13. Transplant Rejection Flashcards
TRANSPLANT REJECTION • Organ transplantation has emerged as a key treatment for patients with end-stage organ disease – \_\_\_\_ donor grafts – \_\_\_\_ grafts • Types of grafts: – \_\_\_\_ – Isografts (syngeneic graft) – \_\_\_\_ (allogeneic, homograft) – Xenografts (heterograft)
• Classify tranplsants based on relationship bt donor-recipient: ○ Cadaverous - coming from deceased indiviudal - can provide any \_\_\_\_ ○ Living - \_\_\_\_ organ range - common grafts: kidney, bone marrow • Further characterized by antigenic and genetic relationship bt donor-recipient ○ Autograft - donor and recipient are one and the \_\_\_\_; i.e. skin (burn victims, labs will harvest skin from victim and grow new sheets to transplant back on individual), bypass surgery (coronary bypass, BV from legs to heart); never immunologically \_\_\_\_ (if it doesn't work - it's bc of \_\_\_\_ complications [typically infection]) ○ Isograft - bt two individuals that are genetically \_\_\_\_ [twins]; not immunologically \_\_\_\_, but rarely can be rejected; don't require immunlogic \_\_\_\_ (along with autografts) ○ Allograft - most \_\_\_\_, bt donor/recipient of same species; most transplants are allografts [geneticlaly and antigenically not identical]; also referred to as allogeneic and homografts ○ Xenograft - largest pool of donor tissue (bt \_\_\_\_ species); more \_\_\_\_, have been some successes where tissue from pig/other animal is used temporarily to keep a patient going when an organ failed and human tissue is unavailable; an active area of research; these grafts are almost always rejected without major \_\_\_\_
living
cadaverous
autografts
allografts
organ limited same rejected surgical
common
diff
experimental
intervention
Registered U.S. Patients Waiting for Transplants
• 35,000 transplants/year in the US • \_\_\_\_ is the most common transplant, followed by liver, heart, lung, combined kidney/panc, panc alone, and then small intestine, and \_\_\_\_ ○ Numbers are dictated by \_\_\_\_ of the end stage organ disease (renal most common), as well as with \_\_\_\_ of tissue • Number of transplants in US from 1990-2015 has \_\_\_\_ over time (holding at 35,000 currently) • Number of donors available regardless of organ at any given time - 16,000 • Number of patients waiting for transplant - 120,000 • Disparity bt the number of patients who require, and th enumber of donors available ○ Having a donor being availble to donate doesn't make the tissue sutiable > it has to match the needs of the recipient (antigenic/genetic match, which is difficult to attain) • End stage organ can be surgically readily treated if organs were available and if tissues did not reject tissue • Table shows breakdown of patients waiting for donors by organ
kidney heart/lung commonality availability doubled
Transplant Rejection • Major histocompatibility antigens – Requires \_\_\_\_ typing • Minor histocompatibility antigens – Difficult to \_\_\_\_ • Blood group antigens – ABO – Typing is performed
• 1 year survival for all organs: 90% - highest: 97% \_\_\_\_, lowest: 85% for lung - indicates that surgical expertise is not the issue! • Problem in 3-5 years - organ survival falls down - 5 years: 25% heart, 25% liver, 90% kidney, and 50% lung survive - something is happening here! The graft is being rejected by immune system • What is immune system responding to? Early on is the \_\_\_\_ antigens, but after the intiail attempts of transplantation, it was found that all transplants do not cross blood group barrier > limit in terms of blood groups; generally, do not cross ABO barrier, and easily is attained by tissue typing [confusing!] • Group of antigens - minor HC - drives immmune response; only minor bc we don't know much about them; but some of minor have been classified as major, eventually will be defined, drive immune response just like \_\_\_\_ HC • MHC - proteins encoded by MHC - encode for proteins expressed on cells > play primary role in \_\_\_\_ activation > through MHC restriction > CD4 cells require anitgen be processed and expressed in context of MHC\_\_\_\_; CD8 cells requrie antigen processed and expressed in context of MHC\_\_\_\_ That's why Immune-regulatory genes and proteins evolved - did not evolve as targets for \_\_\_\_;
tissue type kidney blood group major T-cell II I rejection
Transplant rejection
• Transplatn rejeciton is a product of modern medicine; unfortunately HLA antigens (first discovered on lmypho’s, as a component of the response against transplanted tissue in animals) > primary function: T cell activation > discovered as histocompability targets
• Two major classes of MHC genes > class I (divided into ____ loci > HLA-A, B and C); on graph, breakdown of chromosome ____ > there are other classes of HLA:
○ E,F,G groups do not worry - minor category
○ A, B, C - major, only focus on these
○ Class I proteins > located on all ____ cells
• Class II MHC proteins > one loci: ____ > now divided into subloci, but we’re gonna treat as one loci
○ Class II expressed on ____ (dendritic cells, antigen-presenting macro’s in the lymph nodes, most ____ will express)
• Each gene encodes for protein, these are ____ genes (one from each parent and both are expressed) > so every cell in the body expresses at least ____ of these proteins (A, B, C), and if APC they express 2 more (class II) > all ____
• Class I/II - ____ proteins > extend out of PM into external environment
• Class III (in textbook) - genes that exist bt I/II on chromosome; encode for cytokines, complement components (____ proteins, non-PM, not ____ but important for immune response)
3
6
nucleated
HLA-D
APC
macrophages
codominatn
6
8
memrane/structural
non-structural
histocompatibiilty
HISTOCOMPATIBILITY MOLECULES
• MHC; HLA
• Originally identified as antigens responsible for graft rejection
• Principle role in ____ activation (MHC restriction)
• Types:
– Class I MHC (heterodimer w ____)
– Class II MHC (____)
• Genes: MHC; proteins: HLA; textbook uses interchangeably • Primary function: T-cell activation • I > two peptides that transcend plasma membrane ○ Contain \_\_\_\_ microglobulin • II > two peptides (\_\_\_\_ chain) • Both have pit where present proteins to lymphocyte • Targets of immune system ○ Problem: each inherits 2 genes at each loci, but within human pop there are 100's of genes/alleles you can inherit from > HLA-A locus (200 alleles in human pop); B has over 400; C has about 100; Class II MHC > several hundred ○ 4 loci, 2 genes at each loci > hundreds in the pool > lots of combinations (millions) > why we are \_\_\_\_ immunologically (at max share maybe 2 of out 8 loci between ourselves) > the odds of finding a donor-recipient match at any loci is slim • Heard about MHC in 3 contexts: role in \_\_\_\_ activation, inheritance of HLA genes as increasing risk towards \_\_\_\_ diseases which may be due to how MHC regualtes immune system and how certain genes contribute to auto directed response, could be bc they're transmembrane proteins > may serve as receptors for \_\_\_\_ pathogens; and origianlly discovered as targets for \_\_\_\_ rejection
T-cell beta-microglobulin heterodimer alpha/beta alpha/beta
diverse T-cell autoimmune infectious graft
HLA inheritance
• Lots of genes can be inherited • HLA-A > green; HLA-B > yellow, and so on • Each set of genes exists as a haplotype - group of genes inherited \_\_\_\_ • Number in each box represents 1 of 100's of genes that exist in each poopulation • Left pairing: female; has haplotype little a that has a gene for HLA-A, B, C and D that was derived from one parent, and another haplotype (b) from another parents ○ These genes will be diff from each other ○ Has two haplotypes that encode for 2 A genes, B genes, and so on • Right: male also has two haplotypes (here, c and d); at each loci, has a gene where he inherited one haplotype from one parent and one from the other • In box is the different genetic outocmes for a child: ○ Can be ac, ad, bc and bd ○ Odds of two siblings be HLA identical > \_\_\_\_%; chance of two siblings have no HLA identiy > \_\_\_\_% (just bc you're related, you can be identical or non-identical); \_\_\_\_% chance that you share one haplotype (not good enough for a HLA match) \_\_\_\_% that you can serve as donor, and \_\_\_\_% there's no chance at all, and \_\_\_\_% it's still highly unlikely
together
25
50
25
25
25
50
HLA inheritance
* Relationship bt mother-child and father-child is that you share \_\_\_\_, but you're not identical * Look randomly through population > very \_\_\_\_ population due to this concept! * Making it even more cumbersome > co-dominant genes > each gene will be expressed and will be expressed on surface of cells making every \_\_\_\_ a target * Combined problem of inheriting these haplotypes > diversity of human population makes a match bt donor and recipient v rare/difficult > goal: minimize rejection > both haplotypes of recipient should match two haplotypes of the donor (rare!); most transplants will go forward with \_\_\_\_ identity (which is why transplanted tissue is rejected)
haplotype
diverse
cell
parallel
Determining HLA compatability
READ THE BOXES!
• Showing that the cells will express both genes on surface, and they must be identified • In order for tranplsant > donor/recpieint have to be \_\_\_\_ typed; origianlly was done \_\_\_\_ (for all 100's of diff genes that encode for all diff proteins, we have immunologic reagents/ab's that differentiate and recognize each loci) ○ Prior to transplant, lympho's and serum from donor and recipient put into micro-titer wells, and diff ab in each well > if it bound and detected via fluoreenscne > sera that reacted identified the \_\_\_\_ protein that was being expressed > looking for ab that recongized the same antigen in both donor and recipient (2 for each loci, so you needed at least \_\_\_\_) ○ This could only be done for HLA-A, B, C, did not exist for \_\_\_\_! • HLA-D typing > used \_\_\_\_; D antigen, if disparity here > triggers lympho's to \_\_\_\_ rapidly > so lympho's from donor and recipieint obtained > either donor/recpient treated with drug so can't \_\_\_\_ (not dead!), both cell types mixed, if identity > there would be \_\_\_\_, and if non-idenfity > they would \_\_\_\_ ○ Would take a \_\_\_\_ to tissue type a donor and a recipient > problem, bc transplanted tissue is not sitting > come in following sudden death of donor and tissue can only be kept alive so ong • Today most typing > replaced by \_\_\_\_ assays that can be done rapidly > gene sequencing that region of chromosome 6 for those loci
tissue
serologically
HLA
6
D
MLC
proliferate
proliferate
no proflieration
prolfierate
week
molecualr
Types of Graft Rejection • Hyperacute rejection: occurs \_\_\_\_ – Due to \_\_\_\_ antibodies to HLA and ABO • \_\_\_\_ women • Previous blood transfusions or grafts • \_\_\_\_
- Acute cellular rejection: occurs within days to weeks – Primarily ____ response
- CD4 T-cells, cytokines, macrophages, CTL – controlled by ____
• Acute humoral rejection (____)
– ____ react against endothelial cells
• Chronic rejection: occurs months to years post-transplant – CD4 ____, cytokines, macrophages, CTL, ____
• Goal to identify a donor-recipeint pairing that are identical at each loci for 4 genes • Full identiyt is rare - so transplants go froward with partial identity ○ Early years, only required that \_\_\_\_ loci match with partial at A, B, C (bc D was such a stimulating antigen that would promote rapid rejection, but not entirely true now…) ○ Judgement based on which specific loci the donor/recpieient exhibit disapairty and the antigenic relationship bt those ○ If patient is not treated > organs will be rejected • Middle box (acute rejection) - shows that mediated by T cells/ab - but mostly a \_\_\_\_ event; only place where ab plays a role > \_\_\_\_ rejection and \_\_\_\_ rejection (this is experimental rejection involving xenografts); this rarely occurs, bc in addiotont to typing recipeint cells, and serum is typed for presence of \_\_\_\_ ab Chronic rejection is also \_\_\_\_ mediate
immediately
preformed
multiparous
anti-isohmeagglutinins
T-cell
immunotherapy
xenografts
antibodies
T-cells
fibrosis
D
T-cell
hyperacute
acute humoral
anti-HLA
T-cell
Hyperacute Rejection
• Primary target: HLA class ____ on vascular endothelial cells
• Immediate
• ____ and ____ mediated
– Destruction of ____ cells (vasculitis), edema, and local hemorrhage
– Activation of ____ - thrombotic occlusion
• Organ becomes ____ and hemorrhagic
* Primary target: HLA antigens on eodnthelium of transplanted organ > occurs in indiviudals with \_\_\_\_ ab's due to prior exposure of HLA * As soon as blood supply restablished; ab from recipient binds immediately to HLA antigens on endothelium > actiavatest complement > lysis of endothelium, attract PMNs > endothelial are destroyed by a \_\_\_\_ (not immune complex bc anitgen is \_\_\_\_ to cell), edema bc of destruction of BV, \_\_\_\_ lesion (kidney, top left), lumen of BV is occluded due to activation of coagg system (top right) > blood isn't perfusing in transplant, the trnaplsnat doesn’t take > organ fails (within hours it's dead) * Bottom left > kidney > hemorrhage in glomerulus, blood in tubules; bottom right > immunofluorescne showing presence of ab lining endothelium (type \_\_\_\_ reaction: regular/homogenous staining bc the antigen is uniformly deposited on endothelium) * Rarely a problem bc of \_\_\_\_ of cells and serum for the presence of these ab's
I antibody complement endothelial coagulation cyanotic
preformed
vasculitis
fixed
hemorhagic
II
pre-typing
Acute Graft Rejection
• Occurs within days to months or years (w/IS)
• Mechanism of rejection:
– ____ T-cells respond to Class ____ MHC:
cytokines, macrophages
– ____ T-cells respond to Class ____ MHC
– Ab?
• Histopathology: – Interstitial infiltrate of \_\_\_\_ cells – Edema – Interstitial hemorrhage due to \_\_\_\_- mediated endothelitis • Normally responds to \_\_\_\_ therapy
• T cells responding to disparities in Class II MHC > CD4 response that will result in cytokine/macro accumulation and these enzymes will damage the organ; if class I > CD8 cells (including CTL that kill target cells) • Ab > textbook refers, but primarily from experimetnal results with xenografts • Will look like \_\_\_\_ immunity/\_\_\_\_: ○ Reads list ○ Lesion attacks endothelium bc it's the first thing the immune system sees > endothelitis due to \_\_\_\_ cells attacking the edoliteium • Normal immune response; the grafted organ (antigenic debris) ends up in the recipeint's immune system (sometimes may be dnedtritic cells in trasnpalnted organ that migrate outa dn activate immune system in recipeint's lymphoid tissue) > immune response generated > \_\_\_\_ come on scene and carry out effector mechanisms
CD4
II
CD8
I
mononuclear
CD8
IS
cell-mediated
DTH
CD8
T cells
Acute Graft Rejection
- Tissue is not as striking: not as ____; more subtle reaction
- Top right - advanced stage - mononuc infiltrate > destory glomeruli and ducts
- Bottom right > invading cells are T and macro’s
- Middle left - earlier stages, destrution of ducts, starting to compact; atrophy of the ducts due to mono nuc infiltrate and action of T cells
- Bottom left - destructio of BV endothelium > endothelitis
- Histopathology: Intersitial mononuc infiltrate, organ is edematous, and some hemorrahge but not as extensive of hyperacute
- Any ____ all looks the same following rejection (rejection of liver, heart etc. will all look the same microscopically)
hemorrhagic
tissue
Chronic Rejection
• Chronic rejection: occurs months to years posttransplant
• – ____ T-cells, cytokines, ____, CTL
• Histopathology: – Vascular pathology • Intimal \_\_\_\_ muscle proliferation, extracellular matrix synthesis and \_\_\_\_ leads to obstruction and \_\_\_\_ – Cellular infiltrate – \_\_\_\_ fibrosis
- ____ loss of function
- Does not respond well to ____ therapy
- Occurs after many episodes of acute rejection
- Due to long term waxing/waning: episodes of immunologic activity towards transplanted organ
- Due to disparities of HLA patient becomes refractory to immunosuppressive therapy; over years, if new regimens don’t work and immune system breaks through > you get acute rejections reuslting in chronic rjeection
- Hallmark: major changes at ____ and at intersitum of organ > ____
- There will be celluar infiltrate (mononuc, like acute) but more severe
- Lumen becomes ____, due to thickening of blood vessel wall due to inflam cells and action of cytokines on Smooth MC so the intimal cells proliferate > additional produciton of ECM > eventually, BV become fibrotic and non-functional > perfusion is a problem
- Parenchymal tissue > becomes fibrotic (collagen deposition) > collectively, results in a loss of function
- Chornic is not responsive to immunosupressive therapy; happens after IS therapy/therappeutic approaches have been exhuasted
CD4 macrophages smooth fibrosis ischemia interstitial
progressive
IS
vasculatutre
fibrosis
compromised
Chronic Rejection
* Top left - relatively normal, but the bottom left part is \_\_\_\_; top right - almost entirely fibrotic * Bottom left - BV, changes in \_\_\_\_ muscle cell prolif, deposition of ECM, and eventually the lumen is compromised > disappears (right) and fibrotic * Recognize difference bt hyperaccute, acute, and chronic
fibrotic
smooth
Graft vs. Host Disease (GvHD)
• Complication of ____ transplants
– Rarely occurs with ____ organ transplants: few
immune cells contained in solid organs
• Occurs days - weeks following transplant; involves
epithelial cell ____:
– Skin and mucosa—–rash (often desquamation)
• Patchy epithelial cell death; mononuclear cell infiltrate
• Oral>80% exhibit lesions (fine ____ network of white striae; similar to oral ____): tongue, ____ and buccal; histopath similar to LP (____, short and pointed rete ridges, degeneration of basal cell layer; less intense inflammatory response
– GI tract–bloody ____, nausea, vomiting
– Liver—destruction of bile ducts leads to
____ and jaundice
– Lung-interstitial ____
• Mediated by ____ T-cells and ____ derived from ____
• This is rejection in reverse ○ When lymphos within trasnplatns \_\_\_\_ reject the \_\_\_\_ ○ Hyperacute,acute chronic - lympho's from recipeint is rejecting the organ • Today only seen as complication of BM transplant, bc most of solid organ transpatns don’t' contain enough lympho's, or sometimes treated with low levels of irridation to keep low levels of lympho's from proliferating • Cancer of bone marrow, irradiate patient and treat with chemotherapeutic agents, and then you give them fresh bone marrow ○ Before, did it from recipient-donor; today, try to do it as an \_\_\_\_ but doesn't always work • But when donor-recipient are antigenitcally \_\_\_\_ tGvHD is a real problem! • Most exmaples of GvHD > \_\_\_\_ sof epithelial cells due to immune repsonse against the recipeient (still an HLA disparity) > skin, intesinte, liver and the lung
bone marrow
necrosis
reticular
lichen planus
labial
hyperorthokeratosis
diarrhea
cholestasis
penumonia
CD4/CD8
NK
donor
tissue
host
autograft
dissimilar
necrosis
