Type 1 DM: Islet transplantation!

Question 1

Define allotransplantation

Answer 1

between individuals of the same species

Question 2

define autologous transplantation

Answer 2

same individual ‘here you go me, a present from me’

Question 3

define syngeneic transplants

Answer 3

genetically identical

Question 4

define xenotransplantation

Answer 4

different species -porcine islets

Question 5

what is the current situation with islant transplantation?

Answer 5

in 2k1 we though woah son, in 10 years time islet transplantations gonna b all the rage wat, but then 2010 rolled around and just like hoverboards islet transplantation was nowhere to be found we are rUINING THE FUTURE GUYS. most people who do manage god knows how to get a transplantation return to near full insulin replacement within 5 years.

Question 6

How many UK centres are currently performing transplants?

Answer 6

9

Question 7

What are NINE problems with islet transplantation?

Answer 7

1) islet yield 2) islet stress 3)non-specific intra-islet inflammation 4)blood mediated inflammatory reponse 5)glucotoxicity 6)host rejection 7)immunosuppressant 8)revascularisation 9)recurrence of autoimmunity

Question 8

Obstacle: loss of islet cell viability during isolation

Answer 8

Approach: improved extraction and culture conditions (normoxic conditions, growth factor supplementation)

Question 9

Obstacle: revascularisation of transplanted tissues

Answer 9

Approach: growth factor supplementation, gene based approaches

Question 10

obstacle: host induced inflammation, recurrence of auto immunit and non-specific intra islet inflammation

Answer 10

approach: drug targets, gene based approaches and encapsulation

Question 11

obstacle: poor islet cell mass aquired for transplant

Answer 11

approach: increase beta cell proliferation in transplanted tissues, donor availability and improved survival/retention of grafted tissues

Question 12

Prob with using pig islets

Answer 12

zoonotic infection and immunological barriers

Question 13

probs with cellular reprogramming

Answer 13

feasibility

Question 14

probs with cadaveric islets

Answer 14

limited supply and quality control difficult

Question 15

probs with embryonic stem cells

Answer 15

ethics and teratogenic potential

Question 16

probs wtih induced pluripotent stem cell

Answer 16

transcription factor induced transformation means teratogenic potential

Question 17

How many donors are required for transplantation?

Answer 17

up to 4

Question 18

immediate cell loss?

Answer 18

up to 70% within days

Question 19

Intra-hepatic via portal vein as transplantation site:

Answer 19

high success rate, has a near optimal O2 tension and avoids systemic hyperinsulinaemia. BUT inflammatory response so immunosuppresent levels :/ difficult to biopsy

Question 20

alternative sites for transplant?

Answer 20

kidney capsule, anterior eye chamber, subcutaneous, intramuscular and intrapancreatic

Question 21

IBMR?

Answer 21

Instant blood-mediated inflammatory reponse, a non-specific innate response that leads to massive early cell loss. coagulation system/complement so drug targetss?

Question 22

Caspase inhibition as a drug target?

Answer 22

IDN-6556, oral admin, improved safety, improves early survival in models. improves glucose tolerance 1 month after transplantation and improved insulin content

Question 23

IDN-6556?

Answer 23

CASPASE INHIBITOR SON

Question 24

what reduced apop after 24 hrs?

Answer 24

IDN-6556

Question 25

What is another inhibitor of apoptosis?

Answer 25

Casp-3 siRNA - reduces casp 3 expression in human cells.

Question 26

What are 4 gene based approaches to help grafts?

Answer 26

1) over expressing a gene to promote engraftment 2) over expressing genes to prevent cell loss 3) expressing a construct to silence expression of pro-apop genes 4)construction of bipartite vectors

Question 27

What are 3 types of artificial pancreas?

Answer 27

1) micro-encapsulation 2)macro encapsulation 3) blood perfusion type

Question 28

What is good about encapsulation?

Answer 28

negates host rejection and prevents recurrent auto-immunity

Question 29

What is microencapsulation in alginate?

Answer 29

additional surface ‘coats’ to modify proteins. variable islet volume a problem, as is incomplete encapsulation and the fact it can increase fibrosis.

Question 30

Why is cell surface coating awesome?

Answer 30

pretty much total immune evasion.

Question 31

What are 3 pitfalls of encapsulation?

Answer 31

1)biocompatibility leads to fibrosis plus theres the innate immune system 2)immune response from small molecule permeability 3)hypoxia; capsule limits revascularisation, needs tons of islets and hypoxia makes the other 2 worse