lecture 21 Flashcards

Question 1

Q

How many cadaveric donors/solid organ transplants do we have compared to patients on the waiting list?

Answer

A

1998 - 2004: always much high numbers on the waiting list than transplants that occur
~ 1800 patients waiting for a transplant
700 patients get transplants
200 cadaveric donors (this doesn’t match up)
before about 1978 there wasn’t really a waiting list, ~ 500 translplants
1978 waiting list appears and increass exponentially
number of transplants rises but plateaus
1978 was when the technique for immunosuppression was approved (cyclosporin?)

Question 2

Q

What are transplantation statistics?

Answer

A

UK:
- ‘92 - ‘95 1700 transplants/year
- waiting list grew from 4,000 to 5,000
USA:
- 45,000 patients waiting for transplants
- <6,000 cadaveric donors = 20,000 organs

no way for supply to meet the demand

~10-15% chance of dying while waiting for an organ, not unique to australia

Question 3

Q

Why do transplants?

Answer

A

costs

dialysis $40,000
kidney transplant $30,000 in first year
$8,000 per year

improved quality of life

Question 4

Q

Why is there a shortage of donors?

Answer

A

decrease in road accidents
family permission less
not suitable (age, disease, etc)
time factor
greater demand

Question 5

Q

What are possible solutions to this shortage?

Answer

A

increase donors
- e.g. donor games
- getting older so not necessarily the solution
artificial organs
stem cells –> organs/tissue
animal as donors: xenografts
- first transplantations were chimpanzee kidneys to human

Question 6

Q

What were patient attitudes towards xenografts?

Answer

A

131 renal patients:

51% would accept xenograft
39% unsure, wanted more information
10% unacceptable

Question 7

Q

Why did we revisit xenografts?

Answer

A

molecular biology

- transgenesis/animal cloning

Question 8

Q

What are problems with xenografts?

Answer

A

physiological
ethical
biological
infection
immunological

Question 9

Q

What are physiological problems of xenografts?

Answer

A

size e.g. can’t use a mouse (too small) or a horse (too big), maybe a kangaroo? but we use sheep/pig
complexity of function
e. g. sheep regulate insulin by glucose AND fatty acids –> not the same

Question 10

Q

What are ethical considerations of xenografts?

Answer

A

emotional
conservation

e.g. chimps etc are probably the best immunologically speaking, but people have issues with taking organs from this animal, cf pig

considerations for use of pigs:

food (as long as people are willing to slaughter pigs for food, they should be able to be used for donating organs)
insulin (major source of insulin for diabetics)
heparin (anticoagulant)
heart valves (used to replace broken valves in humans)
breeding (a forerunner for genetic manipulation)

Question 11

Q

What are biological considerations of xenografts?

Answer

A

adaptability to captivity
- pigs breed well in captivity
- primates breed poorly in captivity
litter size
- pigs: 10
- primates: 1
pig husbandry relatively easy
gnotobiotic pigs available (germ designed/germ free)

Question 12

Q

What are infectious considerations of xenografts?

Answer

A

primates: potential source of infection, especially viruses
pigs: lower potential source for infection
human viruses could infect primates, but not pigs

Question 13

Q

What are immunological problems associated with xenografts?

Answer

A

hyperacute rejection: antibody causes immediate graft loss
delayed xenograft rejection: macrophages/NK cells
cell mediated rejection: T cells

Question 14

Q

What is hyperacute rejection?

Answer

A

antibody
antigen
complement
immediate
clots
loss of vascular endothelium
haemmhorage and oedema
not unique to xenografts
e.g. mis-match blood transfusion

Question 15

Q

Do we have an ‘anti-pig’ antibody?

Answer

A

yes: normal, present in all humans
IgM, IgG, IgA
1-2% of all Ig
> 95% to Gal-alpha (1,3) Gal

Question 16

Q

What is the xenoantigen?

Answer

Study These Flashcards

A

Gal-alpha (1,3) Gal
present on many different molecules
expressed in most tissues
alpha 1,3, galactosyltransferase
GKO: mice, pigs

Question 17

Q

How has transgenesis played a role in xenotransplantation?

Answer

Study These Flashcards

A

CD46 transgenic pigs:

ubiquitously expressed human complement regulator
renal transplants to non-immunosuppressed baboons
- > 72 hr (normal <1hr)
- histologically normal

pancreatic islets

destroyed by anti-pig antibodies
protected by expression of CD46

Question 18

Q

How can you use ES cells?

Answer

Study These Flashcards

A

get rid of the antigen in mice

- can’t use ES cells of pigs

Question 19

Q

What are Gal o/o pigs?

Answer

Study These Flashcards

A

cloned pigs
reported by 4 groups
Gal- survive >150 days
HAR/DXR solved

Question 20

Q

What pig transplantations have occured?

Answer

Study These Flashcards

A

pig heart transplants

baboons (n=8)
anti-CD154 mAb, mycophenolate mofetil, and methylprednisolone
no HAR
graft survival extended to between 2 and 6 mo
thrombotic microangiopathy

pig kidney transplantation

baboons (n=11)
tolerance induction, including thymectomy, splenectomy, T-cell depletion, anti-CD154 monoclonal antibody and mycophenolate mofetil, with or without low-dose steroids
no HAR
graft survival extended to 83 days (now more than 160)
thrombotic microangiopathy

pig kidney transplantation 2

baboons (n=3)
no immunosuppression
no HAR
graft survival extended to 4 days
antibody and C’ deposition, platelet deposition, perivascular infiltrate
intravascular coagulopathy

pancreatic islets: more than a year

looking a blocking costimulation

Question 21

Q

What are some factors to consider in transgenesis?

Answer

Study These Flashcards

A

microinjection –> 1%
xeno transgenes
– DAF 1992
– DAF + CD59 1998
– CD46 2000
ie. 1-2 genes in 10 years
= 100 year programme unless SMGT
nuclear transfer 0.5% : Gal knock out (some groups claim up to 10% in pigs… more in mice)
retrovirus: Lenti virus in mice