The transplantation of gastrointestinal organs

GASTROENTEROLOGY

The Transplantation THOMAS

E. STARZL,

Pittsburgh

T

Transplant

he history

Institute,

began

to fill during

of Pittsburgh

grafting

ANDREAS Health

through

to the kidney.’

plant

with

laboratories

which

and thoracic the

TZAKIS,

Science

1959

The vacuum

the mid and late 1950s with

in several

models

TODO,

University

confined

development dominal

SATORU

of whole-organ

was largely

of Gastrointestinal

of canine

the

trans-

to study all of the intra-ab-

organs.

preciated

at

outset,

metabolic,

and immunologic

Although the

relationships

on its transplantation. Welch or right allograft

istence

except experiments

by azathioprine

paravertebral hepatic

artery

gutter

stored

by rerouting

the high-volume

return

of the host

inferior

portal

vein. the livers were destroyed

the nonimmunosuppressed

cava within

animals,

ple.5 As new growth origin

in

from

flow was re-

systemic

vena

by re-

liver into the

was revascularized

into

Insulin

venous the graft

a few days in

it was concluded

was solely responsible. This was an uninterpretation. After nearly 80 years of

research on the experimental procedure of Eck’s fistula (portacaval shunt), the dogma of 1955 was that the high concentration of hormones and nutrients in splanchnic venous blood had no relevance to liver structure or function or the capacity for regeneration.3 The presumed nonspecificity of splanchnic venous blood was the central strut of the seemingly impregnable flow hypothesis of portal physiology which held that “all blood is equal.” In spite of his mistake in attributing auxiliary graft destruction to rejection alone, what Welch had done

blood

protected

im-

from

of splanchnic

reve-

that

the liver

with

of first

was able to remove

sub-

that little was left for the combut it has long been

hepatotrophic factors available

in recent

or screened

auxiliary

substances

known

and enteric

years, they have

with nontransplant are direct

allograft

of

are multi-

of pancreatic

els that in one way or other the original

When

was the most easily identified

factors,

have become

been discovered

veins.

in 1963 under

a few days to a fraction

blood

so completely organ.

livers

apparent

the portal

of the recipient.2

and the portal

peting

became

to the portal

of the blood

portal

but deprived

nous inflow shrank within their original size.4

that the so-called

who described

of an extra (auxiliary)

auxiliary

organ

in 1955 by C.

and native were repeated

of

with identical

for the constituency

to the graft

Welch’s

model

was the coex-

of two livers in the same animal

conditions

in hu-

transplantation

literature

New York,

or iliac artery,

that rejection derstandable

yielded

Hepatic

to the scientific

dogs the insertion

successfully

of the secrets

of Albany,

a unique

it was the first vital

to be engrafted

search

was introduced

When

of the model

stance(s)

not only because the kidney

the aorta

an experimental

The principle

jection

the liver occupied

but also because

The

was to create

great power.

It soon

mans,

pelvis

unwittingly

access

In this revolution,

FUNG

Pennsylvania

of each of

The Liver

Stuart

JOHN

munosuppression,

the others.

position,

and Pittsburgh,

anatomic,

the intra-abdominal viscera (Figure 1) eventually influenced the conditions for transplantation of all of

beyond

Organs

delivered

it was not ap-

intimate

Center,

1993;104:673-679

mod-

descendents

(double-liver)

of

prepara-

tions.’ The liver-replacement plantation) ported

operation

in common

clinical

by Jack Cannon

who cited Welch’s

for his own

“several

article

of California, as the stimulus

successful”

replacement

survival

of the patient.“7

in dogs “without

trans-

use today was first re-

of the University

Los Angeles, tions

(orthotopic

operaWith

the assumption that the liver played an important role in rejection, Cannon speculated that the graft would not contribute

to its own

new operation

were not given,

repudiation.

Details

of his

and the procedure

re-

mained virtually unknown until major programs of canine “orthotopic” liver transplantation were begun at the Peter Bent Brigham Hospital (Harvard)’ and independently at Northwestern University in Chicago.” At the time, there was no effective way to prevent rejection, nor would this objective be achievable for several more years. 0 1993 by the American

Gastroenteroiogical 00 16-5085/93/$3.00

Association

674

STARZL

Figure

1.

The complex

The Boston Moore tutional tended initial

GASTROENTEROLOGY

ET AL.

of intra-abdominal

effort under

the direction

was part of an immunologically commitment back

a modulator

than

of insulin a new

activity

of Francis

The

D.

instithat exwith

an

that the liver was

technique

of the metabolic of total

operation),”

in-

hepatectomy and ulti-

the insertion of an allograft into the vacated fossa,” were viewed at first as tools for meta-

bolic investigations. The superior liver-supporting

qualities

of portal

ve-

nous blood were easily demonstrable by the results of the transplant experiments.” The other requirements for successful liver replacement also were straightforward. Intraportal infusion of the transplanted liver with chilled solutions during its removal allowed effective short-term storage in much the same way as in clinical operating rooms today.’ Improved infusates in the succeeding years13*14 eventually replaced the originally used lactated Ringer’s and saline solutions. Since 1987, the University of Wisconsin solution developed by Belzer and Southard15 has permitted the safe refrigeration of human livers for 18-24 hours. Orthotopic

liver

transplantation

could

not

liver-pancreas,

be ac-

intestine,

complished

consistently

nal

bypasses

venous

from

the

pools

to the superior

anhepatic

Northwestern

or in turn was governed

In the course

(the first half of a transplant

from which come

oriented

previously

from a hypothesis

b Y this hormone.” vestigations,

a decade

on the kidney.”

stemmed

(center)

to organ transplantation

more

emphasis

initiative

mately hepatic

viscera

formed

occluded

in dogs without passively

splanchnic

stage while

vena

No. 3

or liver grafts (periphery).

pancreas,

that

Vol. 104,

and

exterblood

systemic

cava during

recipient

plastic

redirected

venous

the so-called

hepatectomy

was per-

and the new liver was sewn in.8,9 Such venous

decompression most

clinical

ever,

the

introduction

passes without stressful competent

was later

shown

to be expendable

cases by experienced in 1983

anticoagulation

and placed general

surgeons.16 of pump-driven

by-

made the operation

less

it well within and vascular

in

How-

the grasp of most

surgeons.”

The sense of futility in the late 1950s at developing an operation that had no conceivable clinical use changed

abruptly

Dameshek of 6-mercaptopurine

with the discovery the

by Schwartz

immunosuppressive qualities in nontransplant models. With

and of the

demonstration by Schwartz and Dameshek and workers in other laboratories that the drug mitigated the rejection of skin and kidney allografts in rats and dogs, respectively, the stage was set for the introduction by Murray et al. of the 6-mercaptopurine analogue azathioprine for clinical renal transplantation.18 The combination of this drug with prednisone’” permitted a treatment policy to be evolved that could be used with a succession of baseline drugs - azathioprine, cyclophosphamide, cyclosporine, and FK 506 -over the

March

1993

TRANSPLANTATION

next 30 years. In these drug cocktails, verable

prednisone

modulation

allowed

on a day-to-day

phocyte

globulin

adjunct

for induction

substitute

(ALG)

for

ALGs

changes

basis.

treatment

or as a prednisone

preparations

were succeeded

laboratory

sity of Colorado, sone was shown

there.

of kidney

when

coagulopathy

operating

of

room

General

the rest of 1963 and January

attempts

were made-four

Boston

and Paris.

6’/2-23

days, pessimism

self-imposed

When

moratorium

cipal concerns did not allow

in Denver settled

1,

atresia in the

duction

ended

combined

with

prednisone

first 12 liver

recipients

worldwide

achievable.

experience, center

available immunosuppression trol rejection. By the summer at least partially laboratory

had become

research,

first long survivor a time

cancer

during

an intensive

and on July

had been period

23 the trial

was re-

girl whose

liver contained

Although

she became

The

child

died

a the

it was

of recurrent

rate never fell below

50% in cases that

liver

also recorded court

liver

graft

in a multi-

transplantation

of last appeal

liver diseases, otherwise

The principal became

and

for al-

and even for se-

nonresectable

limitation

an inadequate

hepatic

of the technol-

supply

of organs

to

needs.

Multivisceraland Intestinal Transplantation

of

after 400 days, and for the next dozen years the

1 -year mortality

with

that

15% in the Pittsburgh

By now,

the accepted

patients

ogy quickly

to con-

after liver transplantation,22

of triumph.

lected

patient

another

trial.

meet the burgeoning

of 1967, these deficiencies rectified

sumed with a 1 M-year-old nonresectable hepatoma. not

was inadequate

the

and

of FK 506 for cyclo-

l-year

an improvement

European

malignancies.

that

cyclosporine

1 year,25 and 7 are

rate of at least 70% was readily

With the substitution

enough

and

with

in

Of our

as the news was confirmed

survival

most all nonneoplastic

to be manageable,

depletion

still alive more than a dozen years later. New programs

such a complex operation, that the intraoperative medical management (including coagulation) was not well understood

treated

rate increased

of

intro-

this drug was

cocktails.24

11 lived for more than

survival

performance

use.

clinical

or lymphoid

the first of the cyclosporine-based

of

from the

its practical Calne’s

in 1979,23 when

with

of preservation

after

of cyclosporine

benefits

but always with

rate resulting

was too great to allow frustration

1968.

(Bismuth,

miraculous

that the mortality

in 1989,26 the

a

Paris

it was successful,

di-

who had

in Hannover,

and

the nearly

when

sporine

that lasted 3 years. The prin-

for the deliberate

1972)

died after

in worldwide

subsequently

1974) also reported

a 1 -year patient

and one each in

program

this operation

proliferated

1964, six more

liver

established

(Pichlmayr,

prednisone,

Hospital.

all of the patients

were that the methods time

on March

bled to death

Colorado

in

in 1962 and

a child with biliary

and an intractable

in February

a second teams

jus-

were being

opened

The

therapy

could

England,

operation

on to the liver.21

replacement

this far. The same questions

675

liver trans-

rected to Roy Calne of Cambridge,

the notation

transplantation

recipients

to move

at liver

1963, ended tragically

experi-

to the Univer-

antirejection

transplant

was made

first attempt

Through

kidney

effort that had brought

Germany

After azathioprine-predni-

to be effective

1963, a decision The

was moved

and a clinical

was started

a handful

by mono-

University

if such a small dividend

tify the prodigious

Other

such as 0KT3.

transplant

program

eventually

ORGANS

asked increasingly plantation

as a short-term

intervention2’;

In late 1961, the Northwestern mental

in immune

In 1966, antilym-

was added

secondary

these polyclonal clonal

quick

the dose-maneu-

OF GASTROINTESTINAL

At the same orthotopic ment

in Boston

University tinal

liver

time

in the summer

transplantation and Chicago,

of Minnesota

transplantation

the first of numerous

of 1958

was under Richard

began

studies

as

develop-

Lillehei

of the

of small

intes-

in dogs2’ that led 8 years later to unsuccessful

clinical

trials.28 Be-

were accrued at the rate of about one per month. The terrible losses were concentrated in the first few post-

tween failed

operative

usually with the death of the patient.2” Although improvements in immunosuppression were being made that allowed long survival after intestinal transplanta-

months.

After

this,

the life survival

curve

flattened, leaving a residual group of stable and remarkably well survivors. Thirty (18%) of the first 170 patients in the consecutive series that started March 1,

1967 and 1987, more than a dozen attempts during the operation or up to 76 days later,

1963, and ended in December 1979 lived more than a decade, and 23 of these are still alive after 13-23 years.

tion in dogs and pigs, none of these human grafts throughout the two-decade span provided significant nutritional function.

They were all treated with azathioprine (or cyclophosphamide), prednisone, and polyclonal ALG. The continuing survival of these patients was a mute testimonial for liver transplantation, but it was

This barrier was tion was recorded cadaveric intestine graft in a recipient

broken in 1987 when graft funcfor more than a half year from a that was part of a multivisceral treated with cyclosporine, predni-

676

STARZL

GASTROENTEROLOGY

ET AL.

sane,

and OKT3.30

been

developed

1959 during

cording stem

artery

organs,

operation

could

to the surgical

The grapes,

be removed objectives,

but

both

were preserved.

The

was kept intact

up to or beyond

the liver.

The first patient who survived operation under cyclosporine-based other

died

after

patients

have been treated operation

dure in which

only

2B) was described

the liver

operation

has been particularly

the short

gut syndrome

I3 (76.5%)

outflow

lymphoma,

hyperalimentation.33

of I7 patients

tion from the original

liver

Using

modified

the composite when This

the

graft

organs

impression

A

the

was less severe were

transplanted

was confirmed

in 1969 by Calne recipients

of the organs than

under

failure

from

either

(Table

in un-

making

up

found

extended

et a1.,35 who described in pig liver protection of kidney and skin grafts

began

in March

by Goulet from

et a1.36 of

a living

related

Germany. straws in the wind.

intestinal

recipients

I), where intestinal

The routine then became

with

the results

FK

506 in

have been bet-

transplantation

than

with

Eight

operation or its liver-intestine eci of 9 r p ients survive, of whom all

but one are TPN free. The expected for general

use in the near future development

release of FK 506

is certain

to stimulate

of the intestinal

transplan-

field.

When

the intestine

able and usually

is transplanted

possible

into the host portal

vein.

so for technical reasons bypass the hepatotrophic around

was

strategy

the multivisceral

variant.33

tation

transplant

immunosuppression

isolated

rapid further

individually.34

and greatly

These were isolated

ter with

even when

transplantation

segment

by Deltz of Kiel,

Pittsburgh

com-

small intestine

possible

with

from

great to justify

intestinal

the successful

of an ileal

afforded

of the liver

for this draconian

are re-

series are

that

and

in the field

transplantation,

simpler

Enthusiasm

of cadaveric

common use of such complex gasreactivated interest in an observa-

dogs that rejection

a technically

survival

FK 506,

experiments

and intestinal

proce-

et a1.32 This

in the Pittsburgh

multivisceral

liver

surgeon

to the intestine

was sufficiently

No. 3

were performed

transplantation

1989 of a cadaveric donor

alive after @/2-30 months-all but I liberated total parenteral nutrition (TPN) (Table I). The increasingly trointestinal grafts

that the protection

to fade with

with the

useful in patients developed

only

Paris

and small bowel

who

bined

experiments

as late 1991, some workers

the same donor

but

I). A variant by Grant

believed

and by the Japanese

whose

by the concomitant

needed.

successfully

(Table

tained

after prolonged

arterial

venous

using FK 506 and are alive

after as long as I5 months (Figure

ac-

the multivisceral immunosuppres-

192 days of a B-cell

full multivisceral

As recently

or

or retained

donor,

a

with

axis and

24.

the same

Naoski Kamada, in rats.

of the celiac

(Figure

from

in

as a grape cluster

structures

sion

had

dogs

on liver transplantation.31

stem consisting

mesenteric

individual

multivisceral

nonimmunosuppressed

was envisioned

central

superior

The

early research

The allograft double

in

Vol. 104,

the liver

has not

to drain However,

alone,

it is desir-

its venous the inability

outflow to do

and the consequent need to contents of intestinal blood yet caused

serious

hepatic

complications. Another

variation

of the multivisceral

operation

is

Figure 2. The multivisceral transplantation originally developed in dogs (A) and (6) a commonly used variant in which the central organs (pancreas and duodenum) are removed, leaving the liver and small bowel. These two procedures have been used successfully in humans and provided the first examples of functioning bowel allografts. Inset: Anastomosis of host portal vein into graft portal vein.

March

TRANSPLANTATION

1993

Table 1. FK 506: Transplantation of Intestine Alone or As Part of Composite Graft

dominant

TPN free Dates Intestine

5/2/90

Liver-intestine

6/7/92 7/24/90

Total

9

8

7

17

13

12

to to

Partiala -0

and

to

3

3

whole-organ ing only

2

What

1

vided of encephalitis

and need to

above

The remaining as partial

grafts underwent which

of Figure

and intestine

below

1, in which

else’s

is discarded.37

graft has been used

for the organs

remained

differ-

large in the case and

The answers

were pro-

survivors

in the world

after kid-

by the longest

removed

at upper

from

each

liver

of these

or kidney,

well as from the patient’s

the microscope

made

them

the outset.

of the jejunum

the residual

These

grafts

along

tioned

as long as 4% years.

short

the liver

who

gastrointestinal segmental

and pancreas

bowel

have

func-

Graft Acceptance

tissues.

Then,

(immunostaining

history

recipient’s

nor and recipient

by polymerase

gerprinting”)

techniques. experiments

(Figure

nodes,

staining

and

procedures after

fluores-

the tissues were examined from

cells that

the organ

donor,

Alternatively,

chain

reaction

could

(“DNA

these analyses in animals,

the

the do-

to any specimen

came from

fin-

and from

a grand design

3) that was always the same no matter

with

ing the blood

the

special

or both.

be separated

emerged

own skin, lymph

contributions

what the engrafted

to weather

recently

to see if the individual

up had come

tion, it has not been possible to comprehend, nor even to have a plausible theory about, how grafts were able the aid of immunosuppression

after

own body,

new laboratory

of transplanta-

someone

more

or sex identification

As the answers

the modern

bearing

also from

treated recipients of hearts, lungs, and intestines. The samples were taken from the transplanted organ as

under

with

cluster

patients

and

have been

so-called

and a segment

in continuity

was the fate of the

the grafts.

cence in situ hybridization),

Throughout

all

of substituted

as the kidney

to be determined

vacating

recipients,

of these

with

changes,

from

in such organs

colon).

from

similar

ranged

other

tract

that

in the spring and early summer of were ob1992 to be restudied. 38,39 Biopsy specimens

right portion

replacement

the duodenum

of the kid-

it obvious

in the number

abdominal exenteration (spleen, liver, stomach, pancreas, duodenum, proximal jejunum, and ascending

placed

Peyer’s patches,

studies

came to Pittsburgh

pancreaticohepatic

In some

made

677

ney (30 years) or liver (23 years) transplantation,

tained the stomach

organs

of the liver to small

1

propria,

Subsequent

quantitatively

leukocytes

‘Night TPN only. bGraft removed after 239 days because stop immunosuppression therapy.

in the upper

thoracic

tissue leukocytes,

8/ 12/92

shown

nodes.

ORGANS

heart.

g/7/92 10/14/91

Multivisceral

n

Alive (l/29/93)

cells in the lamina

and mesenteric ney

OF GASTROINTESTINAL

organ.

supply

Within

minutes

of any transplant,

after restormyriad

sessile

initial attack by the recipient immune system and later to merge half forgotten into the host. Study of the

but potentially migratory leukocytes that are part of the normal structure of all organs left the graft and

gastrointestinal

migrated

vided

unique

organs insights

the liver became ognized

as having

was noted kocytes within tocytes

and their

have pro-

into these processes.38

the first transplanted a composite

that the Kupffer

became

recipients organ

(chimeric)

structure.

cells and other

predominantly

In 1969, to be rec-

recipient

It

tissue leuphenotype

100 days of transplantation, whereas the hepapermanently retained their donor specificity

(Figure 3). At the time and long afterward, this transformation was assumed to be unique to the hepatic allograft. However,

22 years later, first in rat models

and then

in humans, it was realized that the same process occurred in all successfully transplanted intestines. The epithelium of the bowel remained that of the donor, whereas the lymphoid, dendritic, and other leukocytes of recipient origin quickly invaded and became the

all over the recipient,

while

cells took their place in the transplant ing the

highly

The relocated

specialized donor

donor

and recipient

similar without

parenchymal leukocytes

recipient disturbcells. learned

to live in harmony, provided they were given sufficient protection during their nesting, by immunosuppressive viewed

drugs.

In this new context,

as traffic directors,

allowing

the drugs could be movement

of the

white cells in both directions (to and from the graft) but preventing the immune destruction that is the normal purpose of this traffic. It is not known yet how the two sets of white cellsa small population of predominantly dendritic cells from the donated organ and a large one that is in essence the entire recipient immune system of the paa “truce.” This is so complete in some tient -reach cases that immunosuppression can be stopped, particu-

678

STARZL ET AL.

GASTROENTEROLOGY Vol. 104, No. 3

G

\

V

H

I

Mutual Natural lmmunosuppression

Figure 3. The phenomenon of cell migration (with repopulation and chimerism), which is postulated to be the basis of graft acceptance. Note the interaction at the site of donorrecipient mutual cell engagement. This is thought to be the first step toward donor-specific nonreactivity (tolerance) by a mechanism of peripheral clonal “silencing.”

t

HVG larly after liver transplantation other

organs.

duced

more

planted

the critical clude

easily

by the liver

because

missionary

pluripotent

stem

the explanation

marrow prove

or spleen donor,

matching

information

and then

of various those taken

for use in humans as xenografts. and mixed chimerism phenomena inability

to accurately

predict

to be

the intes-

to shape future

alstrate-

from the bone infused

organs from

to im-

from

that

an animal

5.

The cell-migration make comprehensi-

of donor-recipient the outcome

HLA

6.

of whole

organ transplantation; neither the new organ nor its new host remains the same as at the time of the matching tests.

7. 8.

Summary a period of 33 years, it has become possible to successfully transplant individual intra-abdominal viscera or combinations of these organs. The consequences have been, first, new information about the metabolic interrelations that the visceral organs have in disease or health; second, the addition of several procedures to the treatment armamentarium of gastroOver

and third,

a more profound

by which

all whole

organ

undergrafts

References

in-

liver.

this much

diseases;

of the means

of

apparently

afforded

transplanted

of a donor

ble the unexpected

are accepted.

trans-

content

was thought

cells can be purified

including

by other

cells. This

the “acceptability”

specific

standing

that

a tool with which

gies. The migratory

intestinal

leukocytes

still incomplete,

ready provides

than

with

state can be in-

of the liver’s higher

for the protection

tine by a concomitantly While

but less constantly

Such a stable biological

organs

(Rejection)

9.

10.

11.

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small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 1959; 150:543-560. 28. Lillehei RC, ldezuki Y, Feemster JA, Dietzman RH, Kelly WK, Merkel FK, Goetz FC, Lyons GW, Manax WG. Transplantation of stomach, intestine, and pancreas: experimental and clinical observations. Surgery 1967;62:72 l-74 1. World J 29. Pritchard TJ, Krrkman RL. Small bowel transplantation. Surg 1985;9:860-867. 30. Starzl TE, Rowe M, Todo S, Jaffe R, Tzakis A, Hoffman A, Esquivel C, Porter K, Venkataramanan R, Makowka L, Duquesnoy R. Transplantatron of multiple abdominal viscera. JAMA 1989;

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Address requests for reprints to: Thomas E. Starzl, M.D., Ph.D., Department of Surgery, 3601 Fifth Avenue, 5C Falk Clinic, University 15213. of Pittsburgh, Pittsburgh, Pennsylvania Aided by project grant DK 29961 from the National Institutes of Health, Bethesda, Maryland.