Experimental Study Of HDAF Transgenic Pig On Organ Transplantation

The world-wide shortage of human organs available for transplantation has led to an interest in xenotransptantation.The pig has been suggested as a possible source of organs because of its plentiful supply and many anatomic and phsiological similarities with human hcings.Xenotransplantation between widely disparate species such as pig to primate results in hypercute rejection because of the binding of preformed natural antibodies to 0. -galactosyl carbohydrate cpitopcs on vascular endothclial cells,followed by activation of the complement cascade.Complement activation is inhibited both in the soluble phase and at the cell surface by a species-specific group of proteins called regulators of complement activation. In vitro expression of human regulators of complement activation,such as human decay-accelerating factor(hDAF) on the surface of pig cells has been show to protect them from lysis by human comoplemcnt.ln light of this observation pigs transgenic for hDAF have been developed by Cambridge group by microinjecting a 6.5 kb DAFmini gene in to porcine fertilized ova. It has previously been shown that hearts from hDAF transgenic pigs are not hyperaeutely rejected when transplanted heterotopically into the abdomen of cynornolgus monkeys and that prolonged survival can be achieved by use of immunosuppression with cyclosporine,cyclophosphamide,and methylpredn isolone. Xenoreactive natural antibodies in humans and higher primates are directed predominantly at Gal al-3Gal.These antibodies are thought to initiate hyperacute rejection of porcine organ xenografts.Some studies have confirmed that anti-Gal a-l-3GAI antibodies is the main part of xeno preformed natural antibodies and play a important role to the pathology of HAR.Many assay show that depiction of antibodies from reeil)icnt animals can pretect xenograft from hypcracutc rcjcction,even though complement activity was--900/oof baseline at the time of transplantation.The methods of depletion of antibodes includes: extracorporeal absorption of antibodies from blood using a xenografts conrmected to the animals.extracorporeal absorption of antibodies from plasma using columans with a matrix bearing Gala I -3Gal hi -4G lcNAc and etc.Novartis has developed a new immusupresssion(polyvalent injectable Gal ----GAS) which can be used through IV and absorpt antibodies. Jnprevious studies the cynomolgus were chosen as the recipient of hctcrotopic hDAF transgenic pig hearts largely because of the plentiful supply.However~such captive-bred animals are rarely availal)le with a body weight greater than Skg.Hence,the cynomolgus monkey is an unsuitable recipient for xenotransplantation of hDAF pig because of the technical difficulties Therefore it was necessary to choose a larger primate for such studies.Many of larger primates are endangered species,and it was deemed morally unacceptable to use such aiiimals for this purpose.of the larger primates readily available in sufficient numbers,the baboon was considered to be the most suitable recipient.llowever,it has been shown that hDAF has a variable ability to down-regulate complement of nonhuman primates.lndeed,hDAF has been shown to down-regulate human complement activity by 84%of total plasma complement activity,cynomolgus complement by 72%,baboon complement by 69%,and rhesus complement by 28%.Clearly the rhesus monkey would not be a good choice of experimental recipient for hDAF transgenic organs.i-Jowever,it was not clear whether the 3% difference between the...