Immunity to hepatitis B virus: Passing the torch

SELECTED SUMMARIES Henry J. Binder, M.D. Selected Summaries Editor Yale University School of Medicine New Haven, Connecticut 06520-8019

STAFF OF CONTRIBUTORS Ronald L. Koretz, Sylmar, CA William M. Lee, Dallas, TX Thomas A. Miller, Houston, TX Ravinder K. Mittal, Adelaide, South Australia Linda Rabeneck, Houston, TX Anil K. Rustgi, Boston, MA

Kim E. Barrett, San Diego, CA Grace H. Elta. Ann Arbor, MI Greg Fitz, Durham, NC Lawrence S. Friedman, Boston, MA Vivek V. Gumaste, Elmherst, NY Lynn Hornsby-Lewis, New York, NY Cyrus Kapadia, New Haven, CT

HBV-immune

IMMUNITY TO HEPATITIS B VIRUS: PASSING THE TORCH

donors had normal

12 corresponding ers

Mitchell L. Schubert, Richmond, VA Konrad Schulze-Delrieu, Iowa City, IA Fergus Shanahan, Wilton, Cork, Ireland Joseph G. Sweeting, New York, NY Richard C. Thirlby, Seattle, WA Jacques Van Dam, Boston, MA

recipients

liver function

were negative

After BMT, the 12 recipients

of marrow

l/an Y, Naglw A, Adler R, Naparstek E, Or R. Slavin S, Brautbar

immune

donors

C, Shouval D (Liver Unit,

mIU/mL

(mean value, 92.5 +- 13.3 mIU/mL).

of Bone Marrow Hadassah

University

transfer of immunity allogeneic

Division

of Medicine,

Transplantation,

bone

Hospital,

Jerusalem,

to hepatitis marrow

1993; 18:246-252

and Tissue

Department Typing

Israel).

Unit,

Adoptive

donors

against

B virus after T cell-depleted transplantation.

In the second BMT

Hepatology

HBsAg

(August).

11-30 Bone marrow treatment

transplantation

for various hematologic

ciency disorders,

and aplastic

patients

a variety

against

BMT, including

hepatitis

ful, presumably interactions recipient,

row, immunity

the defective

These

activated

BMT recipients.

the transfer

expand

within

host.

muscular

first analyzed

donor

and

surface antigen (HBsAg), antibody (anti-HBc), and anti-HBs. Of 178 a donor with anti-HBc and antiacquired immunity to HBV. The

for HBsAg,

booster

anti-

Donors and recipients and HLA-DR.

lymphoid

graft rejection.

injections

The

of chemo-

irradiation,

(four male, four female) received (deltoid)

a

All eight cor-

and the for up

All BMT

lo-/.tg dose intra-

of the HBV vaccine

30,

60, and 150 days after BMT. Blood samples were drawn peri-

Despite

and analyzed for the presence

protective

of anti-HBs.

adverse effects after active immunizaimmunization

the short interval

and bone marrow achieving

the feasibility

recipient sera from 178 of the 450 BMT procedures performed at Hadassah University Hospital between 1980 and 1991 for the presence of hepatitis B to hepatitis B core antigen pairs, 12 (6.7%) included HBs, indicating naturally

recipients

tion of donors or booster

the recipient,

antibody.

HLA-B,

after BMT to prevent

J

levels of antibody to hepatitis B surfrom actively immunized donors to

The investigators

to 3 months

There were no significant

1986; 1:339-343).

for

with various combinations

and total

of

1990;76:2470-2475;

Lancet

NJ)

with aplastic anemia also received cyclosporine

odically post-BMT

can be transferred

In the study under review, Ban et al. evaluated of transferring protective face antigen (anti-HBs)

Pseudomonas

(including through

as in a normal

of mar-

agents

Rahway,

In preparation of T cells using

were negative

for HLA-A,

were conditioned

system of the BMT of adop-

leukocyte

were fully matched therapeutic

By actively

eight

were vaccinated

dose of recombinant

donation.

pretransplantation.

patients

donor before donation

B cells (Blood

B cells then

immunity

BMT recipients

cell

lo-/tg

HBc, and anti-HBs patients

of this study,

to HBV

was then depleted

responding

have used the technique

1986;78:959-967;

the marrow

to immunize

T cell-B

from donor to recipient.

presumably

days before bone marrow

171: 104). In an at-

varicella, and diphtheria)

recipient,

stimulated

conferring

immune

to a variety of pathogens

aewginosa, tetanus,

Invest

or absent

(deltoid)

rat anti-human

and post-

>lO

(H-B Vax II; Merck Sharp & Dohme,

monoclonal

pre-BMT

1985; 13[Suppl

the HLA-identical

to the BMT

Attempts

because of improper

several investigators

functional,

anemia.

levels

Each donor (five males, three females) received

immunodefi-

B virus (HBV), have been unsuccess-

tive transfer of immunity immunizing

malignancies,

from naturally

anti-HBs

component

immunity

intramuscular

donation,

is now an accepted

of pathogens

(Exp Hematol

tempt to circumvent

Clin

(BMT)

protective

prospective

without

HBV.

a single

developed

tests, and all

for all HBV mark-

donation,

between all eight

levels of anti-HBs

of the recipients. primary

immunization

donors

seroconverted.

after only one dose of

HBV vaccine (mean titer, 110 -+ 25 mIU/mL). Seroconversion to protective levels of anti-HBs occurred in all eight BMT recipients 9-42 days post-BMT. The response of the recipients to booster immunizations at 30, 60, and 150 days post-BMT was varied: five of the recipients

had only a modest

response to

repeated booster injections but maintained protective antibody levels; one patient showed a secondary response after the third booster immunization with a nearly threefold increase in antiHBs titers within 30 days; two patients (one with graft vs. host disease and the other with recurrent leukemia) lost protec-

May 1994

SELECTED SUMMARIES

tive anti-HBs

levels in the 200 days post-BMT;

patients retained host disease.

protective concluded

that adoptive

HBV can be achieved

marrow

from donors

either

post-BMT,

Comment.

role of HBV

infection

seen in BMT recipients

of routine

screening infection

with HBV post-BMT

procedures

need

multiple

blood

transfusions

donor

Reactivation

with protective

result

the need to document pre-BMT

(Bone Marrow

Transplant

in endemic

donors

and is not considered

(Blood

that

of both

B.

donor

are HBV

carriers

Conversely,

an HBV

with an increased

a contraindication

1991;77:195-200;

risk of a

the relatively

to a poor

outcome

preventable

after

infections

immunity

low risk that HBV infection BMT,

hypothesis

that persists

for months

transfer

this problem. tetanus

Adoptive

toxoid

was tested

have

1986;78:959-967) row donation

been

of immunity to which

exposed.

Saxon

immunized

and showed

most donors

of immunity

donors

(Hepatology

transfer

occurred

anti-diphtheria

doses of recombinant

immunization

ents within

after BMT.

recipient

the first month

could not be ascribed

products.

Three

immunization

with tetanus

In further showed

studies

that in donors

row harvest, suggesting depletion could

antibody

process.

be transferred

response

was greater

secretion

ient generally BMT. vaccine

They

from donor

tetanus

anti-tetanus, which

Wimperis

despite

that

immunity

to recipient

is

to tetanus

toxoid

the antibody

if both the recipient

antibody

the recip-

response

pre-

acting adoptive

study,

received

three additional

the initial marrow

a significant

increase

immunization

harvest.

A subset

response

in anti-HBs;

Adoptive

adoptive

to booster

however,

the

immunization

of

of anti-HBs

oc-

transfer

marrow,

although

was lower than that achieved

levels in the recipient

and maintenance

is accentuated

before BMT and/or multiple

review.

harvest

the

with non-

per protocol

benefit,

immunized

was not

and it is not clear if any

against

of the recipient

from the donor

in the study

of the recipient

as part of the study,

of

of the donor

not settled

immunization

had been

of protective

by immunization

immunizations

is unfortunately

Pretransplant

HBV

at any time

after successful

did not appear

transfer

to confer any

at least in the short term.

of immunity

to HBV poses some unique

of HBV vaccine administered to insure

immunity

129). Given

such a lead time in which

problems.

Three

for a period of several months

against

the urgent

HBV (Am J Infect Control nature

to adequately

of BMT in most cases,

vaccinate

the donor

is often

not feasible.

The fact that all eight donors developed

protective

of anti-HBs

after only one injection

is an unexpected

finding

that would

ascertained studies

depletion,

3

marrow.

1989; 17:126-

T-cell

by the T-cell

after

or not the development

of the recipients

BMT

even though

probably

host,

using standardized with

the optimal

regimen

longer

to determine

Adoptive

to duplicate.

against

HBV has not been fully

so guidelines difficult

for immunization

after BMT are needed transfer.

Moreover,

for immunization to define.

protocols

if pre-BMT

levels

difficult

follow-up

for adoptive

ent offers any additional immunization

prove

will be particularly

and recipient important

of HBV vaccine

immunizations

in the normal

recipients

of both donor

In particular,

immunization

benefit over post-BMT

of

Additional to define it will be

of the BMT recipiimmunization

or no

of the recipient. transfer

of response

to HBV

sponse

to the HBV

closely paralleled

that ob-

address

the broader

the pattern

(40 pg H-B Vax intramuscularly)

et al.

than

to which

In that

of T cell-depleted

titer in recipients

are required

rather

showed

need for pretransplantation

after transplantation

injections

of

and transplanta-

in the past, thereby

before

was not confirmed.

before bone marrow

before bone mar-

and that

and duration

a significant that

but

vaccine

a secondary

the need for booster

toxoid

pretransplantation,

did not mount

booster

response.

continued

in magnitude

also suggested

in serum

B cells were not destroyed

They confirmed

and donor were immunized

a single

64- 154 days post-

1986;1:339-343),

who received

that functional

in the

from blood

28 days of immunization,

immune

(Lancet

toxoids

increase

levels within

with a secondary

transfer

underwent

and diphtheria

an appropriate

not anti-diphtheria,

immunity

to passive antibody

of the BMT recipients

BMT and showed consistent

Acquired

titers in recipi-

pathogen,

1990;76:2470-

the same authors

mice also showed with

Transfer

(Blood

when donors

HBV

documented

additional

are

When

immunization

and recipient

exposed

levels of anti-HBs

immunity

anti-tetanus

important

vaccination

1993; 17:955-959).

of protective

antibody

a clinically

review,

et al.

1 week before mar-

in the recipient

in the BMT recipient.

to HBV in BALBic mice by BMT from immune

Immunization

Invest

of T cell-

antigen.

most readily

and had high

performed

with

under

before BMT.

in serum

of antigen

between

than priming

transfer

under

period

ofantibody-specific

for pretransplant

had been transiently

as a recall rather

antibody

and re-

3 weeks before

because Pseudomonas aeruginosa is a pathogen

nearly all BMT donors

increases

levels and, to a lesser extent,

of the poor

(J Clin

expansion

was also suggested

In this case, the interval

the recipient

a means of addressing

nine BMT donors

significant

all

HBV, the technique

was first attempted

toxin,

using

and recipient

Whether

the compromised

In light

against

may provide

transfer

and diphtheria

recipients

after BMT.

to vaccination

of immunity

given

to avoid

pretransplantation

production

both donor

the recipient

could only be achieved

that a significant

and the presence

antibody

Similar

as the prim-

In this case, transfer

antigen

selection,

aeruginosa, the need

anti-HBs

will contribute

preferable

in the BMT recipient

response of BMT recipients of adoptive

it is clearly

suggesting

Pmdomonas

T cell-depleted

Despite

1990; 144:541-547).

oligoclonal

to sustain

curred

1990;49:708-

713).

and

harvest,

B cell interaction,

previously

to allogeneic

Transplantation

the marrow

was provided.

hemocyanin

from a donor who had been immunized

of the recipient

in up to 80% of BMT recipients

areas, has not been associated

poor outcome

fatal hepatitis

status

1992; 10:189-191). present

from an HBV

in fulminant,

detail

limpet

who had been immunized

Before the study

immunity

1991;77:195-200).

the HBV

and exclude

carrier state in the recipient,

BMT

Blood

B

HBV

1990;49:708-

after transplantation

keyhole

response to the priming

in recipients

required

but little

using

(J Immunol

weeks, perhaps

(Transhepatitis

toxoid,

tion was only 7- 10 days for both donor

the potential

of chronic

(Transplantation

of a BMT recipient

and recipient

tetanus

ceived marrow

2475).

the incidence

and in asymptomatic

in BMT recipients

may on occasion

underscoring

were obtained

this

Because

posttransplantation

713; Dig Dis Sci 1988;33:1185-1191; carrier

banks,

is low despite

in BMT recipients

HBV before transplantation

HBV infection

with

results

B cells in the donor,

the need

but significant.

used by blood

1990;49:708-713).

carriers and occasionally

although

in the liver dysfunction

is small

of primary

against

against

has not been established.

frequently

has been documented

to HBV as a result of

may then respond to booster immuniza-

HBV administered immunizations

plantation

who receive

or active immunization

for such booster

for

served

of an antibody

of immunity

in BMT recipients

infection

HBV. These recipients

The

transfer

who are immune

prior natural

tion against

despite graft vs.

ing antigen

The authors against

and two other

levels of anti-HBs

1389

of immunity vaccine problem

may address

the problem

in the BMT population of nonresponders

of nonre-

but does not

in the general

popula-

1390

SELECTED

tion. A subset (5%protective Infect

GASTROENTEROLOGY

SUMMARIES

14%) of otherwise

levels of anti-HBs

Control

response

with both genetic

For unclear

women

rate and with higher

respond

transplant

anti-HBs

patients

patients,

Intern

Proposed

or nonresponse

may be controlled

family

with

mechanisms

different Tissue

States

a defect in antibody

production

deficits

dysfunction,

T cell-B

1987; 109:89-96),

interleukin

2 production,

tor system

(Kidney

Attempts

gies to overcome

nonresponse

that combines

HBsAg,

with

product

by immunization

because

responsiveness

different

major histocompatibility

of responders

after

of interleukin HBsAg tion

(40 pg/dose)

(Lancet

requires

antibody

with

adoptive

transfer

anti-HBs

reach beyond

bone marrow of immunity

tent HBV infection, protection

against carcinoma

Hepatol

nonresponders

recipients

reinfection

egy has been effective

ever, it cannot to conventional that a similar immune,

HBsAg

Reply.

We wish to respond

In our studies hepatitis

in 74%~

normal

in the hemodialysis

Res 1993; 53:4648-4651).

in hyporesponders

(Clin Exp Immunol

in mice

a practical Preliminary

of bone marrow vaccination

donors

alone.

was conducted had indeed would

and Internal

ter, Minnesota).

Duodenal

synthesis,

immunization

we have extended

and sustain

to HBV.

Available

anti-HBs

several decades. seille,

E. REID, M.D.

our studies;

M.D.

of the above

as stated

to

immunization through

of HBV immune

and logical

that

production

for longer

data do not justify

of BMT recipients.

lymphocytes.

such

pretrans-

Since the initial previously,

Department

Medicine,

M.D.

ILAN. M.D.

ARE

of Medi-

and secretion

Gut 1993; 34: 1261-

of

Mayo Clinic, Roches-

juice total protein

turnover,

The classification

or nonre-

of BMT recipients

It is possible

suggest of HBV

and pancreatic in patients

after

1266.

popula-

of immunity

through

data

transplantation

of Cape Town, South Africa; and Division

Gastroenterology

acute pancreatitis.

S. FRIEDMAN,

to verify that engrafting

occurred.

improve

immunity

Boosting

blood

How-

for the nonresponders

unpublished

through

Clinic Groote Schuur Hospital,

The use

1988;72:383-

induction

was achieved

in BMT recipients.

solution

ACUTE AND CHRONIC PANCREATITIS: THEY REALLY DIFFERENT?

doses of

progress.

and humans,

(J

Immuniza-

HBV is a simple and safe maneu-

of immunity

peripheral

hepato-

B core antigen

YARON

enzyme

immunomodulators

to some of the comments

B in BMT recipients

or hepatitis

DANIEL SHOUVAL,

cine, University

in 29 of

1991;265:2679-2683).

readers on further

of experimental

OgdenJM, O’Keefe SJD, Lam JA, Adams G, Marks IN (Gastroin-

(not intramuscular)

than

vaccina-

testinal

levels persisted

higher

with persis-

to conventional

growth

effect may be obtained

HLA-matched

patients

of for

such a strat-

transfer

vaccination.

groups

of their graft. Furthermore,

donors against

be considered

target

who require

in suppressing

1993; 18:S4; Cancer

that

small group

for HBV infection

expressing

tion of bone marrow

Potential

to HBV include

high-risk

long-term

We believe

the relatively

transplants.

of pancreatitis

Three

major

1963; Cambridge,

report,

we were

not

(Pancreas

1991;6:470).

has been a problem

international

1989; Marseille,

gled to agree on a definition

review and to update

plantation

patients

The

to be established.

pa-

immune

in

seroconversion

LAWRENCE

lasting

of our studies

carrier

BMT from an HBV

1993; 104:1818-1821). remains

to

able to

to

administration

ANDREA

boosting

the results

we were recently

studies

389).

memory

(Gastroenterology

immu-

is often sufficient

in an HBsAg-positive

who underwent

safety of this maneuver

cellular

donors

clearance

of HBV infection

malignant

that single-dose

Indeed,

leukemia

sero-

is linked

loci. However,

to subcutaneous

production study

vaccine

gene products,

Intradermal

has shown promise

further

gene(s)

to the HBV

the Sipre-S

in anti-HBs

with

HBV of bone marrow

of their

memory to combat HBV. with

donor

our hypothesis

(73%)

of their donors

use

(Science

pre-S

1989; 1: 15 - 18). A role for other

that may augment spenders

have included

the

results.

1 year (JAMA

2 in combination

induce tient

relapse

is not useful. Strateencodes

complex

protective

induce

with

No. 5

observed in 6 of 19

was subsequently

disease. These data do support against

immunization

Re-

of the S gene, which

with

nonresponders

B vaccination;

doses of

not prorec-

to these gene products

resulted

been

to most

2O+g

are usually

nonresponse

conflicting

B vaccination

31 (94%) Japanese hepatitis

of

In mice,

have yielded

in contrast with

to HBV vaccination

can be overcome

of hepatitis

recep-

have in general

individuals

probably humans

decreased

Med 1986; 105:356-360).

the product

the

1985;228:1195-1199).

HBV. Loss of anti-HBs

ver to induce adoptive

levels achieved

(Ann Intern

of immunocompromised

of a vaccine

(Cell

of the interleukin-2

to revaccination

and the antibody

tive and are short-lived vaccination

function,

of nonresponders,

will respond

HBV vaccine,

from T-cell

cell interactions

after single-dose

tion, and liver transplant

on the circum-

resulting

of nonresponders

Only 35%-40%

hyporesponders,

in (Ann

1990;36:69-74).

monocyte

and upregulation

haplotypes

Int 1989;36:636-644).

at revaccination

disappointing.

for

impaired

the im-

and Japan

(depending

stance) include Immunol

that

prevalent

Antigens

of nonresponse

for the hu-

by a gene or genes within

in the United

faulty

Med

among

renal failure or liver disease,

is some evidence

1986; 105:356-60;

and/or

is prevalent

virus.

documented

Med

at a greater

that only 19 of 26 BMT recipients

responders, usually in association nization

determinants.

who are seropositive

multigene

but are

levels than do men (Ann Intern

with chronic

mune response to HBsAg the HLA

and nongenetic

There

against

1980;303:833-

The reasons for no or poor

and individuals

man immunodeficiency

nonresponders

to anti-HBs

to the HBV vaccine

1982; 97 :362 - 366). Hyporesponse older individuals,

to observe

converted

(Am J

have not been fully elucidated

likely multifactorial reasons,

surprised

immunization

N Engl J Med

Med 1984; 101:34-40).

to the HBV vaccine

persons do not develop

standard

1989; 17:172-179;

841; Ann Intern

healthy

after

Vol. 106,

conferences

for (Mar-

1988) have strug-

of acute and chronic pancreatitis

The term acute pancreatitis

implies

a

discrete event of pancreatic inflammation with a subsequent return to histological and biochemical normality after the attack.

With

alcoholic

pancreatitis,

however,

it is recognized

that often one cannot make a clinical distinction between an acute attack and an exacerbation of chronic pancreatitis. The latter term implies some degree of persisting structural or functional abnormality. One must frequently depend history of repetitive attacks to make the diagnosis pancreatitis unless secretory studies are performed

and/ on a

of chronic that show

a persisting deficiency of bicarbonate and protein secretion in response to secretin stimulation. Thus, the “secretin test” has been the gold standard for dividing individual episodes of