Type 1 DM: Islet transplantation! Flashcards
Define allotransplantation
between individuals of the same species
define autologous transplantation
same individual ‘here you go me, a present from me’
define syngeneic transplants
genetically identical
define xenotransplantation
different species -porcine islets
what is the current situation with islant transplantation?
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.
How many UK centres are currently performing transplants?
9
What are NINE problems with islet transplantation?
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
Obstacle: loss of islet cell viability during isolation
Approach: improved extraction and culture conditions (normoxic conditions, growth factor supplementation)
Obstacle: revascularisation of transplanted tissues
Approach: growth factor supplementation, gene based approaches
obstacle: host induced inflammation, recurrence of auto immunit and non-specific intra islet inflammation
approach: drug targets, gene based approaches and encapsulation
obstacle: poor islet cell mass aquired for transplant
approach: increase beta cell proliferation in transplanted tissues, donor availability and improved survival/retention of grafted tissues
Prob with using pig islets
zoonotic infection and immunological barriers
probs with cellular reprogramming
feasibility
probs with cadaveric islets
limited supply and quality control difficult
probs with embryonic stem cells
ethics and teratogenic potential
probs wtih induced pluripotent stem cell
transcription factor induced transformation means teratogenic potential
How many donors are required for transplantation?
up to 4
immediate cell loss?
up to 70% within days
Intra-hepatic via portal vein as transplantation site:
high success rate, has a near optimal O2 tension and avoids systemic hyperinsulinaemia. BUT inflammatory response so immunosuppresent levels :/ difficult to biopsy
alternative sites for transplant?
kidney capsule, anterior eye chamber, subcutaneous, intramuscular and intrapancreatic
IBMR?
Instant blood-mediated inflammatory reponse, a non-specific innate response that leads to massive early cell loss. coagulation system/complement so drug targetss?
Caspase inhibition as a drug target?
IDN-6556, oral admin, improved safety, improves early survival in models. improves glucose tolerance 1 month after transplantation and improved insulin content
IDN-6556?
CASPASE INHIBITOR SON
what reduced apop after 24 hrs?
IDN-6556
What is another inhibitor of apoptosis?
Casp-3 siRNA - reduces casp 3 expression in human cells.
What are 4 gene based approaches to help grafts?
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
What are 3 types of artificial pancreas?
1) micro-encapsulation 2)macro encapsulation 3) blood perfusion type
What is good about encapsulation?
negates host rejection and prevents recurrent auto-immunity
What is microencapsulation in alginate?
additional surface ‘coats’ to modify proteins. variable islet volume a problem, as is incomplete encapsulation and the fact it can increase fibrosis.
Why is cell surface coating awesome?
pretty much total immune evasion.
What are 3 pitfalls of encapsulation?
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
