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Istoricul transplantului de esuturi i organe

Transplantul de organ (sinonim cu grefa de organ) nseamn nlocuirea total


sau parial a unui organ sau esut bolnav cu un organ sau esut sntos, sau cu
pri ale acestuia, provenind de la un donator. Organul sau esutul prelevat
pentru transplant (numit i grefon) poate proveni de la donatori vii sau de la
donatori decedai. Beneficiarul unui transplant este numit primitor.
Clasificare
Exist mai multe tipuri de transplant, clasificate dup originea grefonului
Homotransplant (allograft)
Numit i homogref, homotransplantul este un transplant efectuat ntre membrii
ai aceleiai specii. Este cel mai frecvent tip de transplant folosit n practic. n
majoritatea cazurilor sistemul imunitar al primitorului percepe organul
transplantat ca pe un corp strin. De aceea, pentru a evita fenomenul imunologic
de respingere a transplantului, primitorul trebuie s urmeze toat viaa tratament
imunosupresor. Sunt i cazuri care nu impun tratament imunosupresor, cum ar fi
transplantul de cornee.
Isograft (singenic)
Un caz particular de homotransplant l constutuie transplantul ntre organisme
genetic identice (ntre gemeni identici-monozigoti), care se comport
asemntor autotransplantului, din punct de vedere imunologic.
Heterotransplant (xenograft)
Numit i heterogref, heterotransplantul este un transplant efectuat ntre
organisme aparinnd unor specii diferite. Fenomenul de respingere de
transplant este mult mai puternic n cazul heterogrefelor. Unele
heterotransplanturi sunt utilizate curent n medicina uman (de exemplu
transplantul de valve cardiace de porc, la om). Multe heterotransplanturi se
realizeaz experimental ntre diferite specii, n vederea studierii unei posibile
aplicabiliti la om (un exemplu n acest sens este transplantul experimental de
esut insular pancreatic de la peti la primate non-umane).
Autotransplant (autograft)
Autotransplantul, numit i autogref, este acel tip de transplant n care
primitorului i se transplanteaz esuturi proprii, prelevate din alt parte a
corpului. Aceast metod are aplicabilitate numai n cazul transplantului de
esuturi sau celule. Grefoanele se preleveaz din zone regenerabile sau zone cu
exces de esut. Sunt i situaii n care se preleveaz esuturi non-indispensabile
din unele zone, pentru a fi transplantate n zone unde sunt imperios necesare (n
unele proceduri de by-pass arterial realizat din grefon venos).
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Dupa situsul de implantare, transplantul poate fi descris ca ortotopic sau


heterotopic.
Transplantul ortotopic se refera la implantarea tesutului donor intr-o pozitie
anatomic corecta la nivelul primitorului; transplantul heterotopic se refera la
implantarea graftului intr-o zona diferita fata de cea normal anatomica
Preistorie
Cele mai vechi dovezi de autograft ortotopic au fost pastrate din epoca
bronzului. O portiune circulara de os a fost detasata de calvarie pentru a diminua
presiunea intracraniana i mai trziu repozitionata ca autograft. Scrieri vechi din
Egipt, China, India descriu incercari de transplantare. In Egiptul antic se practica
deja transplantul de tesut epitelial. In aghiologia crestina se vorbeste despre
faptul ca sfintii doctori fara de arginti, Cosma si Damian, in sec. al IV-lea au
efectuat transplantul de gamba unui suferind, prelevand gamba de la un om mort
de patru zile. Medicina a facut progrese enorme, dar multa vreme nu s-a
preocupat de posibilitatea si fiabilitatea transplantului.
Un text indian de la 700 BC descrie o procedur de reconstrucie nazala, care
este foarte asemntoare unor metode moderne.
Zorii transplantului modern
Transplant de organ a evoluat dupa dezvoltarea anesteziei i antisepticelor
chirurgicale. n 1540, un alchimist, Valerius Cordus, a sintetizat eterul si a
observat efectele sale pe animale. Utilizarea de eter in chirurgie i stomatologie
a devenit foarte rspndit n secolul 19. Joseph Lister a pus bazele pionieratului
in domeniul chirurgiei aseptice bazat pe descoperirile bacteriologice al lui
Louis Pasteur.
Alexis Carrel este cunoscut drept fondatorul transplantului de organ din cauza
muncii de pionierat in tehnicile de chirurgie vasculara. Activitatea lui Carrel i
Charles Guthrie descrise n Transplantul de organe si vene a servit drept
fundament pentru chirurgia vascular i a transplantul de organ. Un sistem de
perfuzare pentru organe creat de Carrel i Charles Lindbergh a dus la
dezvoltarea bypassului cardiopulmonar de catre John Gibbon, ceea ce a deschis
calea chirurgiei cardiace.
Frank Mann a studiat transplantul renal si de inima, la Clinica Mayo n anii
1930. Primele transplanturi de organe la om au nceput cu allogrefa renala n
1936, si nu au reuit pn la descoperirea imunogeneticii i pana la punerea n
aplicare a drogurilor imunosupresoare.
Evoluia donarii de organe i a achiziiei de organe
n anii 1960, transplantarea organelor de la donatorii cadavru parea s fie
imposibil. Donatori vii au fost unica sursa de organe pentru transplant. In
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Massachusetts General Hospital, a fost recoltat un ficat de la un ofier de poliie


a crui inim era functionala, dar cu leziuni cerebrale grave prin impuscare.
Acest eveniment a dus la dezvoltarea conceptului de moarte cerebrala ca moarte,
mai degrab dect cel de ncetare a circulaiei, care era definita anterior ca
moarte. Conceptul de moarte cerebral a crescut foarte mult numrul de organe
disponibile pentru donare i a mbuntit prezervarea si recoltarea organelor.
Dup ce conceptul de moarte cerebrala a fost stabilit, s-a infiintat si dezvoltat un
sistem de procurare a organelor pentru a asigura calitatea i disponibilitatea
acestora ct mai eficient posibil.
In 1954 s-a realizat primul transplant fiabil de rinichi, iar in 1967 primul
transplant de inima. Ulterior, performantele au continuat, actualmente
realizandu-se transplantul de: rinichi, ficat, pancreas, inima, plaman, inimaplaman (din 1981). Actualmente se vorbeste de posibilitatea transplantului de
parti ale creierului si chiar de transplant de cap. In ceea ce priveste tipurile de
transplant, actualmente se efectueaza transplanturi de tesuturi: sange, vene, oase
lungi, valve cardiace, cornee, maduva osoasa, piele; transplant de celule izolate,
transplant de organe regenerabile (ficatul) si neregenerabile duble (rinichii),
unice (inima, plaman, intestin subtire, pancreas).
Posibilitatea teoretica a fiabilitatii heterotransplantului ridica multe probleme,
dintre care putem aminti cateva:
- riscul esecului datorat reactiei de respingere pe care o va avea organismul
uman cand organul de animal va intra in contact cu sangele uman. In asemenea
situatii, se stabileste imediat o reactie antigen-anticorp cu activarea
complementului si distrugerea endoteliului vascular. In ciuda incercarilor de a
bloca aceasta reactie a organismului primitor, rezultatele nu sunt concludente si
nici validate.

Istoria transplantului de organe si tesuturi in Romania


Primele incercari de transplant de organe in Romania dateaza inca de la
inceputul secolului XX si se datoreaza doctorului Florescu care, lucrand in
cadrul laboratorului de chirurgie experimentala al Facultatii de Medicina din
Bucuresti a efectuat mai multe transplante experimentale de rinichi. Operatiile
nu au fost incununate de succes, iar Dr. Florescu a considerat ca aceasta se
datoreaza unui unghi de implantare deficitar al vaselor sanguine (rinichii
deveneau pana la urma necrotici), motiv pentru care a incercat diferite locuri din
organism pentru transplant in speranta ca va gasi unghiul potrivit. Acest lucru nu
s-a intamplat, desigur, si experimentele au fost abandonate.
In 1958 Prof. Dr. Agrippa Ionescu realizeaza primul transplant de piele intr-un
cadru spitalicesc organizat, iar in 1962 este efectuat primul transplant de cornee.
In a doua jumatate a secolului trecut, Sergiu Duca la Cluj-Napoca si Vladimir
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Fluture la Timisoara si Dumitru Popescu-Falticeni impreuna cu Emil Papahagi la


Spritalul de Urgenta Floreasca Bucuresti, efectueaza transplant experimental de
ficat.
Primul transplant reusit al unui organ solid din Romania la om a fost cel efectuat
de Profesorul Eugeniu Proca, in februarie 1980 la Spitalul Fundeni, cu rinichi de
la donator in viata (mama receptorului). Acest transplant a fost urmat la scurt
timp de un transplant renal de la donator decedat, efectuat la Timisoara de o
echipa condusa de Prof. Dr. Petru Dragan. Pana in decembrie 1989 se efectueaza
doar transplanturi de rinichi si acestea intr-un numar relativ redus.
In anul 1992 se pun bazele primului program modern de transplant renal din
Romania, de catre Prof. Dr. Mihai Lucan, la Clinica de Urologie a Spitalului
Judetean Cluj-Napoca (devenita ulterior Institutul Clinic de Urologie si
Transplant Renal Cluj-Napoca).
Incepand din 1995 se intensifica eforturile de organizare a unei retele nationale
de transplant, desfasurate in mai multe etape :
stabilirea protocolului de diagnostic si declarare a mortii cerebrale
(Prof. Dr. Dan Tulbure)
stabilirea conditiilor de prelevare a organelor de la donatorul decedat
din punct de vedere medico-legal (Prof. Dr. Vladimir Belis)
campanie in mass-media de explicare a mortii cerebrale si de
promovare a donarii de organe
efectuarea primelor prelevari multiorgane (1997); in februarie a fost
prelevat un rinichi de la o donatoare aflata in moarte cerebrala in
Clinica de Chirurgie Generala a Spitalului Fundeni (echipa
chirurgicala Irinel Popescu, Ioanel Sinescu, Vladislav Brasoveanu,
Radu Soare, anestezist Dan Tulbure), iar in iunie o prelevare de ficat si
rinichi la Spitalul de Urgenta Floreasca (echipa chirurgicala a fost
coordonata de Prof. Dr. Irinel Popescu, iar echipa anestezica de Dr.
Ioana Grintescu). Un rol important a revenit ulterior Spitalului
Judetean Targu-Mures, unde Prof. Dr. Radu Deac si Dr. Pia Moldovan
au reusit sa mentina in conditii fiziologice mai multi donatori in
moarte cerebrala, iar familiile acestora au fost de acord cu donarea
incepe formarea coordonatorilor de transplant, primul dintre acestia
fiind Dr. Victor Zota, actualul Director al Agentiei Nationale de
Transplant. Se stabilesc regulile repartitiei organelor la nivel national
si al schimburilor de organe cu alte tari europene cu care se semneaza
acorduri de cooperare
in 1997 ia fiinta asociatia profesionala "ROMTRANSPLANT" care va
juca un rol important, atat pe plan stiintific, cat si pe plan
organizatoric, in dezvoltarea transplantului romanesc. Cele 5 congrese
nationale, cu participare internationala, ale acestei asociatii (1998 :
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Cluj-Napoca - presedinte Prof. Dr. Mihai Lucan; 2000 : Bucuresti presedinte Prof. Dr. Irinel Popescu; 2002 : Targu-Mures - presedinte
Prof. Dr. Radu Deac; 2004 : Constanta-Eforie Nord - presedinte Prof.
Dr. Vasile Sarbu si 2006 : Cluj-Napoca - presedinte Prof. Dr. Mihai
Lucan) au reprezentat momente de referinta din toate punctele de
vedere
In aprilie 2000 este efectuat primul transplant hepatic cu supravietuirea
bolnavului de catre Prof. Dr. Irinel Popescu la Spitalul Fundeni, iar in octombrie
2000, primul transplant de ficat de la donator in viata, de catre aceeasi echipa
(transplant de la mama la fiica).
In anul 2001 Prof. Dr. Margit Serban efectueaza in centrul universitar Timisoara
primul transplant medular, urmata, la scurt timp, de echipa Spitalului Fundeni
(Prof. Dr. Dan Colita, Prof. Dr. Constantin Arion).
In 2003 echipa de la Spitalul Judetean Constanta (Prof. Dr. Vasile Sarbu, Dr.
Simona Dima) efectueaza primul autotransplant de insule pancreatice, in 2004 la
Institutul de Urologie si Transplant Cluj-Napoca Prof. Dr. Mihai Lucan
efectueaza primul transplant combinat de rinichi si pancreas, iar in 2005 la
Institutul Clinic Fundeni (Prof. Dr. Irinel Popescu, Dr. Simona Dima) se
efectueaza primul allotransplant de insule pancreatice la un bolnav cu ciroza si
diabet, caruia i s-a efectuat un transplant combinat de ficat si insule pancreatice.
Transplantul de celule stem a fost efectuat pentru prima data in anul 2004 pentru
o afectiune a miocardului (Prof. Dr. Stefan Dragulescu, Prof. Dr. Virgil Paunescu
- la Institutul de Cardiologie din Timisoara), si in anul 2005 pentru o afectiune a
ficatului (Prof. Dr. Irinel Popescu, Dr. Simona Dima - la Institutul Clinic
Fundeni). In tot acest timp, atat legislatia, cat si cadrul organizatoric au cunoscut
imbunatatiri permanente.
In anul 1998 a fost introdusa prima lege moderna a transplantului din Romania Legea nr. 2/1998 "privind prelevarea si transplantul de tesuturi si organe umane"
in care erau specificate toate conditiile de prelevare si transplantare a organelor
si tesuturilor. Aceasta a fost inlocuita in prezent de Titlul VI "Efectuarea
prelevarii si transplantului de organe, tesuturi si celule de origine umane in scop
terapeutic" din Legea 95/2006 "privind reforma in domeniul sanatatii" in care
apare, in plus, un capitol detaliat asupra transplantului de celule si tesuturi, iar
reglementarile privind transplantul de organe sunt aduse la zi. Alinierea la
legislatia europeana este si rezultatul prezentei unui reprezentant al Romaniei
(Prof. Dr. Irinel Popescu) in Comisia de transplant de organe si tesuturi a
Consiliului Europei.
In anul 2004 apare Legea nr. 588, de infiintare a Agentiei Nationale de
Transplant, iar Dr. Victor Zota este numit Director Executiv al Agentiei, care
este instalata in actualul sediu si incadrata cu o schema de personal. Prof. Dr.
Irinel Popescu devine presedinte al Consiliului Stiintific al Agentiei.
Ca rezultat al activitatii de transplant, in prezent in Romania s-au efectuat peste
1000 de transplante renale (in centrele universitare Bucuresti, Cluj-Napoca,
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Timisoara, Iasi, Constanta si Oradea), peste 100 de transplante hepatice in


Institutul Clinic Fundeni, peste 50 de transplanturi medulare, peste 30 de
transplante cardiace, etc.

Early history of transplantation immunology


The predominant early theory regarding the mechanism of rejection was
malnutrition of grafted tissue as suggested by Paul Ehrlich in 1906. Similarly, in
1910, Carrel noted that physiological disturbances in transplanted organs were
likely caused by biological factors. Soon thereafter, Viennese pathologist Karl
Landsteiner discovered the ABO blood group system that eventually led to the
introduction of clinical blood transfusion. Sir Peter Medawar, who was awarded
the Nobel Prize for his pioneering work, defined for the first time the
immunologic nature of skin allograft rejection in humans. He confirmed that
these reactions are immunologic based on data from extensive animal
experimentation. In addition, George Snell observed that tumor grafts of normal
tissues were accepted between inbred animals but not between animals of
different strains.
As early as 1914, the fact that lymphocytes infiltrated grafts was recognized;
however, many years elapsed before an understanding of the molecular basis of
T-lymphocyte activation as a cause of acute rejection was developed. Over the
years, researchers recognized that the principal targets of the immune response
are the major histocompatability complex (MHC) molecules on the graft. The T
lymphocytes of the recipient recognize the MHC by 2 different pathways. The
direct pathway initiates CD8+ cytotoxic T cells by interaction of human
leukocyte antigen (HLA); the indirect pathway activates CD4+ helper T cells and
leads to a delayed-type hypersensitivity response, cell-mediated toxicity, and
alloantibody production.
Advances in transplantation immunology
The genes responsible for immunologic reactions leading to graft rejection were
termed histocompatibility genes. Peter Gorer further established that the major
histocompatibility locus was antigene II, and thus named the locus
histocompatibility II. Further work in the area of immunohematology by Jean
Dausset led to the knowledge that MHC genes are the most important markers
of an individual's biological identity. Dausset noted that MHC genes are required
for the presentation of peptide antigens to T-cell receptors, and they play a vital
role in transplantation immunology. Ralph Zinkernagel and Peter Doherty added
to the growing pool of immunological knowledge and stated that the role of the
MHC is to "signal changes in self to the immune system."
Research on humans led to the discovery that genetic control of the HLA resides
on chromosome 6 in a supergene region known as the MHC. Class I MHC
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antigens include HLA-A, HLA-B, and HLA-C. Furthermore, the class II MHC
antigens important in transplantation are governed by HLA-DR, HLA-DP, and
HLA-DQ. These regions on chromosome 6 are tightly linked and constitute a
haplotype.
Manipulating the immune system
Knowledge of immunology led to the first successful kidney transplantation
between identical twins, in 1954. The initial work in this field began with the
recognition that organ allografts may be transplantable. Peter Medawar
performed skin grafts for victims of burns during World War II. However, the
grafts only succeeded when performed between identical twins.
At Peter Bent Brigham Hospital in Boston, the possibility of treating end-stage
renal disease by kidney grafting was under active investigation. In 1952, David
Hume made early attempts at allografting the kidney from an unrelated donor
and found that the kidney graft functioned well for a short period. One of their
grafts survived several months, and Hume reasoned that chronic uremia likely
suppressed the immune function of the recipient.
Joseph E. Murray performed the first successful identical twin renal
transplantation at Peter Bent Brigham Hospital in Boston. In 1959, this team
performed the first successful fraternal twin transplantation. Despite massive
irradiation of the host prior to transplantation, these attempts were largely
unsuccessful. Nonetheless, their efforts set the stage for the evaluation of
rejection and mechanisms to avoid it.
Over the next 25-year period, discoveries in immunosuppression paved the way
for attempts at manipulating the recipient's immune system. These research
efforts eventually led to the discovery of lymphocyte function, the role of the
thymus in the ontogeny of the immune system (1961), the delineation of the
human MHC (1963), the distinction of the T- and B-lymphocyte subsets (1968),
and the demonstration of the MHC-restricted nature of the adaptive immune
response (1974).
Early efforts at immunosuppression
Initial attempts at controlling rejection began with experiments involving total
body irradiation. The initial evidence came in 1958 from Paris, France, where
Mathe, a hematologist, treated 6 Yugoslavians who were accidentally irradiated
on a previous occasion. The bone marrow homografts in these patients were
successful, which led the way for irradiation to be used in other organ
transplantation. Unfortunately, for renal transplantation, irradiation alone led to
dismal outcomes, with only 2 reported successes: a single case by Merrill in
1960 and another by Hamburger in 1962.

Further efforts to avoid and control rejection of transplanted organs led to the
investigations of medications. Robert Schwartz and William Dameshek showed
that the drug 6-mercaptopurine could prevent rabbits from producing antibodies
to foreign proteins. In 1961, Joseph Murray prescribed 6-mercaptopurine for the
first time to a human kidney transplant recipient. The patient unfortunately died
from drug toxicity. Roy Calne at the Peter Bent Brigham Hospital experimented
with 6-mercaptopurine and its close relative azathioprine, after he had
disappointing experience with total body irradiation.
Azathioprine used alone was not very effective in human transplantation.
Careful studies undertaken by Thomas E. Starzl in the early 1960s, while he was
in Denver, demonstrated that a combination of corticosteroids and azathioprine
led to much better success. The work of Thomas Starzl transformed clinical
transplantation into a clinical service and ushered in the proliferation of
transplantation programs in kidney transplantation worldwide. Cortisone had
been discovered in 1936, as an adrenal gland steroid with immunosuppressive
properties. Prednisone, a cortisone derivative, was used subsequently in
cadaveric kidney transplant recipients. In 1964, David Hume noted that
prednisone not only was useful in preventing graft failure in regular doses, but it
was useful for reversing renal allograft rejection in larger doses. However,
continued use of corticosteroids permanently alters normal immune function and
produces other very serious adverse effects.
Discovery of cyclosporine
In 1972, Swiss biochemist Jean-Franois Borel discovered cyclosporine in
natural fungal byproducts. Cyclosporine improved graft rejection in animals by
inhibiting T-lymphocyte activity. Roy Calne investigated the effects of
cyclosporin in dogs with renal allografts and pigs with orthotopic heart grafts.
His work proved that cyclosporine was a much better immunosuppressive agent
than corticosteroids, azathioprine, or a combination of both. Calne also found
that cyclosporine was nephrotoxic; work by other investigators on devising safe
protocols for cyclosporine led to marked improvement not only in kidney
transplantation, but also in successful transplantation of the lungs, heart, heart
and lungs, pancreas, and liver.
In the late 1970s, cyclosporine increased the 1-year survival rate of liver
allografts from 18% to 68%. Although cyclosporine is generally associated with
significant adverse effects, administration of small doses in a controlled protocol
results in minimal adverse events.
Cocktail approach
The cocktail approach, which combines cyclosporine with steroids and
azathioprine, was found to be the most effective approach to
immunosuppression for organ transplantation patients over the next 10-15 years.
More recently, this combination has been replaced by regimens that include
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newer immunosuppressive agents. Tacrolimus has almost completely replaced


cyclosporine in liver and pancreas transplantation, and it is used in 50% or more
of kidney recipients around the world. Mycophenolate mofetil has largely
replaced azathioprine in most organ transplantation procedures. Additional new
immunosuppressive agents that have been approved include sirolimus,
daclizumab, basiliximab, and antithymocyte globulin (Thymoglobulin).
Furthermore, a number of new regimens are being explored that attempt steroid
withdrawal or avoidance, or calcineurin inhibitor withdrawal or avoidance.
Heart And Heart-lung Transplantation
Early experimentation
In 1905, Carrel and Guthrie performed the first cardiac transplantation in
animals at the University of Chicago. This was a heterotopic experimental
transplantation. Parts of a small dog were transplanted into the neck of a larger
dog by anastomosing the cut ends of the jugular vein and carotid artery to the
aorta, the pulmonary artery, one of the vena cavae, and the pulmonary vein. In
1933, Mann transplanted a canine heart into the carotid-jugular circulation with
establishment of coronary perfusion. The longest survival was 8 days, and he
observed evidence of allograft rejection as the heart was infiltrated with
lymphocytes, mononuclear cells, and polymorphonuclear cells. The work of
Marcus and colleagues at Chicago Medical School contributed to donor graft
preservation and improved coronary perfusion techniques.
Pioneering work by Demikhov
Vladimir Demikhov's research greatly advanced the field of experimental
cardiac transplantation. His published works documented many experiments,
including transplantation of the head, transplantation of halves of the body, and
surgical combination of 2 animals with the creation of single circulation. His
initial work in cardiac transplantation involved canine heterotopic cardiac
transplants to the inguinal region. His monograph reported a long series of 250
experimental efforts at transplanting a heterotopic intrathoracic cardiac graft.
On June 30, 1946, Demikhov transplanted a heterotopic heart and lung; the
animal survived for 9 hours and 26 minutes. A subsequent experiment on a dog
resulted in 25 days of survival, and the cause of death was probably dehiscence
of the tracheobronchial suture line.
Graft preservation
Experiments in orthotopic transplantation began with Demikhov, who attempted
to maintain donor and recipient perfusion during anastomosis. Problems
associated with maintaining the recipient during transfer and preserving the graft
were addressed by Neptune and colleagues. Neptune's team transplanted the
entire heart-lung block and maintained both the donor and recipient in a cooler
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to maintain hypothermia. Webb and Howard demonstrated that canine hearts


that were heparinized and flushed in potassium citrate could survive prolonged
periods at low temperature. When transplanted heterotopically, the function of
these organs returned. Webb and Howard also performed successful orthotopic
heart-lung transplantations in which the recipient was maintained with
cardiopulmonary bypass during transfer.
Advances in surgical techniques
In 1958, Goldberg and colleagues at the University of Maryland performed
orthotopic cardiac transplantations using an innovative technique in which the
left auricle was anastomosed with the left atrium. This circumvented the
problems associated with anastomoses of individual pulmonary veins. This
technique was further refined by Cass and Brock, who used right and left atrial
cuffs.
In 1960, Richard Lower and Norman Shumway described the modern surgical
technique of orthotopic cardiac transplantation. The recipient was kept alive on
cardiopulmonary bypass; the donor heart was immersed in cold saline; and
anastomoses were performed to the atria, pulmonary artery, and aorta. The dogs
that underwent transplantation survived and resumed their regular activity; this
generated an immense interest in cardiac transplantation and further
experimental work by other investigators, including D.A. Blumenstock, who in
1963 reported that 50 of his dogs survived for periods ranging from 1-42 days.
Deaths in these dogs occurred secondary to acute rejection. Subsequent
investigators used immunosuppression and improved long-term survival; the
immunosuppressive drugs used included steroids, cyclosporine, and
azathioprine.
Human heart transplantation
By the mid 1960s, surgical techniques, methods of recipient support, and
methods of myocardial protection had been described. In addition, transplant
allograft rejection had been reported, and methods of diagnosing and treating
rejection were available. Legal and logistic issues were the next hurdles that
prevented heart transplantation in humans. On December 3, 1967, the first
successful human cardiac transplantation was performed by Christiaan Barnard
at Groote Schuur Hospital in Cape Town, South Africa. The transplant recipient
was a 54-year-old man with end-stage ischemic heart disease; the donor was a
young man with a severe brain injury. The recipient initially recovered but
subsequently died of Pseudomonas pneumonia 18 days later.
In 1967, Barnard described the operation: "The achievement did not come as a
surprise to the medical world. Steady progress towards this goal has been made
by immunologists, biochemists, surgeons, and specialists in other branches of
medical science all over the world during the past decade to ensure that this, the
ultimate in cardiac surgery, would be a success."
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On December 6, 1967, Adrian Kantrowitz performed a transplantation from an


anencephalic infant to an 18-month-old child using deep hypothermia and
circulatory arrest. Although the surgery went well, postoperatively, the recipient
developed metabolic and respiratory acidosis, leading to cardiac arrest, and
survived only 6.5 hours. The autopsy showed diffuse atelectasis of both lungs.
After multiple attempts at cardiac transplantation in the late 1960s, poor
outcomes were achieved and interest in this procedure waned. However, during
the 1970s, an organized approach to cardiac transplantation (mostly by the group
at Stanford University) improved the 1-year survival rate from 22% in 1968 to
65% in 1978. This success occurred because of improved management of
infectious complications, better donor and recipient selection, and improved
capabilities of diagnosing and aggressively treating rejection. The widespread
adoption of cyclosporine use in the 1980s resulted in increased worldwide
enthusiasm for cardiac transplantation and much-improved long-term survival.
Human heart-lung transplantation
Denton Cooley performed the first clinical heart-lung transplantation on
September 15, 1968. The team replaced the heart and lungs of a 2-month-old
infant who had an atrioventricular canal defect with the heart and lungs of an
anencephalic infant donor; the recipient survived only 14 hours, succumbing to
respiratory failure. In 1982, Bruce A. Reitz published the first successful clinical
series of heart-lung transplantations; the use of cyclosporine and the Stanford
University's group experience with experimental cardiopulmonary
transplantation were important contributing factors.
Lung Transplantation
Early experiments
Experiments in lung transplantation were underway during the 1940s, long
before human heart transplantation became a reality. In May of 1947, Demikhov
performed the first canine transplantation of the lungs alone. In November,
1947, Demikhov reported a successful transplantation of the lower lobe in a dog,
which survived 7 days. Juvenelle performed early experiments in autografting
and reimplantation. Neptune and colleagues began to use the atrial cuff method
for anastomosis. With proper atrial cuff anastomosis, pulmonary hypertension,
which was observed in earlier experimentation as part of the reimplantation
response, could be avoided.
Advances in bronchial anastomosis
Bronchial dehiscence plagued Demikhov's experiments in 1947. Haglin
developed a method for reestablishing the bronchial circulation by vascular
anastomosis. The Toronto Lung Transplant Group used a technique of
omentopexy to reinforce the bronchial anastomosis. Subsequently, telescoping
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the bronchial anastomosis to a depth of one cartilaginous ring was shown to be


equally effective, and thus omentopexy became unnecessary.
Additional advances occurred in the area of lung preservation; these methods
were crucial for successful transplantation. Initial techniques included
hypothermia and flush perfusion of the pulmonary vasculature in the
unventilated lung. The positive index inspiratory pressure during the
procurement procedure increases interalveolar surfactant, which minimizes
pulmonary complications in the graft. Insufflating the lung with 100% oxygen
during procurement coupled with the administration of prostacyclin into the
pulmonary circulation has resulted in acceptable graft function after 6-8 hours of
ischemic time.
Further advances
Lung allografts in mongrel dogs and inbred beagles were performed by Metras
in Marseilles, France, and Blumenstock in Cooperstown, NY. Thomas and
Blumenstock experimented with immunosuppressive regimens to combat lung
transplant rejection. A 300-day survival in a lung allograft recipient was
achieved with the help of immunosuppressive agents. Another hurdle that
needed to be overcome concerned the healing of tracheal and bronchial
anastomoses. The Toronto Lung Transplant Group demonstrated that better
immunosuppression with cyclosporine led to improved healing of the bronchial
anastomosis.
Human lung transplantation
James D. Hardy and his team performed the first single-lung transplantation in a
human at the University of Mississippi Medical Center on June 11, 1963. A 58year-old man with unresectable left lung cancer and obstructive pneumonitis
was the recipient. The donor was a patient who died from a massive myocardial
infarction. The lung transplant recipient received immunosuppression with
azathioprine and irradiation. Unfortunately, the patient died on the eighth
postoperative day because of progressive renal failure despite peritoneal
dialysis. However, at autopsy, the vascular and bronchial anastomoses were
intact and evidence of rejection in the transplanted lung was absent.
Fritz Derom of the University of Ghent in Belgium transplanted a lung in the
1960s into a recipient who had end-stage respiratory failure due to silicosis. The
patient improved significantly and lived for 10.5 months after the operation.
This group of investigators from Ghent was the first to successfully treat and
reverse episodes of rejection and acquired infectious complications in the
recipient.
The growth of lung transplantation was slow due to unclear eligibility criteria
for lung transplant recipients, and, despite clear improvement in function after
transplantation, survival benefits were less clear. In fact, at least one study
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showed patients with end-stage lung disease survived longer than transplant
recipients. By 1978, 38 human lung transplantations had been performed.
Bronchial disruption and the inability to differentiate infection from rejection
appeared to be the major problems. Improved healing of the bronchial
anastomosis was found after the introduction of cyclosporine, and this may have
been due in part to the lower routine doses of corticosteroids.
Unilateral and bilateral sequential lung transplantation
Lessons were learned from en bloc heart-lung transplantation, in which single
distal tracheal anastomosis and maintenance of collateral circulation to the
airway achieved much better anastomotic healing. Limiting the length of the
donor bronchus and extrinsic revascularization by wrapping the anastomosis
with omentum led to advancements in anastomotic techniques. This culminated
in a successful single-lung transplantation, a procedure pioneered by the Toronto
Lung Transplant Group under the leadership of Joel Cooper and Griffith
Pearson.
Subsequently, lung transplantation was performed by G.J Magovern and A.J
Yates at the University of Pittsburgh; this patient survived only a short time. In
1983, the Toronto Lung Transplant Group consisting of Cooper, Pearson, and
Patterson accomplished long-term survival following a successful single-lung
transplantation.
Isolated single-lung transplantation was performed for patients with end-stage
chronic obstructive pulmonary disease and advanced pulmonary fibrosis. This
technique was later expanded to bilateral sequential single-lung transplantation
(ie, isolated double-lung transplantation) for patients with bronchiectasis and
cystic fibrosis. Over time, bilateral sequential single-lung transplantation
became the procedure of choice because en bloc double-lung transplantation was
a procedure of considerable technical complexity. More recently, use of living
donors for lobar allografts has been demonstrated to be a useful alternative for
selected patients who require isolated lung transplantation.
Long-term survival of lung transplant recipients
One-year survival rates for lung and heart-lung transplantations worldwide
remain lower (70% and 62%, respectively) compared with heart transplantations
(83%). The 5-year survival rates are 70% for heart and 45-50% for lung
transplantations. Long-term patient survival rates are dismal for all thoracic
grafts: 22.3% at 18 years for heart, 20% at 9 years for lung, and 25% at 12 years
for heart-lung recipients. The most significant factors responsible for immediate
mortality are related to either the patient's medical condition (patient in intensive
care unit prior to transplantation and/or requires mechanical ventilation) or the
underlying diagnosis. The factors responsible for late mortality continue to be
infection and the presence of chronic rejection manifested pathologically as
bronchiolitis obliterans syndrome.
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Bronchiolitis obliterans syndrome occurs in at least 40% of patients by 2 years


and is the cause of death in 50% of those affected. The focus has now shifted to
the treatment of chronic rejection and bronchiolitis obliterans syndrome as
opposed to technical proficiency. Enhanced induction and maintenance
immunosuppression along with aggressive treatment of acute rejections may
delay the incidence of bronchiolitis obliterans syndrome and improve graft
survival.
Kidney Transplantation
Renal transplantation is the present-day, state-of-the-art therapy for patients with
end-stage renal disease. The history of successful renal transplantation parallels
the advancement of transplantation immunobiology. Experiments in the early
1900s and continued advances in surgery, nephrology, and immunology helped
accomplish this feat.
Early experiments
Experimental intra-abdominal renal grafts were being performed in animals in
the 1930s and 1940s. Autografts generally survived, although homografts were
rejected. On December 25, 1952, Hamburger performed the world's first renal
transplantation in a 15-year-old roofer who injured his solitary kidney. The
donor of the graft was the patient's mother. The graft functioned immediately
following surgery, but it unfortunately ceased to function on the 22nd
postoperative day. The patient died 10 days later due to the unavailability of
hemodialysis. However, this event had a considerable impact on the scientific
community. Surgical inspection of the graft revealed that immunological
rejection, rather than stenosis or thrombosis of the renal artery, led to graft
failure.
Successful kidney transplantation
Joseph Murray and Hartwell Harrison performed the first transplantation of a
kidney graft between identical twins on December 23, 1954. This success was
followed by subsequent attempts by Murray and Merrill that led to 7 successful
transplantations between identical twins in Boston. Most of the recipients of
identical twin kidney grafts performed by Joseph Murray did well; some still
have functioning kidneys more than 30 years after transplantation. However, the
attempts at cadaveric renal transplantation universally resulted in graft failure
due to rejection.
The first attempts to control the immune system used total body irradiation. In
1958, a Boston-area woman who was accidentally irradiated with 6 Gy received
a functional renal graft, although the patient died from bone marrow aplasia. In
1959, Hamburger and Merrill irradiated 2 transplant recipients with a total dose
of 4.5-4.8 Gy; the donors were nonidentical twins. Both of these recipients had
successful outcomes. The patients survived 20 and 26 years, respectively. In
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June 1960, Kuss and colleagues were faced with rejection in a kidney transplant
recipient who received the graft from an unselected donor. The use of 6mercaptopurine in this patient, an immunosuppressive agent previously studied
in animals, reversed the rejection process and ushered in the era of medications
for the prevention and treatment of rejection. In 1964, Crosnier performed
another cadaveric transplantation with long-term successful function.
In the early 1960s, the pioneering work of Thomas Starzl led to further
advancements. His contributions were systematic studies using azathioprine and
prednisone therapy to prolong graft survival. Following the demonstration of
antilymphocyte serum efficacy by Waksman, Starzl conducted the first clinical
trial of antilymphocyte globulin as an adjunct to azathioprine and prednisone in
human kidney transplantation.
Long-term graft survival
At present, the 1-year patient survival rate for living donors is 98%, and the 1year patient survival rate for cadaveric transplants is 95%. The graft half-life for
living donors is approximately 20 years, and the graft half-life for cadaveric
donors is 12 years.
The outcome data from the United Network for Organ Sharing annual report of
2002 shows that the 1-year survival rate for grafts from living donors ranges
from 88.1-95% and the rate for cadaveric grafts increased from 79.7% to 87.1%.
Furthermore, the half-life for grafts from living donors increased steadily from
12.7 to 21.6 years, and that for cadaveric grafts increased from 7.9 to 13.8 years.
These short-term improvements are the possible result of cyclosporine; its effect
on the long-term survival of kidney transplants is not known. Kidney graft
failure occurs because of chronic rejection, graft dysfunction, and
nephrotoxicity, causing the patient to need dialysis and often a new organ. The
development of new therapeutic approaches to prevent chronic rejection is
needed to prolong the long-term survival of kidney transplants.
Liver And Pancreas Transplantation
Liver transplantation
Early history of liver transplantation
The history of liver transplantation began with experimentation by Stuart Welch
in Albany, NY, in 1955. Welch described the experimental transplantation of an
auxiliary liver to the right paravertebral gutter in mongrel dogs. Experiments at
the University of Miami from 1956-1958 led the way to orthotopic liver
transplantation. In 1958, orthotopic liver transplantations following hepatectomy
were performed, although these attempts were marred by poor performance of
the transplanted liver. The operative procedures were further refined by Jack
Cannon at the University of California at Los Angeles in 1956 and by several
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investigators in Boston and Chicago from 1958-1960. These animals did not
survive for more than 4 days due to a lack of effective immunosuppression;
however, technical principles such as optimal portal revascularization, allograft
preservation, and other techniques were perfected.
Human liver transplantation
Thomas Starzl attempted human liver transplantation in 1963, at the University
of Colorado. Despite years of research into organ preservation, surgical
technique, and understanding the physiological interrelationship of the liver with
other intra-abdominal viscera, this did not prepare his team for the unexpected
difficulties encountered in patients with end-stage liver disease and extensive
portal hypertension. The first patient did not survive surgery, and 2 others died
7.5 and 22 days postoperatively. Subsequent similar failures in Boston and Paris
led to a worldwide moratorium on liver transplantation.
Initial attempts were unsuccessful because of a combination of technical
difficulties and the unavailability of effective means to prevent rejection. As
increased experience was achieved and with improvements in
immunosuppression, prolonged liver recipient survivals were achieved. From
1963 to 1979, 170 patients underwent liver transplantation at the University of
Colorado; 56 survived for 1 year, 25 for 13-22 years, and several remain alive
with follow-ups of 17-31 years. In 1968, Roy Calne of Cambridge University
founded the second liver transplantation program. As with renal grafts, the longterm survival rate after liver transplantation remained poor (18-30% one-year
patient survival) until the advent of cyclosporine.
Pancreas transplantation
Experiments in pancreas transplantation began long before the discovery of
insulin. In 1891, pieces of dog pancreas autotransplanted beneath the skin
prevented diabetes after removal of the intra-abdominal pancreas. Subsequent
experimentation with intrasplenic transplantation did not succeed because of
graft necrosis. In 1916, sliced human pancreas was transplanted into 2 patients,
but the grafts were completely absorbed. The first pancreatic
xenotransplantation was performed in 1893 in London; a 15-year-old boy
underwent subcutaneous implantation of a pancreas.
Despite extensive animal experimentation, pancreatic transplantation did not
become a reality until 1966 when W.D. Kelly performed the first human, wholeorgan pancreatic transplantation for treatment of type 1 diabetes mellitus.
Because of poor outcomes, few procedures were performed until 1978. Much of
the early work was performed by Sutherland and colleagues at the University of
Minnesota. With improved immunosuppressive regimens and newer surgical
techniques, the 1980s ushered in a new era in pancreas transplantation.
According to the International Pancreas Transplant Registry, nearly 10,000
pancreatic transplantations were recorded by 1998.
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Most of the pancreatic transplantations have been performed in patients with


type 1 diabetes mellitus and a lack of insulin production. The most common
indication is renal failure; therefore, the pancreas transplantation is typically
performed simultaneously with a kidney transplantation. In some patients with
hypoglycemic unawareness or other diabetic complications, isolated pancreas
transplantation has been performed. However, the results have been somewhat
inferior to those of the combined procedure.
Various technical concerns must be considered in patients undergoing pancreas
transplantation, including whether or not the venous drainage should be into the
systemic circulation or into the portal vein. Another controversial topic is
whether the exocrine secretions should be drained enterically or into the bladder
as initially described. The complications of graft pancreatitis and bladder
leakage that plagued early experiences with pancreas transplantation have
largely been resolved as a result of both better technical expertise and fewer
rejection- and immunosuppression-related complications.
Cell Transplantation
Bone marrow transplantation
Early history
The history of bone marrow transplantation (BMT) dates back to 1939 when
Osgood unsuccessfully infused a few milliliters of marrow into patients with
aplastic anemia. In 1949, Jacobson discovered that shielding the spleen
protected mice from lethal irradiation. Lorenz performed allogenic BMT in
animals protected by total irradiation. His findings, and research by Barnes and
colleagues, demonstrated that a cellular rather than a humoral factor played a
role in graft survival. Vanbekkum, DeVries, and other scientists performed
important experiments to study immunological reactions in transplantation
recipients. They demonstrated that successfully grafted allogeneic marrow cells
could later produce an immunological reaction against host tissues; this
phenomenon is now known as graft versus host disease (GVHD).
Experimental canine studies during the 1960s resulted in important discoveries
that were applicable to human transplantation. Total body irradiation did not
seem to prevent GVHD; mismatched canine leukocyte antigen always resulted
in graft rejection or GVHD. Methotrexate was also found to be an
immunosuppressive agent that could prevent or ameliorate the graft versus host
reaction.
Human bone marrow transplantation
Although initial attempts at allogeneic BMT in the 1950s and 1960s were
unsuccessful, renewed attempts occurred after additional knowledge of the HLA
system was obtained. Getty performed a successful allogeneic marrow graft in a
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patient with severe combined immunologic deficiency using a sibling donor


with identical HLA. Two similar successes were reported around the same time.
These patients did not require immunosuppressive therapy and survived for
more than 25 years. In the 1970s and 1980s, clinical BMT required matched
HLA haplotypes between the donor and recipient. Although earlier BMT
procedures occurred between siblings, current molecular techniques have
enabled the precise characterization of MHC genes and have allowed the
possibility of matching unrelated individuals.
Stem cell transplantation
In the 1970s, researchers performed a large number of BMT procedures using
HLA-matched sibling donors for patients with end-stage leukemia or aplastic
anemia. These endeavors resulted in mixed success because BMT was only
considered for patients with advanced leukemia after conventional therapy
failed. In the 1980s and 1990s, researchers noted that BMT performed at first
remission or after first relapse resulted in significantly prolonged survival. BMT
procedures for treating other disorders, such as thalassemia major and sickle cell
disease, were also successful when the procedure was performed at an earlier
stage.
Because stem cells have been shown to be present in peripheral blood, these
cells have now been used for autologous grafting. In 1989, Gluckman
successfully transplanted cord-blood stem cells, which are immature and less
likely to cause GVHD. Extensive studies reviewed by Korngold and Brent have
established the role of both T cells and histocompatibility systems in the GVHD
reaction. Even with HLA-matched sibling donors, GVHD occurs half of all
patients. Although corticosteroids and methotrexate partially ameliorated GVHD
in early studies, cyclosporine in combination with other drugs have proven
superior in subsequent studies.
Present status of bone marrow and stem cell transplantation
Following major efforts to determine the effectiveness of autologous BMT in the
1970s and 1980s, autologous BMT has become the therapy of choice for
patients with malignant lymphoma and for selected patients with acute
myelocytic leukemia and other malignancies. Recent research has also shown
that a large number of stem cells from peripheral blood could be harvested
following cytotoxic chemotherapy and specifically after growth factor
administration. Following high-dose chemotherapy, peripheral blood stem cell
therapy results in more rapid recovery of platelets than BMT. In the future, stem
cell transplantation may allow many patients to attain a state of minimal residual
disease so that other treatments, such as chemotherapy maintenance, monoclonal
antibodies, vaccines, nonspecific immune modulators, and dendritic cell
infusions, may be performed.
Pancreatic islet cell transplantation
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Experiments in 1964 and 1965 proved that islet cells could be isolated by
digestion of a whole pancreas and remain viable. Ballinger and Pelacy reported
the first experimental islet cell transplantation in 1970. Approximately 500
isolated islet cells were transplanted intraperitoneally in diabetic rats, with
subsequent long-term amelioration of diabetes. Following these findings, Kemp
described a newer method of implantation, by intraportal injection and
embolization of islet cells into the liver. This technique improved control of
diabetes much more quickly than intraperitoneal transplantation.
Islet cell transplantations in humans are usually allografts, which have higher
rates of failure and require lifelong immunosuppression. C. Ricordi has
performed much of the previous work on islet cell transplantation. The causes of
islet cell graft failure include failure of the initial engraftment, insufficient islet
cell mass, rejection, and islet injury caused by immunosuppressive agents. Islet
cell autograft transplantation in patients with chronic painful pancreatitis does
not require immunosuppression, and patients have better success rates. Because
current immunosuppressive drugs affect islet function, the development of more
effective and less toxic immunosuppressive drugs may improve the success rate
of islet cell transplantation.
Edmonton protocol
James Shapiro and his team at the University of Alberta in Edmonton, Canada,
began a series of islet transplantations in March, 1999, which has revolutionized
the field and helped achieve remarkable success rates. The Edmonton protocol
consists of percutaneous intraportal injection of blood typematched islet cells
under local anesthesia in the radiology department of a hospital. Once the islet
cells embolize into the liver, they develop a blood supply and begin producing
insulin. Most of the recipients of this therapy required 2 procedures performed
over an average of 29 days in order to produce enough insulin to avoid
exogenous insulin administration for maintenance of euglycemia. In the first
published series of 7 consecutive patients with type 1 diabetes undergoing islet
cell transplantation under this protocol, insulin independence was achieved in
80% of those monitored for 2 years. Much of the success of this protocol is
attributed to the novel glucocorticoid-free immunosuppression regimenused.
In the past 5 years, more than 500 patients with type 1 diabetes mellitus received
islet transplants at over 50 institutions worldwide. However, islet function
inevitably decays over time. The benefits of islet transplantation are improved
control of glycosylated hemoglobin and reduced risk of recurrent hypoglycemia.
Further work is needed to develop successful living donor islet transplantation,
single donor protocols, improved engraftment, islet proliferation in vitro and in
the recipient, alternative islet sources, and new immunosuppressive drugs.
Xenotransplantation

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Allograft transplantation has become the therapy of choice for end-stage organ
failure in the 21st century. However, because of the lack of donor organs, the use
of biomechanical and nonhuman organs is being explored as a potential solution
to this shortage. Xenotransplantation is defined as the transplantation of tissue
from a donor of one species to a recipient of a different species.
Early history of xenotransplantation
Xenotransplantation was actually performed long before clinical
allotransplantation. In 1905, French surgeon Princeteau transplanted a slice of
rabbit kidney into a uremic child. Despite noted improvement of renal function,
the child died of pneumonia. Although many other examples of xenografts of
different organs have been reported from this early period, human xenografts
were quickly abandoned because they uniformly failed.
More recently, in 1960, Reemtsma performed a kidney transplantation from a
chimpanzee donor into a human recipient; aggressive immunosuppression led to
a 9-month survival. In 1984, Bailey performed an orthotopic transplantation of a
baboon heart into a human neonate with a hypoplastic left ventricle; the graft
functioned for 20 days. Despite aggressive immunosuppression, graft failure
occurred secondary to vascular rejection. A baboon-to-human liver
transplantation was performed by Starzl in 1993. This graft functioned well for a
time, although the patient died several months later from severe sepsis and organ
rejection. Other xenotransplant efforts include transplantation of dopaminergic
porcine fetal neural cells to the basal ganglia in order to treat Parkinson disease.
Deacon et al performed one such transplantation in 1997.
Several obstacles to xenotransplantation have been uncovered through these
human and other animal experiments, including the presence of alpha 1,3galactose (alpha Gal) antibodies on the surface of animal cells, which are not
present on human cells and are attacked by natural antibodies within normal
human circulation. Along with the immunological barriers found, the animal
organs may produce signals and proteins that are similar but not identical to
humans, which can affect their function.
The future of xenotransplantation
The future of clinical xenotransplantation appears to be progressing in 2
directions. Cellular xenografts, such as pancreatic islet cell transplantation and
neural cell transplantation, may be protected from rejection because of the
absence of vascular tissues. In addition, the consequences of rejection may not
be overly severe. In contrast, xenotransplantation may, in the future, be used as a
lifesaving procedure for critically ill patients who are waiting for allografts but
are dying because of the shortage of organs. This technique may be particularly
helpful for patients with acute liver failure or cardiac failure.

20

The answers may come with the creation of transgenic animals to overcome the
immunologic barriers, and, eventually society may see the introduction of
elective xenotransplantation as an alternative to allotransplantation. Many
researchers hope that successful xenotransplantation procedures will eventually
overcome the ever-increasing donor deficit and provide immense benefit to the
large number of patients who require transplantation and currently have little
hope of receiving a cadaveric allograft.
Keywords
autograft, isograft, syngeneic graft, allograft, homograft, xenograft, heterograft,
heart transplantation, lung transplantation, kidney transplantation, bone marrow
transplantation, BMT, liver transplantation, OLT, xenotransplantation,
immunosuppression, total body irradiation, graft vs host disease, graft versus
host disease, graft-versus-host disease, GVHD, graft rejection, major
histocompatability complex, MHC, human leukocyte antigen, HLA, transplant,
xenotransplant, organ donation, organ donor, UNOS, United Network for Organ
Sharing, organ transplantation, orthotropic transplantation, heterotropic
transplantation, pancreatic transplant, pancreas transplant, pancreatic
transplantation, pancreas transplantation, National Transplant Act

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