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79 Cards in this Set
- Front
- Back
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What are the 3 different kinds of grafts?
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Autografts
Allografts Xenografts |
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What is an autograft?
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Graft from the same person
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What is an allograft?
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Graft from the same species
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What is a xenograft?
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Graft from another species
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When was the 1st successful cornea transplant?
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1905
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When was the 1st successful kidney transplant?
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1954
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When was the 1st successful liver transplant?
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1967
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When was the 1st successful heart transplant?
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1967
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What is the most common transplant?
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Kidney
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What ia the most expensive transplant?
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Heart
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What is the problem with allotransplantation?
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Limited by the availability of human organs
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What are some alternative sources of organs and cells?
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Xenotransplantation
Stem cell technology Human cell lines |
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What is xenotransplantation?
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Transplantation of organs, tissues or cells between species
This includes: 1) Solid animal organs 2) Live animal cells 3) Animal cells or organs for the use of medical devices (i.e. extracorporeal liver perfusion) |
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What are the potential advantages of xenotransplantation?
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-Provides an unlimited and predictable organ supply
-Allows for advanced planning and elective surgery -Allows for immunological pre-treatment -Organs are harvested at the time of requirement -Breeding specific pathogen free (SPF) source animals -Pre-screening organs fr infection prior to harvesting |
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When will xenotransplantation be used?
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When no other options are available
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What were the first species used for xenotransplantation?
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Chimpanzee
Baboon |
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When were pigs first used for treansplantation?
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1992
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What is the problem with using non-human primates for xenotransplantation?
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Slow to attain breeding maturity
Long gestation period Usually only one offspring Large scale farming is difficult Have intellectual and social natures, making their use unethical Chimps= endagered species Very expensive |
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What are the advantages with using pigs for transplantation?
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Attain sexual maturity within 9 months
Short gestation periods (3-5 months) Large scale pig breeding is feasible No ethical issues, not endagered species Transgenic manipulation Adult pig organ size and life expectancy are compatible with adult humans (not all the organs though, only some of them) |
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What are the 4 major hindrances that need to be overcome in xenotransplantation?
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1-Physiological compatability
2- Immunological barriers 3- Genetic barriers 4- Zoonosis |
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Why is physiological compatibility a problem?
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Pigs and humans have a wide phylogenetic disparity
.: difficult to get physiological compatibility, especially for organs with complex biochem and metabolic fcts like kidney and liver |
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When is physiological compatibility less of a problem? (for which organs)
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For organs with dominant mechanical fcts
-->Heart and lung |
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What are the immunological barriers to xenotransplantation?
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*Hyperacute rejection
Delayed xenograft rejection Cellular xenograft rejection |
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What induces hyperacute rejection?
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Naturally occuring Ab vs the donor Ags
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What mediates hyperacute rejection?
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Complement activation
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What is an example of hyperacute rejection?
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Human and old world monkeys have natural Ab vs gal-a1,3-gal residue present on the cell surface of lower mammals and new world monkeys
-->This causes rapid immune response to grafts of animals |
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What induces delayed xenograft rejection?
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Return of anti-Gal Ab or the dev'p of newly formed anti-pig Ab
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What are the ways to reduce hyperacute rejection?
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Long term measurements
Short term measurements HAR |
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What are the long term measurements to reduce hyperacute rejection?
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Genetic engineering of source animal:
-H-transferase pigs -a-Gal KO in pigs -hCRP Tg pigs--> this one activates HAT |
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Describe the short term measurements used to reduce hyperacute rejection?
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Systemic therapy
-Removal of pre-formed a-Gal Ab (immunosuppression) -Tolerance induction in B cells -Cobra venom factor: Cleave C' and stop activation of C' -Soluble C' receptor 1 ==>The last 2 activate HAR |
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What does HAR do?
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Ag-Ab complex activates C'
-->C' targets cells with Gal and removes them |
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What are the main ways to reduce hyperacute rejection?
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Usually KO pigs so no transferase .: can't make a-Gal
Can also remove a-gal Ab |
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What are the genetic barriers to xenotransplantation?
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Blood viscosity, liver metabolism, enz and hormones
Main concern: Incompatibility of coagulation factors leading to the dev'p of pro-coagulation state in the graft, followed by thrombosis |
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What is the treatment for thrombosis?
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Heparin derivatives
Antithrombin III Prostacyclin inhibitor Genetic modifications |
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What is zoonosis?
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Transmission of pathogens btw species
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Why is there an increased risk of zoonosis in xenotransplantation?
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1) Skin and mucosal surfaces are bypassed
2) Use of immunosuppressive therapy enhances the risk of infection by pathogens 3) Genetic modifications of source animals may humanise animal pathogens |
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What happens if you modify a pig?
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Might increase the chance of pig pathogens to pathogenize humans
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What are some porcine zoonotic diseases?
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Viruses: Especially influenza
Bacteria Parasites |
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What is the hidden risk of zoonosis?
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Unidentified pathogens, latent or intracellular pathogens associated with asymptomatic host
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What are teh cases of zoonosis in human history?
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Swine flu 1918: flu went from pigs to humans, then person-person
Encephalitis epidemics in Malaysia and Singapore AIDS pandemic: transmission of AIDS viruses from Chimps and sooty mangabeys |
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Endogenous RV
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Endogenous RV (ERVs)
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What is the distinguishing feature of ERV?
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RV that integrates itself into the host genmome and is inherited as Mendelian traits
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Who was awarded the Nobel prize in recognition of finding RT?
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Howard Temin
David Baltimore |
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What do ERV have to infect?
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Need to infect in Germline Cells so it can be passed on (i.e. HIV is NOT an ERV)
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Describe ERVs
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Result from ancestral RV infections of germline cells
Inherited by host as Mendelian traits Replication-INCOMPETENT in most cases dye to mutations accumulated over evolutionary time |
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Have live ERV been ID'd in animals?
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Yes, have been ID'd in chickens, mice, cats, primates and pigs
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What's the problem with having live ERV?
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These viruses may cross species barriers and cause disease in a new host
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What are some examples of this?
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RD114 virus
-->In human rhabdomyosarcoma cell line Was a feline ERV |
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Do humans have any ERV?
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Yes, but they are all inactive
-->Make up 7% of our genome |
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What are the 3 types of transposons?
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RNA transposons
DNA transposons Helitrons |
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What is an RNA transposon?
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Need to go through RT to go from one site to another
-->Can be LTR or non-LTR retrotransposons |
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What mechanism do DNA transposons use?
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Copy paste or cut and paste method
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What % of our genome do non-LTR transposon make up?
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20-21%
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Describe DNA transposons
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Only 1 ptn
Makes up 3% of our genome |
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Describe retrotransposons
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LTR Retrotranposons:
They are like RV, in that they have Gag, Pol, Env 8% of our genome Non-LTR transposons: Has 2 ORFs ORF2 has RT enz (converts RNA-->DNA) 20% of genome |
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What are nonautonomous retrotransposons?
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Don't evade any ptns
Borrow ptn from LINE to jump to different sites Contains alu like gene |
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What is the alu element?
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It is ~100bp
We have a million copies of these Find one ~ every 3 kbp in our DNA |
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How can endogenous retroelements be controlled?
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Accumulation of inactivating mutations
Promoter CpG methylation Small RNA mediated silencing |
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What are these things used to do?
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Mainly to control T of these helements
Major mechanism takes place at Tl step Usually M promoters of these regions |
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Describe the Porcine endogenous RV (PERV)
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Discovered in 1970s
C-type virus particles produced from porcine cell lines Contains RT activity and Gag ->All pig strains express PERV RNA Can infect human embryonic kidney cell lines |
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Where have PERV RNA been detected?
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In several porcine tissues including kidney, lung, skin, heart and pancreatic islets
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Where has RT activity in PERV been detected?
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In the sera of WT pigs
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Where have replication competent PERV been isolated from?
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Porcine plasma
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Describe the PERV infection titres from pig cells
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Extremely low
->PERVs become more infectious when they get int o human cells |
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What does the type of PERV depend on?
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Can be A/B/C depending on the receptor used for infection
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Do all PERVs elong to the same gp of RV?
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No, belong to different gps such as B and gamma
->But not part of lentiviruses |
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Describe the genomic organizationof PERV
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Very simple
Only have Gag, pol and Env |
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What is PERV closely related to?
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Gibbon Ape leukemia virus (GALV)
Endogenous Koala RV (KoRV) Inducible murine ERV (MDEV) |
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What happens if there is no POL or LTR in the pig?
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No PERVs
-->Most ancient pigs don't have PERVs |
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Which ptn is used to classify the ERV as A/B/C?
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Envelope ptn
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Which PERV types are infectious to human cells in vitro?
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PERV A/B
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Can combined types of PERV infect humans?
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Yes, A/C recombinant can
->Infects with even higher titers than PERV-A alone |
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Which human mb receptors can serve as receptors for PERV-A?
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HuPAR-1 and -2
->These cannot be used by PERV-B/C |
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When do PERVs have the potential to infect humans?
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Can infect human cells during xenotransplantation
Can be dangerous for the patient |
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Are pig grafts still infectious if their Gal are deleted?
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Eliminating Gal attenuated the hyperacute rejection
BUT the PERV from the GT-KO pigs also do not have Gal on their surface and thus can escape the C' mediated immunity -->This increases the risk of transmission of PERV to human |
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How can PERV be diagnosed?
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PCR to detect PERV DNA in pig genome
RT-PCR to detect PERV mRNA expression RT assay to monitor the presence of virus particles in cell culture and plasma Western blot and ELISA to detect PERV-specific Ag Detection of PERV-specific IR to follow ongoing PERV infection |
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Describe the transmission of PERV during xenotransplantation
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1) PERV infection has nit been observed in patients treated with porcine cells, tissues or organs
Small animals such as mice have been used as models to study possible PERV transmission during xenotransplantation. Low lvls of PERV infection were detected in SCID mice after porcine islet transplantation Used non-human primates as models to study PERV transmission |
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How can PERV infection be combatted?
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Eliminate replication competent PERV loci within pig genome to reduce the risk of transmission, though may not suffice to exclude the release of PERV due to potential recombination
Antiviral therapy to treat PERV infection of xenotransplantation recipients. Only AZT has anti-PERV activity RNAi to reduce the expression of PERV RNA |
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What is human decay accelerating factor (hDAF) used for?
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Prevent activation of C' when pigs are transplanted
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