Xenotransplantation. Pig as an organ donor

Transcription

1 Xenotransplantation Pig as an organ donor

2 Xenotransplantation Transplantation of solid organs Heart, Kidney, Liver Transplantation of live animal cells Pig neuronal and pig pancreatic islet cells Use of viable animal cells/organs as part of a medical device Extra-corporeal liver perfusion

3 History of Xenotransplantation

4 Maribeth Cook : 1994, stroke, pig fetal cells Amanda Davis : 1999, stroke, pig fetal cells Jim Finn : 1997, stroke, pig fetal cells Robert Pennington : 1997, liver failure, Pig liver

5 History of xenotransplantation

6 Consideration Immune rejection Transgenic animal Delay the acute rejection reaction Pathogen (retrovirus) Endogenous retrovirus AIDS

7 Advantages of xenotransplantation Provides an unlimited and predictable organ supply Allows for advanced planning and elective surgery Allows for immunological pre-treatment, if required Organs are harvested at the time of requirement Breeding specific pathogen free (SPF) source animals minimizes the risk of pathogen exposure Pre-screening organs for infection prior to harvesting

8 Hindrance for using non human primates Slow to attain breeding maturity Long gestation period Usually have only a sigle offspring Large-scale farming is difficult Have intellectual and social natures too similar to humans, making their use unethical Chimpanzees are currently considered an endangered species

9 Advantages of using pigs Attain sexual maturity within 9 months Short gestation periods (3.5 months) Large litters of btw 6-16 piglets Large scale pig-breeding is highly feasible No ethical issues or endnagered species Adult pigs organ size and life expectancy (approximately 30 years) are compatible with adult humans

10 Hindrance for using pig Physiological incompatibility Immunologicl rejection Infection (zoonosis)

11 Physiological compatibility Will the animal organ acts in human without problem? Heart or lungs ; easier to apply Only supports mechanical function Kidneys, liver Complex biochemical, metabolic function

12 Insulin producing beta cells Transplantation of pig beta cells --> mice Released insulin No effect in the recipients

13 Clinical Trials for Type I diabetes One child ; stop insulin injection Five others ; require insulin 2002 Nature

14 Parkinson s Disease Degeneration of dopaminergic (DA) neuron Transplantation of pig embryonal mesencephalic tissue Seven month survival of the DA producing fetal pig neural cells

15 Renal xenograft Proper functioning of erythropoietin Hormone secreted by capillary endothelial cells Regulates the production of erhthrocytes Non-functional in humans

16 Immunological Rejection

17 Immune System

18 Hematopoesis

19 Antibody

20 Phagocytosis

21 Immune System

22

23 Transplantation Syngenic Same individual Allogenic Same species Xenogenic Different species

24 Immunological Rejection Hyperacute rejection (HAR) Pre-Existing Antibody Acute vascular rejection/delayed xenograft rejection (AVR/DXR) T cell recognition of the transplanted tissues Cell mediated rejection Long term Obscure

25 Recognition mechanism

26 Hyperacute rejection Mediated by complement activation Host s pre-formed Ab binds to pig Ag Major Antigen Endothelial carbohydrate antigen/epitope Galactose-alpha(1-3)-galactose (alpha-gal) Alpha1,3-galactosyl transferase (a(1-3)gt) Not expressed in human

27 Concept of Blocking hyperacute Reaction

28 Strategies Depletion of alpha-gal using Ab in patient Using alpha-gal adsorption column Transgenic Pigs

29

30 Expressing high level of H- transferase Competing with (a(1-3)gt) Lowering alpha-gal Decreasing Ab-mediated complement activation

31 Acute vascular rejection/delayed xenograft rejection Type II endothelial activation Involves gene transcriptioin and protein synthesis IgG ; most important factor

32 Cell Mediated Rejection Can be controlled by the administration of immunosuppressive drugs (cyclosporin) Increase the chance of infection Can be used for bridging organ

33 Zoonosis

34 Zoonosis Inadvertant transfer of pathogens between species Zoonotic infection ; influenza virus from pigs 1999 ; Singapore; Nipha-virus SPF (specific pathogen free) breeding Unidentified pathogen Genetic modification --> humanise animal pathogen Host tolerance --> host s susceptibility

35 Endogenous retroviruses

36 Procine viruses

37 Known PERV isolates

38 Viral tropism Can PERV infect human cells? Martin et al Productive infection of primary human endothelial cells by pig endogenous retroviruses (PERV), Xenotransplantation, 2000, 7; Martin et al, Transmission of pig endogenous retroviruses to primary human cells, Transplant Proc, 2000, 32, 1157

39 Pantience et al, Infection of human cells by an endogenous retroviruses of pigs. Nat Med 1997, 3, Wilson et al, Type C retrovirus released from procine primary peripheral blood mononuclear cells infects human cells. J virol, 1998, 352,

40 Viral Receptors Identification of receptors of pig endogenous retrovirus. PNAS, 2003, 100, HuPAR-2 ; expressed in human cells

41 Risks in Xenotransplantation Presence of PERV Could infect human and arise infectious disease Evidence from human trial No evidence of viral infection until now Long term exposure?

42 Qari et al, Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors. J Virol 2001, 75, Drug Treatment for porcine retroviruses