Versus Cardiac - Semantic Scholar

Comparative Strategies to Induce Long-Term Graft Acceptance in Fully Allogeneic Renal Versus Cardiac Allograft Models by CD28-B7 T Cell Costimulatory Blockade: Role of Thymus and Spleen MEIKE

SCHAUB,*

JOHN

THOMAS

P. VELLA,*

LAURENCE

of Immunogenetics ScIwol,

Boston,

University

Blocking

Abstract. by the

fusion

long-term

graft

models. CTLA4Ig not clear ences

in various

in the

the

with

effect

murine

cardiac

different

models,

d) in 54%

of

the

rat

activated T cell

(2).

receptor

histocompatibility senting

APC

with

an antigen

(APC).

immune

signal

(3-7).

The

of this

second

(8,9).

consisting

of the extracelbular

mobogous

to

murine binding

CD28)

CTLA4Ig,

fused

IgGI, is able to B7-b and

to

an

Fe

±

Portions

August of

American Drs.

study

Society

Schaub

Stadlbauer to Dr.

and

Transplantation.

ton,

MA

Copyright

at

San

Mohamed

equally

H. Sayegh, and

the

Antonio,

contributed

Brigham

signal

and

process

B7

results

a recombinant

of CTLA4

portion

of

induce

Womens

annual November

to

this

of the ©

1998

by the

Society American

phase

of tolerance,

Society

grafts

were

Medical

Wistar-Furth

graft

the

day

induction

of

however,

did

the presence applicability

could

In both

thymus

tolerance. not

plus

transplant

of animals.

the

and

The

require

an

of

Only

splenocytes) of

in 50% models,

time

rejected.

(4 X l0 on

to Lewis

survival

ultimately

acceptance

spleen

maintenance intact

thymus

of a spleen. These data have because human studies with T

blockade

9: 891-898,

Blocking ti-B7

are

being

planned.

(J

Am

Soc

1998)

CD28-B7

in

clinical

in suppressing and

ized

meeting

of

the

1997.

CD28-B7 whether

graft

cardiac

of graft

rejection

here

ments

for

renal

versus

was

the

induction

cardiac MHC

of

I and

There

are

in vascular-

in rodents. reflect

these

two

It is not

the effect

organs.

to determine long-term

allograft

class

re-

of

animal strains or species, differences in the immunobi-

between designed

been

the major

(19.20).

differences

blockade in different they actually represent

mod-

( 13-18).

has

of CTLA4Ig

( I 3, 14) models these

very

trans-

instances

rejection,

survival

efficacy

some

also

of chronic

in the whether

tolerance

CTLA4Ig

long-term

( 1 8) and

however,

albogeneic Street.

to

in

true

models,

be

In transplant

and

and

development

differences

renal

rejection

or an-

to

in various

(I 1,12).

acceptance

albogeneic

barrier

reported

response

models acute

graft

by CTLA4Ig

been

the immune

prevents

to prevent

clear,

has

autoimmune

long-term

reported

costimulation

antibodies

CTLAIg

ported

or

T cell

monoelonal

effective

graft

model. class

The

different the

II incompatible

study

require-

acceptance

using

or

in the

same

fully

strain

corn-

bination. Bos-

The thymus plays the major work from several investigators an

of Nephrology

for

require clinical

acute

in a mean

transplant

costimulatory

on

of Immunogenetics

of Nephrology

*Han,(,r(I

Gene Therapy,

ofdonorcells

graft

required

In non-fully

(ho-

a human

75 Francis

1 $03.0()/0

American

all

renal

were

cell

the

resulted

of CTLA4Ig

and

is

work.

Laboratory Hospital.

into

long-term

induces

1. I 997. TX.

protocol

d, and

cardiac

presented

30th

this

injection

of

fusion

domain

02115.

1046-6673/0905-089 Journal

December

presented

of Nephrology.

and

Correspondence

were

of

injection

plantation

to block this costimulatory signal by B7-2, the two ligands of CD28 (10).

12. I997. Accepted

this

and

Hunan

Institute

16.9

a single

obogy Received

‘s Hospital

and

model

concomitant

els,

specificity

on T cells

signaling

unresponsiveness

to a major

costimulatory

of CD28

of

on antigen-pre-

antigen

H. SAYEGH*

Women

kidneys.

as peptide

defines

24.7

Nephrol

by interaction

molecule

second,

interaction

Failure

bound

signal

en-

(>100

process ( 1 ). It is now two signals to become

is provided

(MHC)

This

response.

through

T cell protein

first

complex

cells

provided

The

acceptance

allograft

but did important

combi-

of Wistar-Furth

Allograft rejection is a T cell-dependent well accepted that T cells require at least

and

2 d after

heart

the

complete

strain

graft

recipients

renal

same

CTLA4Ig

study

costimula-

of acute

using

complex-incompatible

Lewis

This

T cell

in rat models

rejection

histocompatibility

the

Transferring

induces

transplant

reported.

CD28-B7

nation. A single injection of murine graftment was able to induce long-term

the

and

experimental

studies

of blocking

CTLA4Ig

allograft

fully

activation

rejection

and

Pennsylvania.

costimulatory

prevents

CHANDRAKER,*

MOHAMED

Brigham of Medicine

Departinent

There are reported differences in the efficacy of in renal and cardiac rodent allograft models, but it is whether these are due to the strain or species differ-

investigates

major

and

ANIL

and

Transplantation,

Philadelphia,

T cell

CTLA4Ig

acceptance

investigated

tion

Massachusetts;

CD28-B7

A. TURKA,t

and

of Pennsylvania,

protein

H. W. STADLBAUER,*

important

splenie

regulatory

role

role in self tolerance. and recent indicates that it also may play

in acquired cells

have

tolerance been

reported

(2 1.22). to play

In addition, an important

892

Journal

of the American

role in maintenance are

no

of tolerance

reports

animals

on

rendered

this study, spleen for

the

of Nephrobogy

in some

role

tolerant

we report induction

CTLA4Ig

Society

of

by

the

models

thymus

T cell

(23,24). and/or

costimulatory

in

Reagents The murine

In

ehimerie

There

spleen blockade.

on the requirement of the thymus and maintenance of graft acceptance

and by

in vito.

Materials

Linsley

fusion

protein

and a corresponding

protein

L6

(Bristol-Myers

Squibb

Pharmaceutical

attle, WA). CTLA4Ig or control venously into the dorsal penile Research

Institute,

East

ously at a dose of2S maintenance therapy

and Methods

CTLA4Ig

recombinant

were

kindly

control

provided

by

Research

Dr.

Institute,

Ig (0.5 mg) was administered vein. Cyclosporine (CsA:

Hanover,

NJ)

was

administered

mg/kg as induction therapy of a dose of 5 mg/kg.

P. Se-

intraSandoz

subeutane-

for 14 d, followed

by

Animals Inbred

male

Lewis

(LEW)

(RTI

brown Norway (RT1”) strain gue Dawbey (Indianapolis, formed

when

LEW

animals

rats served

reached

as recipients

isografts,

or third-party

National

Institutes

tory

(WF)

(RTbt’),

were purchased from Transplant procedures

a body

weight

of renal

or cardiac

BN grafts.

of Health

Wistar-Furth

‘),

rats IN).

of approximately

Animals

Guide

WF

were

and

of Labora-

LEW cally graft

bilateral previously

reject their for survival,

nephreetomy (17).

graft within 2 wk. rejection is defined

within

assuming

surgical

CTLA4Ig

2 h at 37#{176}C, washed

twice

were injected

48

received

model,

WF

were

renal

animals

typi-

Because animals depend as death of the animals.

h posttranspbant

technical

and

In this

APC

and were

cell

in RPM!,

intravenously

and

40

by

plastic

b06/ml)

X

were

of 20 .tg/ml

b0

X

into LEW

suspensions

isolated

(27). APC (10 at a concentration

excluded

on the Deaths

from

analysis,

failure.

Beating grafts of different protocols were buffered saline, harvested, serially sectioned 3-mm slices, and fixed in paraffin and stained

in 10% formalin. with elastic van

slides

by

were

Allograft were

cells

recipients

for

in 1 ml of

on the day of

using

a scale

(28).

vessels

that

Only

to the infrarenal

techniques.

renal

model, does

previously

heterotopic

cardiac

in this

not rely

great

as described on graft

function

was monitored by daily palpation is defined as the day of complete

and confirmed

elastic

degree

Specimens were embedded Gieson. By bight microscopy, arteriosclerosis/arterial

0 to S as described

were

lamina

of

from

perfused with phosphateinto approximately 2- to

cut

staining

orthogonally

were

intimal

et al.

by Adams

and

displayed

a clear

scored.

Model

transplanted

mierovascular

examined

thickening, internal

C’ardiac

recipient

previously

murine

harvested,

above.

Arteriosclerosis

as described

occurring

the

were

described

as described with

RPMI

Model

rats underwent

Hearts

as

CTL44Ig

spleens

transplantation.

Allograft

albograft.

with

or BN)

prepared

incubated

Animals.

Renal

were

(WF

LEW to

ofAPC

Donor

adherence

according Use

Incubation

200 g.

albografts.

housed

for the Care

and

Harlan Sprawere per-

vessels

by standard

(25).

allograft

for survival.

Statistical

In contrast

to

model, Graft

the

function

Analyses

Differences

P value

in survival

of

unmodified of

in vivo

A single

injec-

acute

rejec-

100 d) in 54% animals and

a murine

survival

In

of celland

vitro

prevented

(Table I ),confirming results of our In comparison, in the heterotopic allograft CTLA4Ig

as effective. they accepted

heart

CTLA4Ig.

graft

all

not

inhibition

responses

murine

2 posttransplant

long-term with

(BN)

donor-specific

used

day

whereas

animals

on day 0 was tolerant because

control

time,

original study. WF into LEW

10.8

Ig

d)

cardiac

injection of 0.5 mg of murine graft survival but did not lead to

CD28-B7

Table

Allograft

1.

Blockade

in Vascularized

Transplantation

893

survival” Category

Survival

(days)

Median

Renal CTLA4Ig

day

2

CTLA4Ig

day

0

14, 17, 1 8, 20,

30, 30,

5, 10, 20,

55,

100

>

100

>

(ii

(ii

control

Ig

4, 5, 6, 7, 32

control

unmodified

5, 13, 13,

7)

=

3)

=

54%

> 1 00

days”

43%

> 100

days”

6

14

13

Cardiac CTLA4Ig

alone

day

0

13,

CTLA4Ig

alone

day

2

10. 16, 16, 16, 36, 54

donor

cells

+ CTLA4Ig

day

0

donor

cells

+ CTLA4Ig

day

2

BN

cells

+

irradiated

CTLA4Ig

donor

donor

APC

day

cells

12,

0

with

day

0

CTLA4Ig

day

0

a b

BN,

p

cP


100 dayse

acceptance of

in the of

mg)

prolong

graft

survival;

all

(Table

1). In

addition,

donor

X

later

survival

were

majority

4

1). However,

grafts

survival

in these

when

long-term ofdonor

not

days

specific term

of

survivors

on day

(>

tance

in this

(WF)

the

recipients

single

result

day in

day

were

rejected

within

of

specificity

was

confirmed

9

of

d

by

with

4

10

in an islet that

ex

vivo

prevents recipients

their in the

Similar

autoimmune

could

was

the

long-

rejected

(WF)

improved

heart accep-

to 67% infused

2-wk

2

donor-

two

graft

were by

from day long-

true into

graft

cell

APC

transplant

of

on the

course

rejection absence

when

were model.

CTLA4Ig

of donor

of

also the

islet

et

cells into

administration

reported

in which and

Steurer

transplanted

of systemic

observations with

model,

preineubation

encephabomyelitis of

day

in 30%

Long-term be

we

to the

grafts

donor-spbenoeytes followed

studies

of CTLA4Ig.

other

a donor-strain d).

of sur-

CTLA4Ig.

demonstrate (BN)

1).

1).

showed

CTLA4Ig

I 00

regimen

x

every

A third-party (>

(Table

acceptance.

resulted

whereas

tolerizing

(Table

albogeneic

eubation

d).

transplantation

CTLA4Ig al. (30)

graft acceptance cells alone did not

100

not differ-

of

second

in

of

injection

In contrast

To

l0)

day

allograft

graft

regimen 1 ).

transplanted

accepted

when

In recent

with donor

(Table we

8 postengraftment,

recipi-

prolong

of CTLA4Ig this

acceptance tolerance,

was alone

administration doses.

the

a single

did

of seven

protocol,

graft

model

X

on

CTLA4Ig

permanent

mg

(4

given

recipients

with

repeated

a total

single-injection term

induce 0.5

14 for

splenocytes

transplant

of

received

2 to

permanently

a

not

effect

Recipients

treated

test).

mg)

2 posttransplant

could the

was

both

on

but

(BN)

cardiac

on day

studied

LEW

compared when

in the

CTLA4Ig vivab

third-party

that in animals

Because

day

by

did

by log-rank

allograft

ent from

rather

donor

(assessed

transplant;

2 d later of

l0

administered

of recipients had 1). Administration

the

followed

2 d

of graft (Table

on

model

all

( 14) reported

ci’ al.

0 in the cardiac

(0.5

the

into

of CTLA4Ig

transplant

(0.5

to renal

BN

cells

injection

8.5

CTLA4Ig

passenger

in the Lin

8.5

1 1, 11

of

I).

because

to “tolerize”

of donor

CTLA4Ig

(ii

with

we can

donor-derived

model,

days”

7’

combination

1 1 d (Table

combination,

fact,

administration

prolongation

transplant, 50% (>100 d) (Table

In

by a single

CTLA4Ig

2 CTLA4Ig

be easier

allograft

model,

within

of

administration

long-term In

18,

administration

1 ). Control a similar protocol

hypothesized

(17).

cardiac

>100 175d.e

on

of CTLA4Ig was significompared with the kidney

number

it may

allografts

grafts mg)

effective;

with

allografts

been

day

33 d (Table

donor-recipient

It has

cells

their (0.5

marginally

treated

Ig rejected

donor

+

rejected

within

and animals their

50%

cell. groups.

of CTLA4Ig

allografts

animals

6)

=

13,

70, 9.

CTLA4Ig

animals

of control

ents.

68,

14

rat; APC, antigen-presenting with organ-specific control

with

(ii

14,

6, 6, 7, 10,

transplant

unmodified

kidney

2 to

1). Administration

rejected

>100

6, 8, 9, 10

acceptance;

54 d (Table

animals

65,

unmodified

brown Norway 0.001 compared 0.01.




100

d)

These

grafts

displayed

score,

0.83

±

isograft

controls

separate

group

relevant

protocol

for

d).

100

being

(Figures

was

not

score.

These 0.4, 2)

cells

and

significantly ±

was

(5 mg/d

for

treated

of WF

cardiac

ii

7:

mean

with

a significant

with CTLA4Ig-treated animals were not

harvest

from a

a clinically by

1 mg/d

severe

earlier

vessel

111 ±

(P

difference


100

kidney heart

(ii

7, 9, 15, 8, 14,

Splenectomy kidney

day

3)

=

136

16,

16

+14 18. 21,

26,

29,

>100

(pi

I)

=

a Thymeetomy or splenectomy was performed 7 to 14 d before or 14 d after transplantation. In the renal allograft model, CTLA4Ig was given on day 2, in the cardiac model CTLA4Ig and donor cells were concomitantly administered on the day of engraftment.

Allograft,

CTLA4Ig

Cells

+

the same combination.

MHC class I and class II incompatible As we have shown previously, a single

of CTLA4Ig

2 d after

lograft

rejection

and

>50%

of recipients

cardiac

allograft

combination,

Only

bination

with

resulted

that

long-term

graft

Our

Cyclosporine

strain

infusion

to induce

long-term

diac

allografts

the best was

with

the

strain

CTLA4

Although the costimulatory

(37).

with main

of B7-l patterns

unknown

mechanisms blockade

(14,16),

it

donor alloantigens results rendering the animal more ade. Figure

2.

controls, cells

Representative albografts

on the day

sections

treated

with

of engraftment,

(from top to bottom, XbOO).

respectively,

of coronary a single and

from elastic

dose

arteries

albografts van

from

isograft

of CTLA4Ig+ Gieson;

treated

donor with

magnification,

CsA

Alternatively,

earlier important

donor

progenitors)

that of

B7

costimulatory

the

most

ap-

may

vary

be related

to temporal

molecules

in the target

of the

been in

negative

T cell

donor graft that

shown vitro and regu-

activation

cells synergize acceptance re-

administration

of

in upregulation of B7 molecules, susceptible to costimubatory blockadministration of CTLA4,

of tolerance

express

study,

administration

initial

is possible

of car-

in that

and B7-2 has after activation

of how to promote

antigen

bone

that

to be necessary

blockade

after

of expression

in induction

Premature deficient

donor

upregulation

( 14) in

showed

Therefore,

may

of

recipi-

et al.

they

CTLA4Ig

expression

occurs

induction

albograft

in rat recipients

of costimulatory

In addition,

molecule

of recipients.

of Lin

costimulatory

and

in corn-

for

However.

when

in

of transplantation

seems

2 posttransplant.

T cell combination,

splenocytes

studies

survival

of

(34-36).

latory

strain graft

cardiac

CTLA4Ig.

organ. Indeed, expression to follow distinct temporal in vivo

WF to LEW permanent

in which

obtained

of expression

acute

day

splenocytes

with

was

to the

in >50%

and

with

albograft

to day timing

patterns

in renal

al-

protocol

requirements

combination,

treated

delayed

the

survival

different

of donor

outcome

propriate

are

are consistent

additional

on

renal

acceptance

of donor

given

survival

rat

acute

graft

model in the same not able to induce

allograft

there

data

this

administration

in long-term

a different

Applying

CTLA4Ig

indicating

ents.

Allograft,

rejection were

prevents

in long-term

(1 7).

we

acceptance.

engraftment results

rat strain injection

result

in

may

be

(38).

marrow-derived MHC

may which

class molecules

cells

(dendritic

II molecules induced

cell but

alloantigen-

are

896

Journal

specific

of the American

hyporesponsiveness

ported

studies

approach

APC

in our

vaseularized

with

planation

ciently

provided

direct

MHC

on donor

recognizing

to

may

solid

islet

organ

(30),

that

entity.

experimental (41).

intragraft

expression that

dependent

rejection

shown prevents in both

albogeneic

that cardiac

and

study,

long-term

strated

minimal

intimal

thickening

and

isograft

controls.

In the

relevant

protocol

of chronic

opment

of chronic

costimulatory

cell long-term

degree

of transplant

strategies

vent

role

and

chronic

It has

role

portant

mic

injections

been

shown

but

in initiating

than

immunosuppression

that

to induce

induction Yamada

ci’ a!. indicate

cells

permanent that

acquired

the

responsible

for maintaining

and

thymus

maintenance In summary,

to

under-

to

allograft thymus

has

spleen

play

(21-24). survival a central

of Th2

Our

the

that

presumably these

cells

The

phenotype

of tolerance.

these cells

observations

spleen,

and

cells

are

function

currently

remain

are

under

as regulatory

tolerance

data

as the sole

cells

in

controversial

results

suggest

of T cell

activation

regimen

to induce

long-term

specific

tolerance

in vascularized

MHC

compare

class

different our

graft

I and

importance spleen

also

of organ

blockade

induce

phases

of

of

be confirmed

tolerance

long-term

requires and

distinct

address

the

transplantation.

of

the

thymus

and

to ablografts.

are being thymus

in large in adult

T cell

versus

mechanisms may be of imclinical trials with costimuthe

to involute

targeting

of

tolerance

recipients

requirement

is known

of

the

to

kidney

in cardiac robe

donor-

Using

combination

models

pivotal

in transplant

efficacy

allografts.

pathway

of these because

even

induction

cell transfusion

A greater understanding portant clinical relevance.

the

that organ

different

is a potent

and

strain

costimulatory

the

of costimu-

engraftment

indicate

highlight

in mediating

the thymus

organ

in different

of donor

data

acceptance

II incompatible

observations in blocking

blockade

by CTLA4Ig

graft

models

acceptance

that

animal life,

planned.

for

studies, and

costimulation

In

induction this as

of

because may

limit

a means

to

in humans.

of chronic

a means

donor

in

a state

is depen-

Our

or deletion

thymus,

allograft our

pathway

latory

latory

the

as

responses

of

should

tolerance

or soluble

the

function

tolerance

of developing

and

in

Whether

do-

only

our data

regulatory

investigation.

pre-

Acknowledgments This

immune

of donor

initially

the

to minimize

the process

originating

exist

procedure,

thymus.

in our model.

cells

however,

the

acceptance

not

of anergy

acceptance

phase,

after

graft

but

highly

had been splenectorejected their grafts

2 wk

spleen

a state

regulatory

particular,

with not

that

that

(45).

in regulating

indicating

to

devel-

indicate

In addition,

the importance

affect

way also

mild

similar

not

against

of graft

suggest

Our

a clinically

in combination

vaseulopathy.

(21,22),

did

is a powerful

of T cells

very

observations

acceptance,

suggested

of

regimen

These

mechanism

of

The

is also

maintenance

of permanent

presence

argue

the

within

14 d

survival.

acceptance

recipients that almost entirely

loss

the time Seventy-

thymectomy

long-term

graft

during

a state

the

undergone

on to have

to be

its presence

i.e. , after

phase,

had

(46).

seems

of tolerance,

not to be mandatory.

permanent

allograft that

on

regimens

demon-

with

combination,

by CTLA4Ig

rejection

been

CsA

highlight

rather

in

heart, re-

In the

allografts

compromise,

strain

have

of non-fully

( 19.20).

that

Splenectomy

same

costimulatory

models

cardiac

luminal

same

rejection.

graft

alloantigen-

chronic

arteriosclerosis

transfusion

induce

the key

of little

blockade

T cell

sug-

We

of

the thyrnus

phase

appears

model

(17,47,48).

of

been

Although

went

phase

transplant

hearts or kidneys that had engraftment rejected their

maintenance

of animals

transplantation

induction

T lym-

cytokines,

(44).

combinations

surviving

in

upregulation

by both

allograft

of

intersti-

and

of experimental

renal

degrees

graft

It has

CD28-B7

strain

current

that

factors

blocking

in-

Studies

inflammatory

is mediated

of

determinant

(19,42,43).

development

(LEW-F344)

nor-specific

and

ar-

understood

(3 1,32).

shown

alloantigen-independent

activation

percent

strongly

to conven-

major

is significant

of activation

chronic

degrees

poorly

during

rejection,

indicating

graft

by macrophages

there

growth-factors

previously

score

allorecognition

responsive

the

have

infiltrated

and and

This

recipient

resulted

1 yr posttransplant

outcome

rejection

In addition,

chemokines,

five

manner.

animal

the induction

of acute

acutely.

of vaseularized

variable

is not

long-term

are

phocytes

than

fibrosis.

which

and

vessels

in the

in a large

dependent on the spleen; mized before engraftment

in contra-

by progressive

becomes

chronic

and

rejection

more and

and

function

jection

direct

manifested

immunosuppression,

gested

albo(recipipeptides

rejection

during

after

would

recognizing

Therefore,

blocking

survive

inflammation

clinicopathobogic

tium

(40).

gbomeruloselerosis,

albograft

this

alborecognition

to prevent

rejection

terioselerosis,

tional

antigen,

in an acute

important

point

effi-

tolerance

allografts

dent

grafts

chronic

terstitiab

will APC.

allografts.

Clinically, develop

cells

CTLA4Ig

albo-MHC-derived

molecule)

not be sufficient

ex-

is most

T cell

indirect

processed

on self-MHC

distinction

not

In our study, rat recipients of WF undergone thymectomy 7 d before

rejection

possible

costimulation

(recipient but

acute

with

the

the of

but not on recipient

presenting

alborecognition

T cell

presented alone

cell

of peripheral

incubation

One

APC

cells,

re-

to

(30),

by

model.

CD28-mediated

cells),

contrast

not abrogate

of donor

the

In

transplantation

abbograft

on donor by

block

cell

could

treatment

that

(39).

of B7 molecules

cardiac

B7 molecules

To the extent

of islet

blockade

CTLA4Ig

is that

block

of Nephrology

i,1 vitro

in a model

of cx s’i’o

donor

ent

Society

an

im-

Intrathy-

antigen

have

or tolerance role

in the

tolerance. More recently, data by that the thymus is required for induction

work

was

Research

Grants

recipient

of

Award.

ship grant supported

in part

34965-03

National

and Kidney

is an established

and Dr. Chandraker from the Juvenile by a fellowship

(Sta 461/b-I). tance.

the

Dr. Turka

Association,

supported Al

We thank

by National Al

Institutes

40629-01.

Foundation

Dr.

of Health

Sayegh

Clinician

investigator

of the American

is the recipient

of a research

is the Scientist Heart fellow-

Diabetes Foundation. Dr. Stadlbauer from Deutsche Forsehungsgemeinsehaft

Cheng

Kwok

for excellent

technical

is

assis-

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