle, in our clels we have mnucleic acid DNA and RNA and DNA is packeaged with histone proteisn and RAN is associated with different poprteisn and ribonucleic proteins, these nucleic porteins compelxes can act as autoantigen if they are rleases in large quantities , necrosis can release chromatic or ribonelocportien and those antibodies when they bind to these nucleic proteicn complexes they will induce the foluble complexes that can be deposite din different organs like the kindyes when fine capillaries and filtration of blood an dit is in those site sthat immune compelxes are deposited and then they can induce an inflammatory response, damaging the function of the glomerular and damage to the kindey -these immuncomplexes can be deposited in the joints and that can cause artheretis 14  Type I diabetes: T cells-mediated destruction of pancreatic β cells Normal pancrea Diabetic pancrea Glucagon (α cells) Glucagon (α cells) Insulin (β cells) Type one diabetes is a autoimmune dieseae that involeves cytotoxic T cells , the normal functioning of the pancease is to produce hormone sinclduing insulin to regulate blood sugra, in normal people our metabolism can get rid of excessive sugar and convert it to other ofrms that can be stored, in diabetic patient witjou insulin they cannot form the same functions, in diabetes type one an dtwo -typoe one is autimmune reponse where type two is not autimmune -killsteh cells that produce insuline like beta cells in the pancrease, different cells in the pancrease , cells tht produce insulin are no longer present , typ eone diabtes lack beta cells but alpha and gamma cells are still present 15  Multiple sclerosis (MS): T cell-mediated neurologic disease Multiple sclerosis (MS) is caused by demyelination of central nervous system tissue, leading to progressive neurologic dysfunction, such as muscle weakness, blindness, paralysis, etc. Few lymphocytes can cross the blood-brain barrier, but if this barrier breaks down, autoreactive T cells can enter the brain where they encounter myelin antigens presented on MHC class II by infiltrating macrophages or microglial cells. Autoreactive TH17 cells specific for myelin basic protein produce cytokines that attract and activate macrophages that damage the myelin sheath of nerve fibers. Autoreactive CTL, autoantibodies, complements and cytokines are also involved in the pathology of MS. Environmental factors such as lack of immunomodulatory vitamin D may be linked to MS development. Multiple sclerosis effects the nervous system and is mediated by T cells and result in detah or destruction of neurons , this is an autimmune disease -MS is demyelination of the central nervous system, myelin sheath is present in neurons and it is important for the function of them, the portectivemyelin sheath allows transmission of signals which is why MS patient shave weakened muscles and so on, these rxns through demyselination is cause dby immune reponse againats myselin basic porteins , brian is a immunological priveleige site but there is a breakdown of the blkood brian barrier causing immune cells to infiltrate into the brain, the only immune cell sin the brain are microglia and are important in function to portect the brain and detect antigens so when infklitatration of T cells occur these macrophages will present to T cells and the cd4 T cells will become activated and they can differentiate into Th-17 cells bc of conditions that allow tehm into pro-inflammatory helper T cell and then they induce an inflammatory immune cell to bring in other immune ceklkls to the site and induce B cells an dantiboduesagaianst myelin basic porteins and degranulate and cause an inflammatory response causeing an attack on the myselin sheath of the neuron eventually comproniming the function of the neuron and lead sto MS 16  Rheumatoid arthritis (RA) is cause by the inflammation of synovial membrane Rheumatoid arthritis (RA) is characterized by chronic inflammation of the joints due to granulocyte/monocyte infiltration, cartilage/collagen destruction by hydrolytic enzymes, fibrin deposition and joint fusion. RA is caused by immune mechanisms involving T cell, B cells, and effectors of the innate immune system. B cells produce autoantibodies of the IgM class (rheumatoid factor) that react with the Fc portion of self IgG. The resulting IgM-IgG immune complexes deposit in the synovia of the joints where complement is activated. RA has an association with a particular MHC class II (HLA-DR) gene, suggesting involvement of CD4 T cells. Activated TH17 cell in the inflamed joints produce cytokines to recruit neutrophils, monocytes/macrophages, which can produce more inflammatory cytokines. Therapeutic antibodies against TNF-α, B cells, and T cell activation have all been used to treat symptoms of the disease. RA is a disease that effects the joints, bc there is immune reponse on the joints and the fluids/tissue sof the joint causes infmattion to occur and limits the movement of the joints , it involvcesnatibodies that get deposited in these joints and recruitment of T cekks to tehse joints , that involve smultiople compnents of the immuje system -cause sinflmattion of the joints -the space between two bones contains cartilage to prevent the bones form direct contacta nd fluid for lubrication so that bones can ove, when cartilage an luid are worn down then direct contact occurs an dthis is very painful bc movement is not as free, this is damage to the joints and called RA -one of the natiboides or factors in RA is immunolgulbin that is profuced against self igG called Rheumatoid factors which attack the IgG of thje person , autrecative B cells with rcepetors and produce antibodiue to bind to igG and formigM-igG complexes and these complexes get deposuited in tehse joints and causes damage to the cartilage -MHC2 HLA-DR gene, this specific allele are mor eprone to develop RA; most people with this allele will develop RA; typically cd4 T cell reactiona nd causes inflmatory reponses with TH-17, by lowering inflammation less pain and is tereatmenet for RA, suppress T cells or B cells with corticoids to prevent immune reponse for famage to the joint 17  Autoimmunity and Transplantation Graft rejection Janeway’s Immunobiology, 9th edition Different mHC haploid time, different antigens will trigger an immune response that will atack the graft 18  Graft rejection Graft rejection is an immunological responses mainly mediated by T cells, but antibodies also play a role in graft rejection. Graft rejection may occurs depending on the type of graft: - Autograft: Grafts between different sites of the same animal or person – no graft rejection - Syngenic graft: Grafts between genetically identical animals or people – no graft rejection - Allograft: Grafts between unrelated or allogeneic members of the same species – graft rejection - Xenograft: Grafts between members of different species – graft rejection Mainly mediated by T cells , it is an adoative immune reponse that imvolves T cells mainly -the rejection depends on where the grafted tissue comes from, donor type and organ transplant can be divided into 4 classes; autogroah, syngeic graft, allograft and xenograft -autgraft- is treansplant tissue from one type of the body to another part of the body such as a skin graft or bone marrow graft , these are coming from the same person or snmail it is typically not rejected because it is the same mHC makeup -syngenic graft; tehse rea grafts between organism that have identical genetic makeup between two individuals with the exact same genetic makeup , such as identical twins and thse swill not result in rejection bc the immune system of the recipient will see the graftas a self bc of the same mH makeup due to the genetic simialrty between the receipent and donor -allograft is the most common type of grafts, two members of the same species such as two humans one as a donor and receipent and this deos trigger an immune reponse between the polymer of the mHc locus ; tow inidivuals are not the same (not twins); alloreacitivut is the recation against polymorphism again alloreactive T cells which if it is not treated with immunsuppressant drugs or tissue tyoing then it will result in rejection of the grfat 19 -Xenograft almost always sreuslt in the a graft rejection it is from organs of a different species (pig aorta in a human heart) -most common graft is the allograft 19  Allograft rejection Antigens that differ between members of the same species are known as alloantigens, and the immune response against such antigens is known as an alloreactive response. Approx. 1-10% of T cells in an individual are said to be alloreactive, i.e. they will respond to stimulation by cells from another, unrelated, member of the same species due to the recognition of allelic polymorphism in MHC molecules. In most tissues these are predominantly MHC class I. MHC matching of recipient and donor may prevent or slow down the transplant rejection process. Accelerated Accelerated No rejection Acute rejection rejection rejection -allografts differ oin the MHc molecules and makeup as well as other antigens, the antigens in the allograft are alloantigens and they trigger an allogenic reponse which is mostly mediated by t cells , this is mainly against the different MHC molecules that they do not recognize as itself -not recativing acgaint the natigens but against the MHC mlecules intsefl -it can be up to 10% of T cells that are activated gaiants this new MHC molecule -this is a large numbe rof cells , 10% of all T cells getting acrivated gaianst a grafted tissue, massive immune reponse 9very hard to control or prevent) -MHC matching is therefore so important , when a person is waiting for an organ to receive an organ theyw ill undergo a lot of blood test and will get their MHC tyoed an dtehy will wiat to find an appropriate organ that isa close match to their own, whenever an orgna becomes available their MHC reulst are compared to see which ones are the clostest match and which patient has a better chance of accepting that organ or survival of that organ , this is to prevent the allorecartive T cell reponse , tehre is no such things as 100% MHC match even if that is what appears there is still management techniques with immunodurgs that are needed to control this organ transplants accapetnacve transplant between allogenic inidivcuals , with different MHC (a or B) (seond panel) this will response in an allo reponse wich results in rejection of the grfat 20 u, T cells must be activated , takes about a weke or two for this to occur -after this first rejection the cativated T cells will differentiate into memory t cells so if a second skin gradt is done that will result in much stronger an d faster rejection, usually in one week they woill reject the grfated skina nd this is because eof the memory reponse from the first transplant -creates a memory reponses bc if you take T cells from the mouse that already had an alloreactive T cell and put it into a naïve mous (inject T cells) then the naïve T cell regardless sof neve having a graft recats extremely rapidly to a skin grafta dn rejects it almost immediately , this porve sthat memory t cells are present \ 20  Even completely MHC matching does not ensure allograft survival In MHC identical grafts, rejection is caused by immune responses against peptides from other alloantigens due to differences in other genetic loci. These are called the minor histocompatibility (minor H) antigens. Graft rejection due to minor H incompatibility occurs slower than the rejection of MHC-disparate grafts. Self proteins are routinely processed and presented as peptide:MHC class I complexes. If a polymorphic protein defers between the graft donor and the recipient, it can give rise to an antigenic peptide that can be recognized by the recipient T cells as non-self. Even identical MHc matching tehre rae some genetic differneces that wuill result in rejectiobn of rthe grfat, this is usually much weaker then alloreactive , -minor H antigesn , this is generally a much weaker recation and results in a delay rejection such as 60 dya sincomaprison to the 10 days -this rejection is mediate dby other natigens these are sene as foreign and are presented to the T cells of the rceopnets that they can recognize bc the MHc are matched and whatever antigens rae presented on the donor tissue they can be reocgnzied by the T cells of the recipient an dtat can trigger their activationa nd immune reponses 21  Presentation of alloantigens to the recipient’s T lymphocytes Two ways of presenting transplant alloantigens to the recipient’s T cells: 1. Direct allorecognition – Antigens are presented by APCs of donor origin also called passenger leukocytes. Donor APCs leave the organ graft and migrate to secondary lymphoid tissues of the recipient where they can activate host T cells. Migration of the APCs occur via the blood and not the lymphatics. 2. Indirect allorecognition – Uptake of allogenic proteins by the recipient’s APC and their presentation to T cells by self MHC molecules. Indirect allorecognition contributes to the development of an antibody response to a graft. Antibodies produced against alloantigens are called alloantibodies. T cells have to make it to the secondary lymphoid tissues , how are these antigens presnete dto t cells to activate them?- two ways -graft associated natigens one way is through the antigen presenting cekkls that ae present in the grafting tissue move out of the graft when the blood supply is stored after transplantation, and they can travel to the secondary lymphoid tissue to activate T cell , this is direct allorecognition; presnt in the donor organ., wbc like dendtric cells are present in tiusues so when we take a =kidney, lung or heart this will contain tissue resident lymphocyte sthese rae passenger lymphocytes and are crrie diwth the donated antigetns and once the blood flow is restored in that organ the dendritic cells and [resnt them to the T cells of the host an dteh MHC are jmatched so that alloreactivity is prevented -once the host T cell sare cativated and create effector cells they will levea the lymphocyte sna dmediate the killing of the organ/ -the second is indirect alloreacognition- mediated by antigens that make it into the secondary lymphoid tissue, once blood flow is restored leukcocytes will pick up antuigens and transport them pakc to ethe lymphoid and cative T cells and some of thses can even trigger B cellre ponses and they do not need antigen presentation by dnetdric clels , indirect is therefore alos reponsibile for stimulating alloreactive B cellks which will produce antibodies -host T cells and B cells are activated agiants the natigens of the tissues 22  Antibodies that react with endothelium cause hyperacute graft rejection Existence of pre-existing alloantibodies against blood group antigens or polymorphic MHC can cause rapid rejection of transplanted organs. Alloantibodies can bind to antigens on the vascular endothelial cells of the graft and initiate the complement and blood clotting cascades, causing blocking and destruction of blood vessels and hemorrhage in the transplanted organ. This reaction is very rapid and can occur within minutes of transplantation, hence called hyperacute graft rejection. This problem can be avoided by cross-matching donor and recipient to determine whether the recipient has pre-existing alloantibdoies. T cells are mainly responsible for rejection of allo graft , but antibodie scan be very destrivtc as well, especially if the inidivual already has antibodies against antigens present in those grfated tissues -if tfor example a person who is receivihgan organ but in the past has rceieved blood transfusion that has the same blood group of the donor, tehynow already have had a rectaion to the blood group type an dprefoirmed antibodies agains the antigens and these are not jusrt expressed on rbc but other tissues like epithelial cells (blood vessels), so when they rceieve the organ and blood flow is restore dthe natibodie sthat they already have in their system they will immediately start to attacke the epithleila cells of the blood evessles that are supply the blood and that leads to an inflmatory repons and compliment activation occurs and formation of blood lcotting that blocke stehse vessles in the grafted tissues which can trigger to hyperacute graft rejection 9occur siwthin minutes afte rblood supply is restored0, -test the receipent beforehand to make sure this doe not happen, take the blood form the donor and mix it from serum from the recipient tpo see if tehre was a rcetion of antibodie sin the serum of the recipient to see if the recipnet already has the antibodies an dthen if they do you need to treat the recipient to get rid of pre-existing natibodie sin their circulation prior to the porgan transplant 23  Chronic graft rejection A major component of late failure of transplanted organs is a chronic reaction called chronic allograft vasculophathy, which is characterized by concentric arteriosclerosis of graft blood vessels, leading to hypoperfusion of the graft and its eventual death. The major cause is thought to be recurring, subclinical acute rejection events due to the development of alloantibodies against the graft vascular endothelium or alloreactive effector T cells. Always need immunsupression to prevent organ rejection even with the best MHC mapping that is done there will always be an immune recation from the donated organ There is always an immune reposne against the graft tissue bc of the contimous presence of the antigens-low clinical subclinical immune reaction that is not amn acute recation of the organespecially blood vessels bc of scarring which rruelst in thickening of blood vessels an dcontrsictingand tehn reduces the flow of blood an dthethickeing of the blood vessel is caused by infilatration of antibodies from scarring and is called arteriosclerosis -this is achronic grfat rejection Check recording 24  The converse of graft rejection is graft-versus-host disease Graft-versus-host disease (GVHD) is a major complication of allogenic bone marrow/hematopoietic stem cell (HSC) transplant. GVHD is caused when mature donor T cells present in the HSC preparations recognize the tissues of the recipient as foreign, causing a severe inflammatory disease involving many organs, in particular the skin, intestines and liver. Strict MHC matching between donor and recipient, and the use of immunosuppressive therapy is recommended in every HSC transplant to prevent graft rejection, as well as GVHD. In. atransplant setting -iimmune reponse mediate dby passenger immunocytesl, converse of the graft rejection this graft vs host reaction -luekcyte sthat are presne in the grfat will be activated again the antigen sof the rceipnet an dwill move to different organs and site of te body and strat to cause dmagaed ot the host tisues, very common in m=bone marrow transplant paitients , therefore you need ot dpelete T cells of the bone barrow before the hemtaopoeitic stems cells rae transplantsed but the patients that rceeiev bone marrow will receive treatments that get rid of their own defective immune cells but theseoateints rae extrenley immunosurppresent during their transplant so when they encounter rtheir antigehs that they reocgniz ethey woill be actuivted ns cause inflammatory reponse sin other organs which can effect the skin, intestine, liver etc and can make the patient extremely sick -to prevent this you need strict MHC mapping and immunosuppressant therapy ; to not only prevent rejection but to lso now prevent grfat vs host diseases 25  Immunosuppressive therapy (FTY720) Immunosuprressive durgs, these are not only used for the grfat transplant but for different disease that have inflammatory underlying costs such as srthertus , one of the nmost coomon is corticosteroids for allergiues, artherius etc Otehre drugs effect other pathways used for activateoon of T and B ceklls; interfering with signal receptors or co-stimulatory isgnals and downstream cytokines -proliferation , cell cycle inhibitors , activate din the secondary lymphoid tissue 26  T cell targets of immunosuppressive drugs T cells are the main cells that mediate the target of immunosuppressant durgs, tehre are many classes of these immunosupressory that effect different signals for T cell activation; durgs that effect CD3 (activation signals) , then tehre rae durgs the effect the co-stimulatory signals which is essential for survivala nd differentiation therefore prevent activation (IL-2), durgs that effect downtrseam signalling pathway sof receptors like ilk-2 receptor signalling , and cell cycle can always be inhibitied (proliferation) they will inhibit T cell activation -all of tehse drugs can prevent organ or tissue rejection mediated by T cells Just need to know the tragtes 27