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The problems of transplanting animal organs into humans

The problems of transplanting animal organs into humans. Jenny Kukielski. Jeong Ryul Lee, M.D. Pediatric Cardiac Surgery Seoul National University Hospital. The end of the night shift Organ transplantation today and tomorrow. The future Donor center Regular working hour

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The problems of transplanting animal organs into humans

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  1. The problems of transplanting animal organs into humans Jenny Kukielski Jeong Ryul Lee, M.D. Pediatric Cardiac Surgery Seoul National University Hospital

  2. The end of the night shift Organ transplantation today and tomorrow • The future • Donor center • Regular working hour • 200 procedures a day • daily-base available • The present • Telephone at 2 AM • A car-accident donor • 1-2 hour-drive for harvest • Get back to hospital at 7 AM • Heart transplantation • Continue regular cases

  3. Animal attraction (1) Supply and demand in the world of organ transplantation • The heart patient • 14 year old previously healthy boy • Virus induced cardiomyopathy • ICU care for 3 weeks • Boy’s heart failure getting worse • Listed in heart transplantation • Transfer to LVAD available center • Risk during transportation • The harsh statistics • 63000 waiting for organ in USA • Listing for organ every 18 minutes • Average waiting over 1 year

  4. Animal attraction(2) Supply and demand in the world of organ transplantation • Closing the donor-recipient gap • Raising the possibilities of organ donation • Presumed consent: donation unless objection • Draw attention from public with newsworthy people • Donor rate: 10-30/ million • Donor rate of hospital death: 4% • Living donors • Increasing unrelated living donor • Organ brokers: the ethical dilemma • Arrange dealing organs from poverty-stricken man • Rewarded gifting

  5. Animal attraction(3) Supply and demand in the world of organ transplantation • The real extent of the problem • Legal and cultural barrier • The borderline candidates • Limited potential of artificial organs

  6. From Icarus to the first transplant(1) Man’s first attempts to bridge the species gap • Daedalus and Icarus in mythology: feather into arm • 1921: Paris, Sexual rejuvenation by xenografting (baboon) • Reemtsma: Tongue into cheek • 1628: Italy, Blood transfusion from sheeps to humans • 1682: Russia, Dog skull into human skull • 1880: Chicago, Dr.Lee’s Lamb, Pedicled skin graft • 1800s: The fashion for frogs, Skin graft • 1907: Alexis Carrel, Vessel anastomosis

  7. From Icarus to the first transplant(2) Man’s first attempts to bridge the species gap • Transplantation of kidney • 1902, Emerich Ullman, Vienna : Pig kidney to human arm vessel • 1905, Princeteau, French: Rabbit kidney slices to child kidney • 1906, Matheu Jaboulay, French:pig and goat kidney to human arm • 1910, Ernest Unger: monkey kidney to human /stillbirth human kidney to baboon • 1963, Keith Reemtsma, Louisiana,13 chimpanzee kidney into human • 1964, Tom Starzl, Colorado, 6 baboon kidney into human(17-60d)

  8. From Icarus to the first transplant(3) Man’s first attempts to bridge the species gap • Transplantation of animal heart • 1964, James Hardy, U Mississippi: chimpanzee heart to human , size mismatch • 1968, Denton Cooley, Donald Ross, Texas and London: sheep and pig heart to human • 1977, Christian Barnard, Cape Town: chimpanzee and baboon heart as auxiliaries • 1984, Leonard Bailey, Loma Linda: Baby Fae (20d) • 1992, Poland, Pig heart to human(24h) • 1996, India (0d)

  9. From Icarus to the first transplant(4) Man’s first attempts to bridge the species gap • Transplantation of animal livers • 1992, Tom Starzl Pittsburgh, baboon liver to human(70d with vigorous immunosuppression) • Extracorporeal liver perfusion, USA, South Africa

  10. All animals are equal, but some are more equal than others The choice of donor • Candidate number 1 : The great apes • The closeness of phylogenetic relationships (98%) • Time-consuming and expensive source of organs • Poor public consensus • Their scarcity problem

  11. All animals are equal, but some are more equal than others The choice of donor • Candidate number 2 : The baboon • Non-human primate • Sufficient number • Closed breeding possible • Possible virus transmission • Size mismatch (40kg adult) • One offspring • Sexual maturation by 3-5 years • 9 years for adult sized growth • Consistency in different environment (thick bile) • Risk of infection : AIDS, SV, • Poor public compliance

  12. All animals are equal, but some are more equal than others The choice of donor • Candidate number 3 : The pig(1) • Less public controversy • Sufficient number • Reproductive maturity within 6 months • Sows mating capable every 3 weeks • Pregnancy less than 4 months (3m+3w+3d) • Easy and cheap to maintain • Rapid growth (1year to adult size) • Miniature pigs (Pigmees) well matching in size • Similar anatomy and physiology to human • Both pigs and humans omnivorous • Extensively studied animal

  13. All animals are equal, but some are more equal than others The choice of donor • Candidate number 3 : The pig(2) • Potential for genetic engineering • Less worrisome zoonosis • Pig disease and defects ( 0.004% cancer ) • Tissue typing in pig ( Class II>Class I) • Weak blood group antigen expression • To be in the center of the study ( humanized/ disease free)

  14. Zero tolerance The rejection of animal organs • The power of nature • The most powerful immunological reaction • Safety tools to defend against microorganisms • A reflex reaction to foreign threat • The human body’s oldest and strongest natural survival mechanism

  15. Zero tolerance The rejection of animal organs • Transplantation between closely related animals: • Antibody- or Antibody+Cell mediated • Large dose immunosuppression : months • Inevitable risk of infection, drug related complication • Inevitable chronic rejection

  16. Zero tolerance The rejection of animal organs • Transplantation between distantly related animals: • The first barrier : Hyperacute rejection • Antibody already circulating in large numbers • The nature of anti pig antibodies: • Surgeons and scientist from Oklahoma(Eugen Koren from Croatia, 1991) Alberta(Heather Good) • Galactose • Uri Galili, Biological detective: Only human, great ape, old world monkey capable of Ab production • The remaining barriers: peeling an onion • NK, macrophage • Cellular rejection

  17. The Spoonful of Sugar Prevention of rejection • Overcoming the first hurdle: • Preventing hyperacute rejection(1) • Perfusion of recipient serum into first pig organ • Refining the technique: Plasma exchange with immunosuppression+splenectomy • Being more specific: depleting anti-Gal antibodies • Accommodating the transplanted organs: after 2-3wk of depletion of Abs • The pioneering work Guy Alexandre (Belgian): • Replace serum with saline or innocuous solution • Splenectomy + immunosuppression • ABO incompatible kidney transplantation

  18. The Spoonful of Sugar Prevention of rejection • Overcoming the first barrier: • Preventing hyperacute rejection(2) • Egidio Romano’s new concepts • Antibody inhibition by injectable sugar • To remove anti-A antibody for A type blood • The scientist as a guinea pig • Therapy at $ 1 million a day: $ 90/mg of sugar (Chembiomed Ltd.) • Gal-filled cartridge: less expensive • Anti-idiotype antibody: antibodies against antibodies • Mouse anti- anti-pig antibodies • Depletion or inhibition of complement • CVF : rapid complement consumption • Soluble complement factor 1 (Fred Sanfilippo from John’s Hopkins)

  19. The Spoonful of Sugar Prevention of rejection • Overcoming the second barrier: • Preventing Delayed antibody-mediated rejection • Antibody-mediated without complement • Fritz Bach from Beth-Israel, Jeff Platt from Duke • The right immunosuppressive combinations + maintenance of low anti-pig antibodies

  20. The Spoonful of Sugar Prevention of rejection • Overcoming the third barrier: • Preventing acute cellular rejection • Antirejection drugs • Azathioprine, British, Sir Roy Calne (1960s) : killing dividing T-cell • Corticosteroid: suppress T-cell • ATG/ALS: Rabbit antihuman-T-cell antibodies, Sir Michael Woodruff(British), Anthony Monaco and Paul Russell(Harvard surgeon) • Cyclosporine (late 1970s) : inhibition of T-cell function • Jean Borel, Swiss immunologist, Sandoz, now Norvatis) • Sir Roy Calne, David White, British: experiment • OKT3 : Killing T-cell • Ben Cosimi, MGH • Mouse anti-T-cell antibodies • Tacrolimus, Tom Starzl: competing cyclosporine • Mycophenolate mofetil : replace azathioprine

  21. The Spoonful of Sugar Prevention of rejection • Overcoming the fourth barrier: • Preventing Chronic rejection • At present no effective tx for chronic rejection • Second transplantation

  22. The ‘Humanized’ Pig Manipulating the genes of the donor • Genetic engineering: Giving the pig human genes(1) • Present technique: • Extremely inefficient: • 10 out of 100 embryos->1-2 transgenic • Possible weak expression • Present technique • Superovulation • Mating within 24 h • Random needling of genes • 25 embryos in 1 sow • 1 fetus live birth • sometimes with no expression • Breeding

  23. The ‘Humanized’ Pig Manipulating the genes of the donor • Genetic engineering: Giving the pig human genes(1) • Gal negative pigs: • Gal Knocking out : Knocking out the sugar • Oklahoma, Melbourne, Austin • not available in pig • GT KO in pig • GAL KO in mice (Tony d’Apice from Melbourne Australia): • Human serum still destroy the mouse organ • Anti-non-Gal Ab • Competing with Gal • A gene for fucosyl transferase • A gene for a-Galactosidase

  24. The ‘Humanized’ Pig Manipulating the genes of the donor • Genetic engineering: Giving the pig human genes(2) • Protection against human complement: • hDAF • MCP • CD59

  25. The ‘Humanized’ Pig Manipulating the genes of the donor • Cloning, the new technology • Keith Campbell, Scottish biotechnology company, PPL Therapeutics • Nuclear transfer technique into egg : fetal or embryo fibroblast • Single generation multiple off-springs

  26. The Immunological Holy Grail Tolerance • The limitations of present day : 50% failure at 10y • The concept of tolerance: • Accept foreign without any long-term drug therapy • Donor specific • Not affecting host immune system • No drug-related cancer development • Free of acute or chronic rejection

  27. The Immunological Holy Grail Tolerance • In search of tolerance (1) • South African experience: • Johannes Myburgh, surgeon • Total lymphoid irradiation(thymus+LN) on recipient baboon Kidney transplantation from donor baboon • Clinically not relevant • The NIH-Harvard experience • David Sachs: successful induction of tolerance in rodents • Ben Cosimi: Bone marrow irradiation+ T-cell cytotoxic drugs+thymus irradiation : insufficient • Plus BM transplantation from the same donor: chimeric immune system (mixed chimerism) kidney transplantation from the same donor • Controllable infection

  28. The Immunological Holy Grail Tolerance • In search of tolerance (2) • Can we learn to tolerate pigs? • B-cell tolerance=absent antibody production: • Anti-pig antibodies fromB-cell/Plasma cell : Ab depletion required, irradiation resistant, • Gal-KO • Molecular incompatibility • Pig BM cell not proliferate well in baboon stroma • Pig specific growth factor required

  29. The Immunological Holy Grail Tolerance • Spontaneous unresponsiveness: • No rejection after cessation of immunosuppressive drugs • Molecular chimerism (new concept): • Pig genes for major antigen cloned, GT gene • BM cell from recipient baboon aspirated • Retroviral vector mediated pig gene transfection into baboon cell • These cell back into baboon BM after whole body irradiation • Pig kidney transplantation into baboon • Induction of chimerism before birth • All developing human fetus injected with pig cells • For future pig organ transplantation

  30. The discordant concert Will the transplanted organ work? • Living out of one’s elements • Physiological biochemical difference • Specific pig organs : • Electrolytes • The effect of evolution • Cholesterol • Clot or bleed • Growth hormone • Aging of tissues • Erythropoietin and red blood cells • A new science : Xenoincompatibility

  31. The Hottest zone The fear of an AIDS-like epidemic • The ever present fear • Transplanting microbes • The risk of cross-species infection • Making the donor pig safe • Monitoring for infectious organism • Mad pig disease • PERV • Human factor • Non-compliant patient

  32. Guinea pig The selection of the first patient • Laboratory to hospital • Are we ready for a clinical transplantation? • A need to be identified • An appropriate group of patient to be identified • A sufficient experimental advances • An ethical appropriateness • Who are the most likely guinea pig? • Those who have nothing to lose • Back-up therapy available group • Is the technology ready ? • When will it happen?

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