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page 2

With regard to influenza~ the f'rst evidence that this virus can
have an iwmunosuppressive effect was reported in 1919 by Bloomfield and
Mateer with their descl"iption of loss of skin '"eactivity to Old Tuberculin

.

by persons experiencing acu~e influenza (2) . . ~lorc recent studies have
confirmed the association of influenza virus infection in humans with
decreased cutaneous reactivity to routtne skin test

~ntigcns

(3.4). and

also ''lith impaired responsiveness of peripheral lyn:phocytc:s to phytoher:lagglutinin

(4.5) •
Other data have shown sensitizatfon of humans to tnf luenza virus

)

itself. by means of delayed cutaneous react.ions (6.7). and by

~

responses of per-tphere l lymphocytes"cultured \...ith virus antigen {:',,9}.
•
~:Oi·le vor , despite the apparent impairment of es tabl i shed ccl l liIt.di:'te

...

111Jl111111010gical respons i venes s dul"ing tnf luenza , evidence concclYin: t..

I

I
I
J

J

!=igr.ificance of this

il~vnunological

prolifc"c1t1v~

system in the host response tu i n

":~,

.,

infection itself is conflicting (7. 10. 11. 12),
In sUlllmary. the available informativn about the effect o:' i :fl';'"
on i:U:ilunologic function suggests a depression of the ce l l-med ie tcr' s. ",: "
during acute infection,
and sens t ttae ttoncf this sys tem to. the v.ru.. i :
,
,

addition to the well-known induction of antibody formation following eX,C$Jre.
Information concerning effects of influenza infection on primary -indlJc.:t10n
cf del ayed hypersens i ti vi,ty and on primary and seccndary anti body responses
to heterologous antigens is meager or li\cking although studies \·lith other

')

ij
~

viruses suggest that 5uch effects might occur.

J
I

~

'.

'Ceate pro toco 1

The functional

statu~

of the immunologic system' seems.likely to'be

important both in the,host response to influenza virus infection and in the
.development of post-influenzal complications. such as secondary bacterial
infections.

Therefore, further information about the effect of i~fluenia

infection on

i~lInol09ic

~

funct ion is desired.

I

l,.

[

Keyhole limpet hemocyanin (KLH) is a protein antigen which has been
shown to be a suitable inuT:unologic probe for study of both delayed hyper-

sensitivity and ahtibody production in humans (13).
I""'nsitization to
~11'imary

~LH

I

Natul'ally acquired

,

.

is rare, and the antigen cart be used to invasti.gate

and secondary immunologic responses ,

l~e

~

propose to use Kl.H

I

.:as ,..ell ·as 4 routine skin test antigens to cvalu.ite the l.!fiects of influenza

infection on immunological functions.
responses of the

subje~ts

to

\:or.: ~l

rtplica~in;

ill ness , antibody response) will a lsI'· t·

<~

.. .:f :-hr.; resui ts
l,

',. r : IS.
:1...

.!, v~ ~"lJ~

r

•

~'1ith

r

sh~ddil1g,

r. ; .f ; ; I.~d.
.

~

.'

.[

Purpose.:
To re-evaluate the previous rep.I)!".:;,

i .. :c~:c:!.: ie) of established

t\

delayed hypersensitivity during in'Fluen:.a ';nf.,ct:c:1, and to explore the
effect of this virus infection on the pl'~mary induc t ton of delayed hyp~r­

r

senst tivi ty and on primary and secondary anti oody responses.

t.
Description

of'Stud~:

This investigation

l
,~i1l b~

performed on vo lunteer inmates at the

Ramsey Unit of the Texas Depar tncnt of Correc t icns ill conjunction with

:

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..

•

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:...'. I

.
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.. :,.'''J ,.'lJ.

~

. ' . page ..

.

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pre.vio~..sl~ ·.~'p~r.oved 'protocol s

I'~'

entitl ed~.,'invnunogeniCi'ir!and i"cfi~?E~ll €flicacy'
•

I

•

;

••

..'

.;.

,.i

t -; CI. ~ ., f-

f'Il "

of -)nfl""enz~ Type A '·lholeVi·rus· and ·Subunit Vaccines" and·,iCoinparison'of ., .
1("; '!'1c.,..r~or,".. ~.·ttb
Homotyp,.i:rz: ,.,lJl.d Jie-tero:typ.tc .Inmuni ty: to .Type A I nfl'u'enza 'V'i rus Infecti 111 _.
"

I

. ' .

:

.'

•••••• }

II

"

on

• . • ,.

, • lf1lllvestlg-arot.:···.··
'
•
Rqllert·.
J..
\ B
h.;i t
' D.: ):.-- W'her'e"l'c'~I
&t'a"Tl"'e,ln'
roe' ii(l~OttjJ~i
nr
( PI'l1'\Y.';I;P.A
;:,C
oue
I'.
I;,
n
1"

)

J

; nfl uenza. (Scotland s tra in of i nf.ltienza·A)· :i s i'n'd',ca!ted tfb~I:'~ubj~dn ~~r J~~!'.: 11.i"

~hi s r~~.~(~s;~;ai~~fr~. : (j~~rl:~'1e.in~~t:~~.~~fs),": ;tJ\~I.~!ffl ,~-li~I\:n~'Y~~1 a)~~.~~~y :YPd.~~ered
. for, partic~p.a~i~~ in ~~.~.o.! .~,he, cat}~er.p'.~~ot('CO~~,J;,:~~Jl ~~~J.rFITzoJ:~~tS.ftf1p.J!1;~
"~f':~·:·'}' ~.·j··~·I' •.;.:.; d ..
r,. v ' • """ . '
•
• .
.
.
. antibod~.;~~, ,:~~ .~r~1.~~~:g;~ V~p'~). ~:~~.,.~s:.~e:~,er~~'~~';·~i?1~~\!,.;~l:11 p'~~C\~.~~~H~Qn911Y
agreed to particfpat~, in th~s i~v~~~~g.~ti.ory.af~~r ~./~lLe~~:,ap.~t:ier,t .• f••J~q~a·
·oJ'';

I
I
)

•

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• . ~j . . :

"~ ••

.~

'

.",.,.,~

I·.': •.·.·

"

men \'lilf·beeonfi.ned to a wing set aside for ~his.purp~~~,~t..thr:.,f"eOlS~t Unit
..

:'( • .

v :

\~':".;'.'"":''':'':'

'.~":

..

t ... _.· ..

~.~'

•• ':"'i

for 2 c!ays prior to intranasal chal l encc \"ith
'.

:.

•.

'J

i

.

.

.I

•

:.

~

~

•

. . '

for approxim~tely·l.O days' after the' .;rtl

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'it . . • . . ,

,Tho$.c-, $.t.lbje.ets who ''Ii 11 no:

~(;

'ii")

.,

.:.

:,

,,,J••..•••.. r • • .

....

,

• .

S':ot·:~rld:irif1~en~~ ...'1i.rus
!

.,. : •

to

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t

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• I

\

,

l~·"·u~e:·"'2.'·":
I c.:
'.

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'. ('C'on't'rol
•

Gr'oups) \'/illbe matched ·in. their lniiu';lii:: a,~t~ji'Jl;.:, ~:'Li";!'S as ~los'elY

~,

as

possilJle with the Influenza Groups berc.:"c.··.c·in;. o·f'i'r-·rl.:·(j :;hc: orr.J.ort:JI',ity to

quarters and daily routines durir.g i;ii·
The design.of the' study ts shewn

L,

~r:

f~·'il

Davs

Groups of 15
volunteers

·0

1.

Control

KLH •

2.

Influenza

KLH

3.

Centrol

28

.Influenza
challenge
C•. T.

."

Infl uenza

:'1iilg "ab'ie:

-_._------------32

'38

KLH

Blood
only

KLH

KLH

Blood
only

KLH

I(LH) PPD)

Influeuz a

Sl~-SD

KUI. ?PD.

challenge C. T. SK-SO

I
.I
I
I
I
I
~

:·t·: .... :.: ;,.:~.

.n

I

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and

~'f:I:;'
.:~re·.-il)lIs
protocols
..:.. ": '1;
.'
.. '
I : .. · ... ;
:;
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• ",,'

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49

Kur, PPO,
C. T. SK-SO
KLH. PPD.

C, T. SK-$O

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.,

-

.

-

Cate prctoco] .

page 5·

Abbreviations: KLH: Keyhole Hmpet hemocyanin, preoared by Hiss Sarah
Dyre in the laboratory of-Dr. Evan M. Hersh, Dept. of Developmental
Therapeutics. Univ. of Texas. r·l. D.-Anderson Hospital. Houston. Texas
77025, for continuing cl inical investigations of that laboratory (13).Doses of 100 mi crogl'ams to be used.
_
PPD = pur; fi ed pl'otei n deri vati ve (5 T.' U. ) s _obta i ned cormerct ally.
C ~ Candidin (1:100). obtained comnercially.
.
SK-SD = Streptokinase--streptodornase (4 uni ts}, obtained cOlTinercially...
All of the test antigens shosn by abbredation in the table are to be

administered in 0.1 ml intradermal injections on the volar aspect ,of the' forearm. ,

'

Each volunteer is to have a 20 ml blood s"mple for f{LH antibody assay collected
prior to each set of intradermal injections; the total blood

collecti~n

for,

. this investigation in combination with the other studies in which the two

.

I
r;1

I

.I

- Influenza- Groups \'Iill be participating \-till be we l l \-l1thin the 450 ml limit
per 6

-

-

Y.LU ant ibcdy assays wi l l be by a double antibody radtctnmunoassey

't/ee.~s.

a l ruady hI use

(·f

in

::-;'ii

tllf~ :,n",q'-'-::l :'~

perp.nr.i en i i:;'

"',::1 :H-:;Qi'dir'!J to iailnunoglobulin class.

1.1 ~ •.. i,-~:, \,"S

AI;;;\':..r·S tc ~b
a~ti~o~y :it~r~

in Cl,)ntro'i

O· ("t:r laboratories (R.D.P.,) and permitting quantit~tion

.. f

-; nc1Ul',; ti on

Cutaneous

at 24 and 48 hcurs.

: )1"-:I':~n!J quest tons \'1111 be! sought by comparing serum

tr ~ ~'fnd cutantous reactivities to the indicated antigens

a~lj ~llflu\.>,Z(:'Groups.

and by corre lat tnqrthese measureuents \-/ith'

respunses ta inflL:nt~ challenge (virus shedding, illness. antibody responses)
~rours:

in the Infl uenza
1.

Does influenza tnf'ect tcn alter primary induction of delayed

hypersensitivity?
2.
(C~mpare

.

(Compare KLH skin reaction at 49 days in groups 3 and 4,)

Does influenza infection el ter the prima,'y antibody response?
KLH antibody titers at 49 day~ in groups 3 and 4.)

'.
"

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..

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m

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)
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.•.• ,

':l ....

3. Does influenza infection alter toe secondary antibody response?
(Comp~re

KlH antibody.titer changes between days 32. 38, and 49 in groups

1 and.2.)

4.

"

J

.I

.,

Does influenza infection
depress established delayed hypersensitivity
.
.
.

I

as previously reported (J. 4)1. (Compare, KUI skin reactions at day 32 in
groups 1 and 2, and changes in skin reactions to other test

anti9~n~

f

between days 32 and 49 in groups 3 and 4.)
5,

How do the above immunologic responses to non-replicating

I

antigens correlate·with responses to replicating influenza virus?

Is

6.'

the prssuned depression of delayed cutaneous reacti,vity dur'inv

active influenza infection gone by 3 weeks after challenge as data of
c'~rr.~~~s·ioh

of delayed cutarieous reactivity at 3 weeks will b:~ r~·tr::tc·'

,,·,tll thepert tnent antigen(s) 6 weeks after influenza cha l l enee

Vclunteer's ''Iill be 18 to 40 year old adult male inmates of
l,;::it of'the Texas Department of Corrections.

t;i~ ;~·\r ~(:~

Detafls of·the selectic:'1

j"."'o'·::$~,

nzve been previously approved.

f

Those men who lack antibody to the Scotland strain of influenza A.
who have aiready been selected as possible control subjects for intranasal
ch~lienge

\-/ho

I

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c,',hers (4) suggests.£hould occur? Any volunteers \'Iho stili exhibit;

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page':6 .....

. Cate protocol

studies with this virus as described in. earlier protocols. and

I
f

have vo lunteered to participate in those studies ,·,ill be offered the

opportunity of participating in the present investigation as

Q

member of

. I
J

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..
•

.t

page' ,.

Cate protocol

,I

influenz~

virus

for·t~e

I

.

.

one of the Influenza Groups.

~

No men will be challenged intranasally with
.

.

".

sole purpose of the present

..

investigation~

I

Men who lack antibody to Scotland influenza but who were not selected as

. :1

r

.

I.

control subjects for intranasal challenge with this' virus will be' offered the
"

~

opportunity of. participating in the present investigation as·a member of one
of the. Control Groups" Other men in the Control Or'oups \'/111 be selected from

.

.

,

j

among'those with low titers of antibody to Scotland influenza.
Vol unteers \·,i 11 be reimbursed

a~

I

the rate of $4 per blood samp.l e and.

$2 per individual skin test for each portion of the study in which. they

:

partic~pate.

f

f
. Th£· \j:!;c;omf· ·'t:.

~:)~.}..;ii'~~ed

intl"c:d~:,:;:r.· f::i;; t(\~·~~~ •

arid 1::::i.. }t1· .~:. ':~'.:"

TIle ··;'·:ti.·.... .•. .•
••" ,....
l'r', ....c.:.
,"'" 1.,(&.
~"!'

with t.his .study are those of venipuncture and

,

.1\11 sl:io tests will be adndnistered by a physician

..; I:.::::

\·,ili· be on hand in the event they are needed.

be sr en by a physician 24 and 48 hours-after their

\lil'l".

:..
.... +,' ··ne:·
• ..... ".h"t
.w,
~

l.
I

\011

·.:.:\Jr.t~:~r!i

~

also have immediate access 24 hours a day to

raotify the responsible physician. and care will be

SCJDit! soreness li1ay develop at sites of intradermal injections.

~

Any

excessive reactions (vesstcutatton, symptomatic regional adenopathy, fe\'er.

..

etc.) will be treated . with topical steroids and/or symptomatic medications
.
as indicated. and the offending antigen will not be administered again.
"

.~
.~

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.

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...... ....

IlL

a
I,
I,
I

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M'

:

f

'1
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potential volunteers verbally prior to the beginning of the study with
explanation that they may elect'not to participate while continuing with
,

any other investigations for which they have volunteered.

.

will be given the

~pportunity

to

Volunteers

.

a~k

any questions they wish, and it will

from the study at any time'.
be' made clear that they can remove themselves
,
They \'Ii 11 then be asked to read and si gn the appended wr;'tten consent form
if ,they wish to participate.
"

Procedures to Minimize Potential Risks:

. 1 •.•

Se" previous section on potential ha carrls ,
will be

.

~t.rictly

t'r"jv,cy

.

protected in presellti,:£ the

\'I.';-u·'";.s

of the volunteers

fir this e tudy,

those subjects \-/ho recei ve the PPD skin test.

The only potential direct benefi ts C:';,

hO\'1

their

respond to a foreign ,ant.igen, and

t:I',:'

;1\~r·.In(1o:

kno\'/~ed~e

(·f

~~lId.:,' tr-

:.....:

~Ii;:::t·l,.ulill

":;',1:

the individual

~:':;t;.:ms

DP.~'i.:.:f·1

are eble to

-

t'cactivity in
ts to sect ety

are in the potential of increased unders ta.id inq of the pathogenesis of
influenza illness and post-influenzal complications.

j

The risks involved in this study Jre negligible and are felt to be
by

I

I
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I
I

Risk-Benefit Ratio:

justified

1

I
I
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'. I

Benefits to the Subject:

I.

~

I

A detailed description of the study to be performed will be given to

volunteers are knowledge of

3,

"_

Method of Obtaining Informed Consent:

I
I

I

.'

the information to be obtained.

.....

_----

"

eel te p.·otoco 1

:

page 9 .
•

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..(

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,cf) () , D;i:1 ,
,.
~. t-: ~~/ttJt:J:.

!
,'j

Thomas R. Cate, M. D.
Princip~l Investigator

[
1

.~

"

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v. r n
...

"P,

"
•"
•, ' ~.~."
..". • t.:'

•? •

_

~

I,','.,

.f

C!,~i·,"~.• e : , ·l~.:::.~"~·:H:·r·!. 0'-:
,,~';( rc ',C j\:>' ;' :..r·... ;i.!i':oJle"gy

.

,~

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. Cate prctcco 1

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page 10 .:

I' .,
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.

.. II

W

'.

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. References:
1.

Salaman, M. H.: I~munodepression by Nanvnalian Viruses and Plasmodia •.
Proc. roy. Soc. Med. ~:1-10. Jan. 1970.

2.

Bloomfield, A. L., and' Mateer, J. G.: Changes in Skin Sensitiveness
to Tuberculin during Epidemic Influenza. Amer. Rev. Tuberculosis
1:166-168. 1919.

3.

.• and ~isch, A. L.: Decreased Skin~Test
Reed. W. P., Olds. J. W
Reactivi~y Associated with Influenza.
J. Inf. Dis. ~:398-402, 1972.

4.

Kantzl~r. G. B•• Lauteria.S. F., Cusumano, e. L.: Lee, J.D••
Ganguly, R•• and ~/aldman. R. H.: Imnunosuppress ton during Influenza
Virus Infection. Inf. Immun • .!Q.:996-1002, 1974.

, 5.

Buckley, C. E. III, Zitt, M. J., and Cate, T. R.: Two Categories of
Lymphocyte Unresponsiveness to Phytohemagglutinin. Cell. Immunol. !:
140-148. ~973.

~

G.

~

C~Yerid!Je,
I~fluenza

7.

Habershon, R. B., and Molyneux, M. E., Slavin, G., Loewi~ G•. i,d
r:ll·r~l1 .. D.' A. J.: Skin Tests with Influenza Virus. ~. HyS.:.l ~,!i.,
755-760, 1973.

"

tate, T. R., and Kelly, 'J. R.: Hong Kong Influenza Antigen Ser.~~l.·iv· r.:/
and uecreased Interferon Response of Periphera 1 Lymphocytes.
!'JI_0!Ui crobi C!..l A~nts and Chemoth~rapY-1970. Ameri can Soci l!tj' fc·;'
:·iicrnbiology (1971). Pp. 156-160.

~.

Ruben, F; L., Jackson, G. G., and Gotoff, S. P.,: Humoral-ar:d
Respon$e in Humans after Inmwnization with Influenza Vaccine.
Jr.f. l~lIun. L:594-596, 1973.

I
I
I

\-1. I. B., and Burnet. F. 11.: A Cutaneous React to., to tile
Viruses. Med. J. Australia 1:85-89. 1944.
~.~:

C~P·:il.r

10.

Hi rsch, H. S., and ~lurphy, F. A.: Effects of Anti -ly'Jiphoid Sera
Viral Infections. Lancet, July 6, 1968, pp. 37-40.

J

11.

Suzul:'i, F., Ohya, J., and Ishida, N.:
on Influenza Virus Infection in Mice.
78-84, 1974.
.

J

12.

cate , T. R., and Hold, N. G.: Increased Influenza Pneumonia NOI~tality
of Hice Adoptively Immunized ''lith Node and Spleen Cells Sen~itized by
Inactivated but not Live Vir'us. Inf. Irr,,;;ull. 1l:908-914, 1975.

13.

Curtis, J. E•• Hersh.-£. t4 .• Butler, H. r.. dod Hassen, R. D.: Antigen
D~!'ein the HUli!cln Imillune RC$!Jonsl!:
Dos~-rcspons~ r.clatiunships in th~
Human Inmune Response to Kc,yilole t.tmpe t Hen.ccyantn. b..J:..ab:-...flin. :-led.
7e.:61-69, 1971.

-I

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C:1

Effect of Antilymphocyte Serum
Proc. Soc. Exp. Diol. 14ed. 146:

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.'.

•
BAYLOR COLLEGE OF ~1.ED1CINE
. TuAS "'ElliCAI. Cr.ST£M
HOUSTON. 'ftXA. 7;025

.

t

~""

REVISED

~
:r
."

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'.

I1"1oon' 0.' ~'t'"kO"ln""',\'"~P l"'\l~NCJl.OCiY
(713t1~9

VOLUNTEER'S
Immunorespons~veness

.

.

CO~SENT

I

FORM

during Influenza Virus Infection

..

. . (KLH plus other skin tests)

r

I understand th~t I am c6nsenting to the injection into the.skin
of n~ forearm of an investigational antigen and 4 commercially available
skin test antigens en 2 to 3 occasions according to a schedule that has
been explained to me. I understand tha~ the injection~ may produce pain.
swelling. redness, heat and/or. a blister at the site of the injection and
that I may feel bad or dev~lop fever. It is possible that other.symptoms .
may occvr.
.

r
f

f

I
,f
;

and

l l recef ve $4 for each blood sample drawn
r: test performed.

U i !.i ..",~~~,~·.!c! ~h~.·;: .. wi
I·;:t·~ : r,:::i \t.; ;!I~,! ! k i

::,"!.'.

': ..- •. :' ~..~..~ d ' .•'..
the :.:.;': t'''', · '.~' .. ~~"'J:
q~f:5,i·I·~ ~ .!r;~!it·:, ,:i:::',:".
Wl

til· ..~. f 1 Ij'i:

.~

I.,. :. '.1:.\:

explained to me and I understand
opportunity to' ask 'any
. , "...
't; J ·,Indp.l·s taud that I ha ve the ri ght to
" :1.~ .~ ~ ~~e ~'I' tJ IOU t Prej udi ce to me.

~t··~: j;,.·:cn clpi'rly
~I:""e t'Jel1 given the

.

;

Signiltur~

.

~

-

_

Datc__

·t
.~

I
I~

~Ii tness

I have careft.:ily·explained the nature, demands, and foreseeable risks
of the above study to the normal volunteers.
Signature_ _._·

_

Date

_

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..

..

:..:.-:..~- --.~-~--~_.

. .. .
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BAYWR COLLEC:E OF l\fF.DJCINE

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Ttu, MElliCAL CESTt:Il
HOUSTON. TEXAS7i025

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VOLUNTEER'S CONSENT

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FOro~

Immunoresponsiveness during Influenza tirus Infection
•
(KJ..H only)

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I understand that I am consenting to the injection into the skin of
forearm of an investigational antigen on 3 to 4 occasions according to
a schedule that has been explained to' me. I understand that ,the injection
may produce pain. swelling. redness. heat and/or a blister at the site of
. the injection and that I may feel bad or develop fever. It is possible
that other symptomsma~ oc~ur.
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I understand that 20 ml of blood will be obta~ned 4 to 5 times' for'tests.·
. I understand that the results of these studies are 'not likely t:; help
me di'rect1y. but that the studies are aimed at helping to understand \':~;.i'
some rer!;Jle get so ill with influenza virus infection and/or devolo:>
com;:lici6tions after the infection •.
~nc $~

I understand that I \'1i11 receive $4 for each blood 'sample l5r&.:~':n

for each individual skin test performed. .

: The proposed study has been clearly explained to me and I 'i'.."': i
the hazards involved. I have been given the opportunity to ~d: :n}'
quest to.is I might desire and I understand that I -have the rlgi:t, cc
Hit:1C:ra\'1 from the study at any time without prejudice to me.
._ _ .

Signature
Date,

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Witnes5

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I have carefully explained the nature. demands. and foreseeable risk:»
of 'the above study, to the norma 1 volunteer ,

'. Signature
Date_.;..,

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-BAYLOR' COLLECiE 01" I\1EDICINE

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'n:xASMEl'ICAIo Ct::nr,l&
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Iloul··I):f.
1'&;:<AS 77025
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: October

..... 01' l'lillill , .. )IrPte....~ ,
CI&IlOraccCO'I:1) ~INI·3:1~

is,

1975

'(713)79~i'l

.'

,Thomas

Cate, M.D.
Departmen~ of Microbiology,' Immunology
Baylor College: of ~edic1ne.
'. Houston, Tex~s' 7702.S·. "
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C,te
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1'he Baylor Institutional Review Board.for· lIuman Research is plcuzsed to'
inform you that your ··rQ~earch propos411 TmM'InorcsponsiYeness During Influenz:l
Virus IDfgctiqn

(NIH SODtr,s;t 61-42528)

was approved on

(RANSEY)

accorging C:O institutional guidelin~s and
the unAltered approval of the institutional comr~ttee in

Os;tn\,er 14, 1975

provid~d it rccc~ves

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. which it is iavol'/cd.
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will be required

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each suhject's exposure

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,-\····,ually.
Ci,anl((» in !'rococol
D'··.. (!~.opn&en i: c:f u\lc>:pected problems or unusual

C~I.!Ipj iCi:tinus'

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Hc:thod c,:i l:uv; m~
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Qu~s:1or.n;,ire (exolupl.e enclosed)
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( j b.
Nt'\f Protocol

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( ) c.
( ) d.

Interview
Other

with,p.incipa~

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invcstinator
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Sincerely yours.
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I .-r-A.u''-_v_~.~ \...
llarold Brown. H.D., Chairman
nQylor'Ins~itutional Review Board
Lor lluman Rcsenrch

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Requesl for Approval of Clinical Inv ~sLigalion Involving
Human Beings

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ErrccL of Corttcosterolds and RcIClt(:cI Compounds on hnmunc

Title:

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p~lnCi
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Experlmental Pretcccl:

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Duration of Sludy:'

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Chairm:tll. Microbiofcg;,' Dcpartment ,
Baylor Colle£j~ of r·.~~dici ne
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Vernon J{night. M. D.'
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Protccols arc

Commitlcc Approval$:

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Enacts of corticosteroids

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.It has been kno\'/n

Oil the immlllle response

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for na'arly 2 decades that cortlscne causes prolor1!1ation
of skin allogrnfls in lab9ratpry animals ( l. 2 >. althou!1h it is less effective Insc , ,.
doing in man (3). Moreover. one particularly useful property of corticosteroid,s is
that of being able to. reverse established states of sensitization ( 4). Clinically.
certleesterclds clearly can reverse acute renal allow'aft rejection' 3.· 5.· '6);'

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Antibody Iormatlen is suppressed in animals givcncorticosteroids under ..
=!,proprj~te ecndltlens., Results of antibody studies, in man are lessconv.f,lcing,
"Idly because most- studies have been done t,sintl dosage schedules mere lil:efy
: in physiologic rather. limn pharmaccloalc.cffects ( 3). MorcoveJ', it ajlpe~r~
·:.):ne systems, the timing of admiilistralion or ccrtlcosterolds ·in rclatlcn te the
• , •. .: •• (!("~C is crucial: once antibody synthe$is is under way. certlccsterclcs may he
. ieros effective' 3 '). A related finding Is that estnbllshed delayed hyperse;1sg iv: r }'
rcactions in man are sUI;pl:essedby aaily. but not by 'alternate-day ".!ll1itl;:.' rE,: jo:~ "Ji
.::ort icosteroids ( ·7).
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Only [lttle is known about the mechanisms by which°':orUc(:::t~I'c;i,:~ :l"~'~;':"
with the immune response •. Acluall}'. the net effect may be the r"stdt C"f r. 'nllm~~ 'f ,7·t
ind:vidu&:!1 actions (3 4). Direct destruction of lymphoid ussues. pc:'lu.;JS '.-:~ c! v.: I '
of binding Lo specific receptor. sites in thymccytes or lymphocytes (8, 9 :. ::~'dLolti.~';1 ,
,,( pha9cc~10sis, anti-inflammatory effects, stabilization of membranes of iY~!_':'(~:l:'''~. ',',
effecter cells. and inhibition of cellular metabolism have.all been implica;':d ·1;', j.l.'<:. :,
mechanisms of actions of corti ccstcrolds Oil Immune reacti ens ( 5 >. lmpc'!'~c.~i~ i ~"! i~ ~ :;
however. is the ract that ccnslderable differences of action exist in diircrl:nt ~r.': "::
and alter different lypes of antigenic stimuli. There fore , for any p~rliclllRr s.::t ..:
elrcumstanees, the effecls of corticosteroids on the immune system can be deter ;:1'. ~~
only by investigation.
Purpose of study

., -

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Despite the widespread clinical lise of corticosteroids. the immunologic
, effects of these agents in man are not clearly understood, Adequate data, does not
, exlst to answer the follo~'/in9 questions:
I. How effective are bcrtlccsterclds in suppressing the immune respense ?
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'

2. 'A"l;ch of the mnny pcsslble co:ticoslcroids avallable are the most
effective agcnts in Slillptessing hnmune rcactlcns ?
3. 'A11at closes are required to cause substanztated Inununosuppressjcn?
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ic giv~n to o~talll maximum '
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propcclies? Do they act'

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, ~~lle~t~':~r'v~'i~II~tee;s sei,eCted for st~ldy'wUlcbe admilted to the G~'I~Qral
Clinifal Rcsearch Center of the Methodist Hospital. , Persons \,,~ith a history of duodenal
ulce~s. diabetes. glaucoma and hypertension will not be accepted for study. After
basel lne studies ,': corlico'steroids' wi n be given according to' protocol (or 7 - '14 days;
'studies \'IiJJ be repeated dllrin9 and,after dr~lg,adnainislr~lion.. Patients \~ill be.examlned
rrequently throughouftlte, study. If.any ~Intoward findings .appear, ccrtlcosterclds will
be immediately wlthdrawn without. rcgard to the status of the cxp~rim~lll.. All studies
\vill be! done vlith lllC ;uH informed consent' of the! patient (see ~t.tacha~ consent form).
;lk;Uilll!li;U~·i(.t Ju:malologlc, endocrinologic. microbiologjc, metabcllc and
ps}'cl'l·.lcnic ~.ll;:;i(~s ,::C n:al:!l~ci~ Not all studies will be done alone time. but rather
eadl "·;<Ii.~ri.,:~:.~ will be <.~~i~!ncd to Incorporate "as many of the studies as possible
wilhol.l n:~c ,clintl \',:1), ~k. ':omrort of
. the p~Liellt. The lyp~s of studies include:
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humoral immunity,
l'~'f;"muglo~lI:;n metabcllsm
{ I • ':»e:r,m, eoncentratlons of IgG. IgA and IgM
j !?). Ptusma eisappearance rates and turnover of isotopically
hbcied immunoglobulins .
/\:ll~:b~idy formation
.l) Primiuy response to keyhole limpet hemocyanin (KLU).
GLAT. etc,
C~.=) Secondary response to eli phtheria and tetanus toxoiCls
~ c. :..~lcoSl;:;'oldson

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2. Effect of ccrttcosterolds on cell-mediated imnllll1ily
a. Delayed-type hyj):!rsensitivily'
,'
b. lymphocyte rt!~ctivitY.l!! vitro
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c. Skin·allograft survival - Determine survival of grafts matched and
unmatched for one or more histocompatibility antigens.
'

3. Effect on immediate - type hyp~rscnsitivity

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with cOI'tfcostcroids?
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6. Is immunosuppression per se the mode of action of steroids'? ,Or. do '
the, steroids' exert
their effects by. anti-inflammatory
or other actions?
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effect for-the .particular. response in questlcn l'
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',4. Errect on inflammatory response
a. Ccllular response delcl'mil1ed by Rebuck s!dn \·,indow tcchnlcue
b. Phagoc}'UC capaclty d~tcrmin~c! :jliunHlc:ltival}1 by uptake of
I '
bac~erj" b,y Ieukocyte s .

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,Effect 'oD:comptement system : '
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"a., QuanUtati've me'i\surement of individual compQnents '
, . , " b. Turnover 'of isotopically labeled complemant. cc:nponents: (later. '
If'fea,slble)
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B~ ,Her,natologic· studies'..
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... ~ Complete blood counts
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2. Bone marrow examlnatlon .csefecled cases) before and once elther during
or after cortlcosterolds,
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C.'. Endocrinolonic studies> Effect

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~( ccrtlcosterolds

on the maior

endo~~ine
.

systems:

I. ' Hypothalnmus and pituital'y axis - radlolmmuncassay of serum ,,"

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, eeneentrauons of A CTU. LI-I and, FSH
"

2. Thyroid .. Serum 'protein bound iodide; T3 and 'T4 uptake
,',
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3. Adrenal - Analysis, of blood andurinc for IThyclJ'0;,y,c9rticosleroids'
'., and 17 ketcsterclds, lolal and rractionaJi.urinarY cpinepllrinc and

.

ner-eplnc r.!1ri ne,

.4•. Gonadal '..

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converslcn pl'oducts ..
lestosteronc/cpile Sl\)5t,~rOi .e
6.. Free-fatty aclds "

Mier~biologjc

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of estriol or estradtol

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M~asurement

pr~gn:incdiol/p ..egnanclriol.

and

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studies

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•CulLures of nasophar)'n:< (slid :IriH~: for LIar.: cria , 'rll~Ji. ,mycobacteria and
viruses
•
E. Metabolic studies

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Serum electrolytes. blooe' ard ~l:';nc.· ~'~ICC'~;~' ;';CI'iHn transamlnases , SC1'um
lactic acrd dchydro'oenases, ;:Ik::!il'~ I ho:· ::'h:ttaf,c, bilfrtibi!1. calcium,
phosphorus and creatlnlne "n:! bie;,o',l iur-a i:it:o~;"ni bone density, weight,
height and girth; chest ;<~:'a}',

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F: Psychologic studies
,

2~

EVCllua~ion

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I: EEG

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by psychorogic testing (later, in selected cases)

P;Ucnt di sco:nforts and hazards
The study requires Irequent blood and uril1~ collections. It is anticipated
that on soma cays larg~ amounts (50 ec) of blood \'Ii·1f be required; on many others, none.
Al no time wi" more lhan 50 cc be drawn on any one day.

•

Numerolls skln tcsts \'Iill be allpl ied. These' r.~n:/ on o:casion cause

lr~:lsjent

redncss.. swelling and local discomfort.

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Less than enepereent of ac!ilils develop reactions to Ir.imunization \·.~ith
Antigens such as diphtheriatoxoid~:', Thesereactlcns may be local or s,Ystemic,' the'
,alia' characterized by. fever and chills of several day, durauon,
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.
.". Sele~teclpatient'swho receive a Rebuck skin \'Iindo"~1 ( 10 ) or skin allo..
. iran. (, ,:1 ') have minimal IQCc11 irritation at the site of api1Iicat'io:l which will- disapp~ar
,.,'hen the te~l is removed.

' .

Side effecls are known to occur' during corticosteroid administration.
;;towever, those most ·orten ocelli' after long-term adminislration of slerqids., Paliell~s
.Yiff be monitored carefully for any evidence or the development of dlabetes, hypertension,
.1eP.Uc ulcer. and other untoward effects. At the firsl sign of sertcus Side effects ,
~orUcosteroids, will be wilhdra~m and appropriate therapy insl~tuted.
.
'(3)

Potential !enefits '
The major benefits will

"I

be ..

(a) EIu:;it1i·Uon 0: the cffec~~ of eorlieoslcroids on the immune response
(b) Def.'r.iL:oJi (,f' tho optimal conditions (01' adminisLration of corticosLeroids to
. ~,uPl::c.:s ;;:11""':11<: reactlcns bo~h il1lransplant palicnts and in patienls with'

;p... ,i~~dc!!ic db.'. dcrs rcquiril\~ Immunosuppress ion. .

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oull lned above will Invade privacy. If in the future
"';:lch ,.~,:~' .. .. ~.'!'j ::',".:.. , ;~ ",'ill hi: dcne primurily to determine whether or not
'.~:U~f}st':':I'c;:~:: ;·.il'.', I!,~ bi1c;.Jinc ability lo carry out slmplcmental functlcns, If Iurther
ir, :'~!,,~h rtpf,icr. ~r~:.l~~" .W:.fl·;.:1le:'::, a separate detailed protocol will ,be submi.lted.
.. "'; r..·,tHy ':1:; ; ....'.ili strictly adhere

to the protocol or procedures described
II' lids a,:pL .:j ir:
,..:-' .:'~r:::h support and \'.'ill not alterthese prccedures in an}' \':a'i
"'Jncernec; w: .:' ~:.ll ~:n ;·'::;;ilgS. without prior submission to and receipt of approval fro:':)
fJ,~ Fa~u:~y :;:";;:".:: ~tH. "r :~~, search Involving Human 8eings".

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CONSENT FORM.
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Effect 'o~ 'Co.ttc~;t~r~fds' and Related c.ompounds ,~n
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'Reaction's ',': '!
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, Immunizations: Patients wlll be lmmunlzed wilh a 'varlet)' of antigens by orie,of the
1OI10win9 routes: intramuscular. intradel'mal or subcutaneous , In some cases antig~n
will be placed directly on lhe mucous membranes, An example of the latter.'woulCf' ba'
the ~ppficatidnof antigen,in nose drops. The antigens to bc' used tnelude.these whlch.
are approved:for use bY,lhe'Food a'lidOfug Adl11ini~taation and those which arc stili.
considcred experimental butwhich have had extensive use in man withput, adverse
side erfects. .
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In general. reactions to the antigens ~·"ill be infrequent •. Local redness ,
' " fi
. swelling. tenderness and itching may last for «bout 24 hours after,inlracutaneoL,'s injections U
of an(Jg~n; although no reaeuen occurs in most perseus. lntl'amuscularl'y,injected'
,.
vaccines can produce local soreness and· redness lasrrn~r two to Lince days, occasionally,' 9,
irritabili~y and anerexla, rarely vomiting and occasionally febrile reactions.,
,
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Skin.Tests: ", The paUenl will be sk.n tested r~r::d 1t.'i'9~· to numerous .substanees
such as'rag\"lee~. foods. d~lsts. molo:{, :mr bar-tea 'i~1 \,;:'a! aud fl\ll~a' products. The
extent of the reaction will 'depend on -:'l~, (fcqrc:~ e! ~ t.n·:· :,/!l y:.i~scnl. and may include
localized sw'cfling. redness and ;<ii:; ;I~ d',~. inj;.:(,:.:~·i: " ';~:. S~'stc·;nic. reaction \·:ilh
prostratlcn and Icver moy OCClll' il~ h:91:1:.- ;d:cr!:r '::, .. "".;.. ~iut this is rare, Scratch
tests will b~ done prior to immec!jc;lc·'~Yr,.: ~j!~in tc .. ~;; ~" .xclude lest matcrlals to v.. hich
subjects are highly sensitive.

.

.

.,.

.-.

2

• The inflammatory r~SJ:C!l:.';; i::, .•,;I~ if'i.: :~'i !:'2:!in~1 llr. abraslen o(a I em
.
area of the skin of the forearm. Tile ;~blj';:'::'11 fli~'i:",.~ 1:,";5k il,fi,,::,mmteryresponsc.
A glass cover slip is taped over the les;c;.n; tl1i£ ::, rc :~:il!:C:(1 at Limed tntcrvals by new
cover slips ul1lilthe abrasion heals •. S:'in gr,\fts no !~r{IOr than I am2 wiI! b.= applied
using slll·gica'i aseptic technlques, 7hf. fjl'dt :lira~ ~c;:collle lnftamcd and reject; the
wound will then heal. p,o~SiblY le~vill9 !,rt~r..
.:
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.

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Radioisotope Studies:
Metabolism of gmnmCJ ~!l(,::'ulin will be studied by injecting
i'idioiodine - lab.eled"purified gamma glo!)u!in. ~'~alerialtl? be injected will be sterlle
by bact.erial culture and \"ill be pyrogen free. based Oil the standard U. S. P. p}'rogen
lest in rabbits; Despite these n~Dalive tests. an occasional person may develop fever
and chills follOWing the irijection.
Steroid 1\C!li1inistration:
Cortlscne or one of the related corticosteroids 0:' pro:1~sleroids
'WITrbe given caily in tablet 01' by injection. These dru9s can cause toxic reactions.

includino dlaberes, high bleed pressure,

P~litic

ulcers, psycholoqlc disLrub,ances. skin
rashes , acne , s~':~"ing CJf the be:1)' tlssucs , r.'!C:!;I~~ss cf musclc s and a num~!r cf ,~hsr
, unpred;cta~le rcactlcns, In 9E:r.~\"al, these raactlcns OCClIl' pi"incipnlly in p::Uen~~ e,l

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s~opp~~ lmmedlately.and appropriate therap~ insli~uled.

...
Patient Disco:n fort:
In addiU on to the above mentioned items. the study requires
lrequent
bloocranaurine
.
.'
. ' collections.
. . '. .
..

..

Inslitulional P.ulhorlzati 011: ' .• All studies to be done'have been approved by the
"Radioisotope CommiL~ec and the Human Studies Conll'littee of Baylor College of
Medicine.'
.
.

.

Signatures:
,. The nature and demands or the study have been clcarl~' explatnad to
'me. and'Tiindcrstand and accept the hazards involved. .1 also understand that if some
. unforeseen ccnpllcatlen occurs. it. too.' is considered to be one of the hazards of the
experlmentIcr which I volunteer as endcrscd bymy sigllaturebelow. ·A p~licnt may.
wilhdraw Irom thestudy at any time of his own choosing•. · .
.

•

_.._-,te._-_..
.

I

espe'lall~'

. " .'. All immunosuppressive d.rL,9 s -iend to tower the body's 're~istance' t~ hifeclio~"
and make it more difficult for tlte'bcdy's own defense meehanlsms to fight"an estiblishcd
Infection." If any eViden~Ef of infection develops during the study. steroids will- be

]

J

\~:eel:s~r mO:lth~·~· ... ~·~?I

for periods' ot r,lnny
An occasional p~tient·. hQl:Jevcr. m3y develop symptO:llS afier only a short time.
If Ile has a history of having
peptic ulcers and SQ forth..
.. '
. had
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cf the above study' t~ .thepatlent, . .
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Billingham •. R~E~~·~roJIll. D.l. and Meda\"lu. P.S.; 'Effecl of corUsolie'
on survival of ~kr.iho.ilo:JraftsJfl
rabbit.s~· Brit~ M~d. J•..!.: I 157.~.·r 95 I,
...
.

;

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.

.2;.·': Morgan. J.k; 'The fnfiucnco"·o.f corti'solle on the survJvalo'f homografLS 'of skill' .
. .•.' 'fn .the rabbit. Surgery. $0: 306. 195 I •
.
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: Brunkhorst. W.I<. lntracelluler binding of ccrttcosteronc il: th:,':"~:"~ '1.:~;Ii:' .•
Biochc.n.
and Biophys
•. Res. Cornmunic•.---.35: a80. 1969..
..._ ..
.
..
•
Eurenius. K.;Oa·lton, T.V •• Lokey, H.J". anclMclnLyl'e, 0.:"
i::':i:::cL~:!i":-j!
or glucocorticoid action on the ph}'Lohcmagglulinin - stimul,.t(!L' :y::....:·:OC:S(· •.
Biochem. 'and Biophys. ACTA 177: 572, 1969.

•o.

I
f

i!ll~emato'ogy~

•

MacGregor, R. R;. Sheagren, J. N.• Lipsett, M. B. amI Vloifr. 5. fl';' l.h":·li~·~\'\"
Day Prednisone Therapy: Evaluation of delayed h}'p~rseii5H ivi~y :·t!rp~::·:::(;s.
control of disease and steroid s;d~ effect. N.EngoJ. Mtd. 3E,~j1 :.:.:,.. 0/. I <'~:. <,

.

•

:~'i'lh SJ1eCialrererel~~~l'~"~;~~H}~n"P!lOCYtic o(

Parker, C. W.. and Vavdra, J. D. hnmuncsuppresstcn. Progrc.ss
I - 81. 1969.

..

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-:
·P.··..
agenls,
.serum. Proc. Roy... Soc. London .174: '.55-172.1969.
.
,...
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'. . .
' . '.
Mannick. J.A. and Egdahl, R. H. Endocrinologic agents. Chi:pler 29'" in
Human Transplanlatioil.· cd, F. T. Rapaport and J. Dau~sct,. Grune and'
Stratton•. New York. 1968.

0

..

I'

Sch\~artz. R~·S •.• Jnllriunosuppress!~c drug therapy. CI~apter ~a .. in'Hu~nan .
Transplantation. ed, F. T. Rapaport 'and J. Dausset. Grune and Stratton.. .

3.

.-

Hersh, E. M. and Frelrelch, E.J. Host defense mechanisms and I :~~~ '. I:..,d. :;c .~i(·:l
..1:. ~55-ii5 :. : 9\',8 ° •

by cancer chemotherapy." Methods of Cancer Research

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Amos. D.B., Seigler. H.F•• Southworth, J.G., and Wal'd, F.E. Sxln gr~rl
rejection between subjects genotyped for HL-A. Transplantation Proc. I: 342346. 1969.
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Chairman. Microbiolc:lgy Department.
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Baylor College of Medicine .:
)/W--C"'./
.. Vernon Knight~ M. D.
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. ::" :'c'qn'::i' ptnnir.sion to incorporate. adminis.traUoll of aspirin to
p~i':lii:. N.~ ;. ;~Clrlt.l'ol in the above experimental protocol.

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"ltil,:;::~d :.IHwe named protocol was submitted in its ori9inal form to
the Ct. ":', ,~'.I.i.' ''':. !~ . ~.". -zrch Jnvoiving Human Beings of Baylor College of Medlclne
on :..~3.c!~ :~{" :';:>J. GI1(j'\'~G :4(Jp,'oved on March 25. 1970. The same protocol
h,,~ al..c b:ei~ ~:;pnwf:'d. t:~, til!" Feh(!l'aJ Clinical Research Center Committee and Ly
the Cr.j·n~· '~t~..: :c.r V :n'c,"· h\ive~ti9~tion Involving Human Beings of M~lhodist' Hcspual,
~

\,," '.J~dm(:iit!. have been carried out so far. Preliminary analysis of
result, ~r.:ik: ·C:Il~ .:i ~l!.yl iJrecnisolone(72-96 mg. po, daily for 3 clays) has
profound ~Ur,;)rc"~!':c rff£c~s on cellular and humeral Immunity, In order to obtilin,.
a reasonable control for the cortisone study we would like at this point to compare
those affe,ts found with corlicosteroicls with those which would occur'following
similar treatment wlthasprrlu, Aspirin has been chosen principally because or its
anli-inflaiT.matory effects and because it has been shewn onl y questionably to alter
immune mechanisms in an.imal experiments. The experimental protocol would be
precisely the s~me ascutllned In the attached protocol.
.

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; ,"I·ptqpQscd dosage of aspirin. 'Ale would aim for a blood sallcylate level
of about 30 mg/I 00 011. Blood levels \'Jill be measured twice-daily durinq the period
or admin~str~~ion of aspirin". According to data supplied tiy the Bayer COmi~41ny Divisio:l

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orSte!.n~·:Drug·lnc

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.... thJs.I.~el::~~.JS~uany:~aclled by th~ third,day.by g.ivi~g.;::>:·

65·mg/pound·.bodY\·'~'SJht·.per:'.24::h~~r$'

. ..
.: ". . .

given in divlded·closes e\If!ry4 hours'.' ',' .: "

.

. We willmon~tqr th~ d~sa9" ac'ccrcUng,:to bloQd .salicyl~te· level, ~i1d:,maintaln a.levef. :.. '. '.
.of about.30 'mg/l 00' mI· fcr'-n'o ronger than 5 days. As was the case in the. .. , -: ...' ;' .
cort.lcoslerpid'studies,· patients will be monitored closely foradverse reactions.

and studies.wHtJnclude daily evaluation of actd-base balance.
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Titre:

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"·'The ultima'te purpose of studying th~ effect of aspirin en the imm'u~~ ;es~~ns~

Is to determine':whether'it will be useful in the treatment of ac.utc', al,lograft rejeetlcn.
Jl would.Jofl9W.~··~heref~re. :that weneed.·to study' a dose ofaspiihl. which WOL!ld correspond
. roughly to that used in the treatment cfother severe acute. inflaanmatory.lesi.ons •. such
as acute rheumatic fever~ . ,It is :;tated .i1J Gordm~n and Gilman (Third Edition. page 329).
"For maximal sUPllres'sion of rheumatic Inflammation. doses that provide a plasma
salleylate.level of 25-35 .mg.~ shoul.d be matntained•• ·••
adults. tolal daily,
dosage of 5 to 8 g•• given at Intervals In I-g. amounts , usually suffices". This'
. statement is consistent with' other studies reported in the review of the liter~ture by
M. L. Tainter and A. J. Ferris CAspirinin Modern Therapy. A Review. Sterling
'Drug ·Inc•• NeW York. 1969).
..'
.' .

Far

a

In order to achieve this therapeuuc dose level it. is our anticip~ted plan to
give asplrln according' to the following schodvlc: tH •. H~ch.;,z;n. in Pharmacology.
2nd editiop. "'!. B. Saunders. Phi(4ide:phi~. : 96 !;. l:.~lli .1 2t1-hour dosage of 65 mg
CI gr.) per pound of body weight. adl11i:li.',;~:.'r'.':; ;:·u:tiu~.(!:.r by mouth at 4-hol!r interval$
around the clock. this titer of 30 t« :1'~ 1',') p~"r IOC iJ;: ';., i!~wdfv reached by the thlrd
day. Once Ute level is achleved :t !:Ji' r',.;i:!i~' li~: 1I1~·:i'iI;-,iiil·"; :i/ .br same dosage at
6-hour intervals instead of 4-hour h;tf:: \ us ",
Modulation· of Oosa~le of Aspirin
I. If persistent tinnitus and gaslroint~·r.i.inaf
accordingly.
.
2. If any sign of a serteus reaction O(;:~t:"":1 :-,sp:l':n t···. f\'.roll~nl wi:llmmediately
cease. Incluced in this catcg(J:': " :(J; r.:,·.:·:·.···:·~;it. rm, :t;.'ns, dermat.ologie
reactions. allergic reactions. t~Sl:L'~'i"~';1 i ' 'Il'(";rli.\gt. renal reactions.
respiratory reactions ann dlsturbances in ~~c;:;"""$" bz.lance •.
3. If the blood salicylate level exceeds :.t~, mg /0 c:l al~Y lime curing the study.
all aspirin will be stopped until the blood level faHs to below :30 mg Yo at
which time treatment will be re-started at a lower dose level•
. Patient Selection

•

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In addition to excludingpatienLs from th~ study with a history of duodenal
ulcers. diabetes. glaucoma and hypertension as cutt Ined in the original proposal. we
will also exclude patients (rom the aspirin !lud:,· with a history of asthma. allergic
disorders. and deafness as determined by audiometer h~!ilin9.
.

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CO~SEN!, FORM

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TItle

of Study:

. Effe,ct of As~irin ,o~ Immune

Re~cti ons in Man.•

Immunl~lions:

PaUents \ViII be immunized with a varie'ty ~f anug~ns by one of
the lO11owing routes: lntramuscular,' intravenous, Intradermal. or subcutaneous.
The 'antigens to be used include those whlch are approved for lise by the Food and
·Drug AdministraUon and those which are still considered experimental· but which have
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had extensive use in man without adverse side effects.···

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. I,n general, reactions'to the anUgenswiH be Infrequent. 'Local
redness. sviellfng, tenderness' and itching may last for about 24 hours after intracutaneous injections of ~ntigen. although no reaction occurs in most persons.
Intramuscularljf injected vacctnes can produce local soreness and redness lasting
t\Vo to three days, occasionally Irritability and anorexia. rarely vomiting and
occasionally febrile reacuens.
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Skin Tests:
. The patient will be skin tested for allcrgy to numerous substances
such as ragweed. Icods , dusts. molds and bacterial v.ral and .fungal prodecrs , The
.:cnt of the reaction will depend en the degree of r,c:nsitivity present. and may
.' ::.·:;alized swelling. redness and pair at til(> i r.';·~cr.:on site. Systemic reaction
prostrafion and fever may occur in highl:' 'aller~'ic PC/·i.orls. bu~ this Is rare,

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Radioisotope S t u d i e s : .
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Metabolism of g3n::n~. glc')~:J:rl .,",!l :J~ :';~l.Ic!icd by injecting
radioiodine -'Iabeled purified gamma ~:Ic:.'·."i:.. r'!!;:li,,-i7': ir' he ilijected will be
sterile by bacterial culture and will be P)'WCJ:';I:I~ ;;;;.e. !' ;~.~(·d (.Ii- the standard tests
of the United States Pharmacopeia. D-=!pi tr~ i,;j .~~ :l::·.;:,l!·"c .ests , an occasional
person may develop fever and chHls ("I: ""':n. :11\,\ 1l1Jr,(.~ Ion,
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Aspirin Administration:
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Aspirin will be given in tz:bici.:: at t.;-h"~lJi intervaJs for a period
no longer lhan 5 days. Many persons wiil CE:vc·lop gv~~tl'();lllu~tinaf irritation or
ringing in the ears; if so. the dosage wili be re~~u(l d. If an" Sig:1 of serious reaction
Occurs. aspirin treatment wi" immediately stop 3m: ah'lrc.l):·i~te corrective treatment
will be given. The types of reacttcns that hr.ve occur.ed. but only very rarelyIn
comparison to the total amount of aspirin that is consumed c!nily in the United States
(approximately 30 tens) include skin rashes. allergic reactions. bleeding in the
stomach and disturbances in the acid-base balance in the blood. The overall Inciccnce
of all lypes of hypersensitivity to aspirin has been estimated at about 2 per 1000
populati on.
f~nt Dlsc crnfcrt r In addition to the above mentloncd items. the study requires

lrequc'nl blood and urine collections.

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Instilutional Authoriz'ation:
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AII-studles'to be done have been approved by the Radioisot,ope
Comm'iltee,and the Human Studies Committee of Baylor College of Medicine.
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Signatures:,
The nature and demands of the stu~y have been clear',)' explained
to me. and I ,understand andaccept the hazards involved. J a'50 understand that if,
some unforeseen complication occurs. it .. teo. is considered to, be one of the hazQrds
of the experiment for which I volunteer as endorsed oy'my signature below'. A.patient
may wlthdrav from the
study
at any time. of his own choosing.
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"h ?<s of the, above ~tudy to the patient.

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Comintttee on Resoareh JilVolvfng Human Beings
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Baylor Colf.eoe of Mcdlchle .. '
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. Determination 'of the ability of knewn antigens
I, -Title:
• to Induce antibody (onnath)n Inman,
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WilHam T.· Buller. M. D.
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I ,'nvcsU2!tors: . '. ·',Evan
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MoO Hersh. M. D., .
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Roger D. Rossen. M. D•.
I J. Method
•See attached sa~lprc.
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. Expcrimental Protocol:
To fully evaluate the ~freclivenes!l of c~rLain ~mrr:lIn~'sllPpressivc
agents. a quanlitalive measure of the capabl! it)' of all lndlvidua] to produ.ce
specific anlibocly is required. This is done by inj~ctin9 antigens at p~riodic
lntervals and by Illoasuring the circulating itllt.HJody lhat subseqllcntly develops•.
Antigen injections are given intra(!en.~(ll:y. sut-cutanecusty cr Intrameseularly ill
doses or' O. I to 0.5 ml usin~ stcrIe lC:l,;h!i:'iLli;~. In some eases•. antigelis
wifl also be 'applied dlrcctlv io mucous r.:'~ir::)fi:;.;.(!!: ~u:h as the nasal mucosa. '
local redness. s\';e!Jing, leilc~·; :':.; :. ~r.\.: .: . ::1:-:',! r.;,~y last r();· abou: 24 hours
after lntracutanecus injccUc';!; .: ". ;.;~n, ;·:th,)' :i;~ li~~ rcacticn eceurs in most

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persons.

IntraIl1115cllliiil~.1 iI',:':' ,,'. vr'.. i'~··~ ;;':.:!

redness lasting two to three ~L".
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pi...rluce local cereuess and
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The Cllitig!::l51 t» C~. ~,i: :.i i;:' . ". '::('O;:.,r:O il'.~~ 2 !Ir~ups. these
". which arc FDA.r.,p,'o'o'cd ':lli~· L:' _ .. ' .:.. '. ":';' i.'\:f':;la(;!~. cmd these Which i:re
stiil experimental but have I'.~d :;~: ...... :':.;. :.~: in mi'·.l \·:ilhout.advers~ . si.de elleets.
.
The first group of ali:':r;,

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~ ':"!,::, :;c!::S I.:~rmatophytin, aermatop!wUn

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candida. varldase , strcptccccc.» ~ .Y,i:: •. !!!::'dndla extract, brucellergen;
hlsteplasmin, ccccldtcdiu,' tube cu.in I ,m mr:; ;ttlli~·~n. blastcmycln, diphi.hciiil

toxin and toxoid, tetanus tcxolc, l}'p/tllid- paratyphoid, and so forth.

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The second group Includes keyhole llmpet hemocyanin (KLH),
ether hcmocyanins and synthetic amino acid co-polymers such as glLllalii/cJysin~-alanine-lryp~e:;han(GLAT). These compounds have been given in
doses of J to 5000 1-'-9r lntradermally or subcutaneously, withollt serious
side effect by the fo!lo~'Ji:1!J invcstigalors:

I.

Swanson. M.A. and Schwartz. R.S. lmrnuncsuppresslve Therapy.
New Englnnd.J. (-.led. 277:163-170:' J 967.

2.

Maurer. P.H.,

G~rlllnt,

B.F •• and Ptncluck , P. Antigenicity of

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of obtaining informed consent:

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Polypeptide s , VU. Stlicli::r, iii lI~lIi:dns. J. Expl/. t\~~c!. 116:52~··;:;~:?.
1962.

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Hersh. E.M•• Harris. J.E•• ,Mc;Bride. ,,C. and'
Frelreich. E.J. The l:Iu:l1an Primary ·Jnlm,lIlle Response to
Keyhole, Limpet Hemocyanin. Jillerl~~,atio~ship of Oe'a~'ed ,
, • HyperscnsiliviLy. AntiBody Response and in vitro Blastogenesis.
(Submilled for publication)..
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, Hersh. E. M. Kinetics orthe Nor:mal Human"lmmune 'Response.
Annual Repolt 10.lhe.NIAIO. 'u.s,. .Govt. .PrioUng,Of(ipe
•.1969~
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No invasion of Indlvldual privacy-will occur.

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..) certiry that I will slricLl}' adhere to the prolocol of procedures described
In this appllcatlcn for research SUPPOlt and wlll net alter those procedures
In any V/Cl.Y concerned with human b~in9s. wilholltprior sub;nissJo:l to and
receipt of approval from the Faculty Commillee on Research Jnvolvilii)
Human Beings. II
Siy nat lire s:
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August 26. 1969

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or Study:,:·::'Delermlnat'ion or-Ule abllityo~r known'anligen$ to Induce
, a'nlibody formation in man".

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Genera; ,Deseri pU on of Resepreh" Procedure: ' '

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'. Patients ,\'Ii'll be 'f~lInuni2'ed with a, wriety'of'a~igens by'one 'of:~he (ollowing
routes: Intramuscular. inusdermaf' ersubeutaneeus; .ln some cases-,antigen 'wilI be
placed directly en-the mucous membran3s.An eX2lnll)le oflhe lallerwoufd be the
application of antigen in nOse drops', ' The anLigen$' to be used tnclucfe"Lhose ,",hich
are approved for use by the Food and Orug AdmfofstraUon and,tho.se 'which are sUB
considered experimental but which have had extensive use inman ,;jithouL adverse '
side effects.
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All procedures undertaken VIii I be done \'lith the' approval of the Human Studies
Committees of Baylor College of Medicine and of the Hospltal,
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Potent ial Hazards of the Study: .

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• , In £Ienel·al. reactions' to the antigens will b~ inrrequeh~. LOC,el1 i('c!i',,:'.:",.
swelling. tenderness and itching may last (01' aboul 24 hours ,~il(~r'intl'~Cl!~~.:1. :)~r: :-'0: :,i""
of antigen. although no reaclion occurs in 1110St persons. Inlra'~lH..c:lIi.ir:::' iiJjr"lt;, : 0 1
vacclnes can produce focal soreness and redness lasling twete l.h!'cc:,,:aJ~. ,,:':ca~1,'I';I::f _
frril1lbility and anorexia. rarely vomiling and occasionally Iebrl!c rcac: ;~::l~.

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Authorizations
. The nature 'and demands of the. Sludy have been clearl~' C):pfr.;:;:-\.i '." .,.
undel'sl"&l~d i:·:C';t it to: .;!..'
unfcreseencempllcattcn ocelli'S, ire too. is considered to be one of thti hc:zi.l(,: ,:~
the experiment for which I volunteer as endorsed by my s;'gnalure bslcw.

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and J understand and accept the hazards involved. I also

Signature

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Date

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J have carefully explained the nature. demands. and foreseeable risks of
the above stud)' to the patient.'

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Signature

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'. General Clinical Research Center
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. Baylor Universl.ty College of Medicine

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Butler, M.D.
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To study the syslemlc and. local antibody responses
. anti£lcns applled to uie nasal membranes and tonsils.

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to ncn-repllcatlna protein
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have lndlrated that forJowing experlmentally-lndueed upper'

resplra'..-r; ·!i.·, ; :0. ·'· ..l'(;ii, \h:o' 19/.\ content of nasal secretions increases at a

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susLainr:c' .."...~Il ~ .:;1:;: te,\i:l _':e:cks, "lid is associated with locally produced
spec;Hl' ar.t.. <:', . :"'~ ::ir:j:rv~CcJ studies are planned to determine whcth"r locally
produced n!'.l:; ... :.' cr.r !.: .. i.ii.:l::tq· i:y nen-rcpucauna antigen as well.
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Purpose:

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• Subject: Proposed St~dy of Diphtheria Immunization In Volunteers' '. :"':' .
InvcsUgalors:' VVi lIiam T. Butler, M. 0.,
Roger O. Rossen, M.O.
Reuben D. Wende

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To: Dr, :Rob~rt· ·B·. Couch,. 'prograrn pirector.

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1. ';'Yi"~. "."'.!I". :'. "'.. :i I.. be lfi- to 40-year-old inmates 'of the Texas
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oUY'ation of study.

Nine volunteers; six weeks.

:3. Scl£:clion. \lolunl'.:(:r~ will be solicited from the general pcpulatlon of
one or mere institutions of the Texas Slate Department of Correction.
The investigators will visit the institution and describe the research
" protocol to prcspectlve volunteers ° Medical records will be screened .......
. on those men who volunteer. Final selectlcn.wlll be based on willingness
to partlctpate and good general emetlcnal and physical health. The
Department of Corrcctlon Vii 1\ then screen sultable candidates from the.
custodla! point of view. •
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1. Blood specimens (5 ml) w; II· be obtained daiIy.· In no ease wi II more

than 600 ml bloodbe obtained (rom a subject ouring a single study.
Volunteers wi II be advi sed not 10 donate blood for threemonths after
completion of the study.
2. N'asal wash specimens will be ·\~t;.io(,Ll c",n~" 'rb\~se will be done by
Instilling 5 ml lactated l~ill:.;cl'.· ::~I;,d:~I' ,n' o each .~o!'t.r.il, ~nd havin~
the volunteer lean forwCld"ic :,Li~', t!~f. :!·::t;:·I.:... :~~ :::It"l it beaker• .

Biologic Reagents:

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Exper; menta I Protoco I:

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Following collection of baseline bleed ~:n~ f1~;~~! ~ei.reCon specimens, six
volunteers Vii II be inoculated with a st..mLiai'Q : li;it~l::lhi '':u dos'.: of fluid ,diphtheria
toxoid and three with' control medium a~ foll(.;~·,!;: .
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4. Medical precedures, Suitable 'Voluait~ers will be admitted to Melhodtst .
. Hospital in Houston' foi final medleal e~amination and scre,,.tng ~ .. , :',
On admission,. ~omph!te medical histories and. 'physicarexamfnations
will be performed •. .Laboratory studiesmust be within nermal limits '
and will Include urinalysis, complete 'bleed ~oul't"eleclrocardiosra:m,'
chest end a!>dominal x-rays, blood urea nitrogen, blood sugar, transamtnase(SG,OT)~ serologic test.fer syphilis~ totaLseruin pro'tein
,
concentration and albumln-alobulln ratlo, s'eru~n electrepheresfs, and'
serum immunoglobulin level's UgG, IgA, and IgM). '
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Immunizing

A.g~

Diphtheria toxoid
Diphtheria toxoid
Control medium

Route of Tmmunizi\lion
Intramuscular
• Intramuscular,
Intramuscular

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: Diphtheria t~xo.fd
:Diphtheria' t'oxoid ,
. 'ConJrolmedi um

In~rato~stlla;: , ,
'IntratonsllJar "'.
,1n1ratonsl;Iai' , '

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Intranasal
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. 'Olphth'eria,'toxoid .
. Diphtheria toxoid
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The Intranasal and intratonsillar iminunlzaUons 'will be dC)ne by.swabbing
the fluid toxoid onto cotton 'swabs and p.lacing the swab in the nasal passages
. and Into the tonsillar crypts, respectively.

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Hazards to the Volunteer:
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Purified fluid diphtheria toxoid prep".re~1 b)' the Texas-State Department of
Health is known to give a local or systemic reaction in less than one PC! cent 0(the adult population. It can produce a !(.IC"cl.i ::cr,,'r.&.'~.:,. and redness lasUng Lwo t~
three days; occasionally irritability
,m:: ~=.':)j 1:';':;:: I :::jr; l.:.rc!y, vomitiag.
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In gene,.~I,..toxoids precipitate-d \·'H:. :'I:";:: d .l~'1 ti,I"S~ eommonly used in
the U.S.' (or immunization) cause rr:OI'( r", (;li·~n th:'!) the (wid to):oicis that we '
will'use in the present study.

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Benefits to the Subject: .

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The booster immunization to diph:hc:-;a ~.iloIJ:d.:Jro...,;dc:d added protection
against this disease.,
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Ge~eral Description. or ;Research Proc~durc:
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, Volunteers will be immunized with purtfled ·diphtherla toxoid b)"one' 0" Ulree '. :
.
- routes: Intramuscular, Intranasal; .and Intratens! liar. Blood 5P~c.im¢ns a~d na~aJ : .. ' .. ', '.'
secretions will be eetleeted dajl y.for about six weeks, ' ':.: :> :.. :,. . . '.', :;:~; ':,..... . .
proce~ures· ~~~e·rtaken win b.e done, ~/lt,h.lh'eappr~~~1 ~i~~,~ Hu~~·~?·)': . , ". ::"
Volunteer Studies Committee' of the Bayror UnlversJttColJege:()f.Medicine·to ensure:'
safety of the experiment as well as its scie.ntific value. '. '
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Pdtcnlial Hazards of the Study:' :.
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Purified fluid diphtheria toxoid prepared by the Texas StatcO~partlrie~l:.of·
Hearth is known to give a local or systemic reaetlcn in lessthanone pCt' cent' of the
adult population. It can produce a local soreness and redness lasUng tw~ .to· three'
days, occasionally irritablli1y and anerexla, and rarely, ·,vomiting •.. ;'.
'.
".In general, toxoids precipitat.ed wlth alum (i .: ~., these ccmmcnly used in the
. U.S. for Immunlzatlcn) cause more reaction U":3:-. f.!,;· i'!':id toY')ids U:''=lt we wi II use, '.
In the present stud y•
.
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Authcrizat ions:
Thenature and demands oi the s'uc, :;.....;

h~."I; c..-:cw ;~: ,,~:"!",lfai:1cd

to me and 1
understand and accept the hazards involv '. . l :: :~,:I ··:·'J~r:.t;.:··d~r.~~·if'~ome unfcre-'
seen compllcatlen occurs, it, teo I is Ct.;I': :;:; r."~; '.') L- . J .. • (:! t~'E' lr.vards of being
a vcluntccr, Furthermore, I understand r :0.1 ; ::,: 'f wU."::·::';: ih ..j .:i'-' study if I fhid
that J am u.nC\.bre to continue.'
. .'
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--------7· --:-... ... -------------_..._---_ ... _.....-.---

Volunteer's Signature
Dale

--~.-----

J have carefully explained the natui e, C:~r.l:!IH;S,
above study 10 the normal volunteer.
Jnvesligalor's Signature
Dale

itnt: IU!Cs::.~".brc

risks of the

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General Description of Research Procedure:

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Y~lunteers will be immunized with purifiC!d di~hth~r;atcxoid eithe~ the
Intramusclll~r or intranasal route, In some cases th~ 'c!iv;th~ria toxoid \'Iii" be

by

f

labeJJe~f~~icactiv~ iodine. The length of the stud:l'~'/iJJ '~~ ilbou~ tV/o weeks.
Blood specimens will be taken frequenlfy and nasal secreticns dally.··. '.

All procedures uncertaken will be done with the: ar/r-ro'lai .of the Hu,r.~ri·
Volunteer Studies CommiUec.sof the Baylor University Cr.,IIi:ge of Medicine'
and Methodist Hospital and by the Radio Isotope apprcNal ,ommitte~s of the
same lnstltutlcns,

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Potentia' Haz~rds of the Study:

Purified diphtheria toxoid prepared by the TeY-fJs Sta~(f Department of Health ;5
'known to gi\'e a local or systcmic rcacucn in less than one per cent of the adL:lt
poPUlilt;on. It can produce a local soreness and redness lasting two to three ria}·:;.
occasionally irritability and anorexia, and rarely, vomiting.

..

Th~ vaccine preparation volunteers ~'/ill receive ls the same one- "'..:.:..:
able rCJ:"l"SC by prlvatephystctans in Texas. .
.

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The amount of radioisotope approved for administrCltion is
, "::cid::red to be hazardous.
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T!.: na,lifC and demands of the study have bf\cn clcllrly cxplarnc : ; ,
. understand and acccp; the hazards involved. J also undcrsu n.j th~~ ;, :::".' i" !,'," ,,!
seon ~:''';lplication occurs. it, too, is considered to bc one of the ha::ur:,~: . ';!;I ,:
IOrllr,t·~c(. Furthermore, I understand thal J may withdraw (rom the s~ud~t if I iii";
that J am unable: to continue.
.

--------------Vate.:'
---_:-_---------------Volunteer's Signature

. I have carefully explained the nature. demands, and foresceable risks of the
above: -.' tidy to the normal volunteer.
'
lilvcsti!J~lor's

Date

Signature

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TUle of Study: . 'Diphtheria JrnmunizaUon .

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