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The effect of cimetidine treatment on suppressor T cells in duodenal ulcer patients
Immunologt Letters.
"7.q19841 285-288
E Ise~~er
Imlet 453
THE EFFECT OF CIMETIDINE TREATMENT ON SUPPRESSOR T CELLS IN D U O D E N A L ULCER PATIENTS Henryk T C H O R Z E W S K I , Konstanty M A R K I E W I C Z and Piotr M A L E C 90-549 .E&t~. and
IDel~arttnent o f Internal Me, he me. In~tttute ~?1 Internal .~h,dtc me. 3Ie~h~ a1.4 cademt, td Zeromsklego 113.
Departmetlt ol" Pathol~h.; stoh~gt, htslttttte o[" Bastt .~letht al St tern e~. .~lettit a1.4~ a~h,on. PL 9 Mata I. 90,64" ~c&t-. Poland
(Recmxed 18 Noxember 19831 {Accepted 15 December 19831
I. Summary
Changes in the suppressor T-lymphocyte activity were studied in I I patients with duodenal ulcer during treatment with cimetidine. The drug was administered intravenously, in a dose of 200 mg four times a day for a fortnight. Suppressor T-cell activity was determined by the Shou et al. method using t ~ o stage culture before treatment, after 4 da3 s of the treatment, just before drug withdrawal, and 2 days and 2 wk after the treatment. Suppressor T-cell activity significantly decreased soon after starting the treatment, remained low throughout the treatment. and rapidl3 and significantly increased following drug withdrawal.
2. Introduction
Histamine ma2, affect the immune system by stimulating the H_,-receptors ~ hich ha~e been identified, among others, on T lymphocytes [I-5]. Cimetidine, a selective antagonist of H,-receptors, is therapeutically used to inhibit gastric acid secretion and to facilitate healing of ulceratke lesions in the gastrointestinal tract. In addition, it is also thought to act as an immunomodulator. This ~ iew is based on
he~" ~,ords" cimetidine suppressor T-lymphocxte actn'.Lt.~duodenal ulcer d,sease
H. Tch0rzev,skn. Zaklad Patofiz ologil IN P WAM. Plac 9 Maja I. 90-647-'UrdL Poland Corre~,pondem e to"
0165 247t~ 84 $3.00 ~, ElsexnerScience Publishers B.V.
the Iinding that cimetidine treatment is accompanied by increased skin test reacti~ ity to a number of antigens [6-8], reversion of tolerance to dinitrochlorobenzene (DNCB) during the treatment of alopecia areata [9,10], accelerated rejection of transplanted kidneys [I I, 12], appearance of a u t o i m m u n o h e m o lytic anemia [13], Quincke's edema [14], nephropathy and polymyositis [ 15], and enhanced mitogen responsi~ chess of lymphocytes in vitro [ 16-20]. However. some authors ~ere unable to detect any effect of cimetidine on the immune system [21-26]. Palacios and Alarcon-Segovia [27] obserwed that cimetidine diminished the suppressor T-lymphocyte activity in xitro ~hich may be responsible for immunological disturbances. The aim of the present study was to determine the suppressor activity of Tlymphocytes in duodenal ulcer patients treated with cimetidine. It was found that drug affects the suppressor activity of human I.~mphocytes in ~ ivo.
3. Material and Methods 3. I. M a t e r i a l
The subjects were I I hospitalized patients, 8 males and 3 females, aged 20-55, mean 32.4 ± 10.9 with duodenal ulcer disease. In all cases gastric acid secretion levels ~ere in the upper range of the norm or a b m e it. Cimetidine (Belomet, Podravka-Belupo) was administered in a dose of 200 mg intravenously four times a day for a fortnight. Blood samples for the investigations were taken twice: to induce the suppressors with concanavalin A (Con A) and, 48 h 285
to measure the suppression. This '`'`as performed (I) before d r u g administration, (11) after 4 days of the treatment, (111) before t e r m i n a t i o n of the cimetidine therapy, (IV) 2 days after d r u g withdrav,al, and (V) 2 wk later. In 7 subjects the whole series of 5 investigations x',as performed, in I patient there '`,,'ere 4 in,,estigations, and 3 in the remaining 3 patients. later,
cells '`,,'ere treated u, ith 50 ~g ml n m o m v c i n C ( M C . Sign'm) for 30 min to inhibit proliferation. The cells prepared in this v, a3 ',,,'ere '`xashed fi',e times ,~ith H B S S and reconstituted to I × 10" cells ml in the m e d i u m described above. T h e n fresh a u t o l o g o u s res p o n d e r lymphocytes (R-cells) suspended in m e d i u m described a b o v e '`~ere added to the culture in a rauo I:1: I x 105 S and R ceils as ,,,,ell as C and R cells. respecti'`ely. 4 x 0.2 ml of each culture '`,,ere carried out in round b o t t o m microtiter plates (Linbro) in the presence of 10,ug ml C o n A for another 120 h, adding to each ',~ell I ,uCi of [~H]th3 midine Ispecific activity 25 Ci m M , IRLIR, Prague) 5 h before the cells '`~ere har'`ested in a '`~ater-water s'`>tem u.,,mg S k a t r o n multi-cell harvester. The degree of[~H] th3midine i n c o r p o r a t i o n '`,,as determined as the n u m b e r of isotope desintegrations per minute [ D P M I in an L K B - M a l l a c - 8 1 0 0 liquid scintillation counter using Bre3's scintillator. The single results represent arithmetic means from four measurements. The percentage of suppression '`~as calculated from the formula:
3.2. Determination o/'suppressor T-lymphocyte activitv T h e suppressor acti'` it3' of T-13 mphocytes '`~as determined in t'`',o-stage culture a c c o r d i n g to S h o u et al. [28]. Blood samples '`~ere taken on heparin from the '`enous blood at 10 12 a.m. The 13mphocytes ',~ere isolated on the F i c o l l - P a q u e density gradient ( P h a r m a c i a ) a c c o r d i n g to B 6 y u m [29]. M o n o n u clears from the interphase ',,,'ere '`',ashed with Hanks" balanced salt solution ( H B S S ) and brought to a c o n c e n t r a t i o n of I × 10t' ml in a Parker's m e d i u m enriched with 20c~ heat-inactivated calf serum. 2 / u m o l ml L-glutamine ( F l o w Laboratories) and 10 ~ug' ml gentamycin. T h e suppressor 13 mphocytes IS-cells) '`,,'ere stimulated '`~ith 20 p.g ml C o n A (Sigma): the control cultures '`',ere set up parallel without an~ C o n A (C-cells). In both cases the lymphocytes were cultured 48 h at a '`olume of 3 \ I ml at 37 ° C in humidified 5% C O , incubator. Next, the
"~ ,uppre,slondpm R-cell~cultured m the pre,.ence ol b-cell,, II
b • I0()
dpm R-cell>cultured m the pre,ence
ol
C-cell,,
The statistical significance of obtained results ',xas scored x',ith W i l c o x o n R a n k signs test.
Table I The acti', it) c,f suppre>.,or I.'.mphocx tesm duodenal ulcer pattent> during c~meudme treatment No.
Patient
.Age
Sex
Percent suppresston I
II
III
IV
I
.I.R.
22
m
_4.,
I0 O
0 5
6 4
2 3
P D S U.
20 52
m m
39 6 12 1
13 4 22
222.5 3"2
I I ,', 4"11
4
.I.M.
34
I
62 O
I" 4
2g 0
55. ~
5 6 " 8 9
KB K.M G.A. K.S SE ~,~, Z. B P.
54 22 24 55 23 24 26
f m m m I m m
16 3 19 75 4 ~0 36.3 4.0 40.5
31 3 I1.1 39.3 150 2 22 l) 13 6 60 9
4.2 4" ".9 138. I 14.4 94." 331.8
21 x "q3 20 6 4 .7
IO
II
Arithmetic means and SD
28.8 ± Ils "
31.2 ±440
e,7.7 ± 114.~
36 3 ± 23 5
\
34 3 221 40 4i 11.4 51 44
I" I + 15 3
Inxe,qigauons: I. before therap.~. II. alter 4 da~.--,o1 therap.,.: Ill. belore termination of therap,.: I\. 2 daxs alter eJmetidme +~lthdrax~al. x. 2 v.k after cimetidme w~thdrav,al. . not done 286
4. Results The results are presented in Table I. Individual percentages of suppression range widel3, which is in agreement with the results of other authors [30]. The general direction of individual changes ~as identical in all cases. After 4 da3s of cimetidine treatment all patients exhibited the decreased suppressor activity of lymphocytes t P < 0.005) and almost all of them sho~ed negative suppression, i.e. instead of suppression of proliferation measured as incorporation of tritium-labelled th.~ midine, they sho~ed stimulation. .At the end of second ~eek of the therap3 I! mphoc~tes from 8 patients had slightly increased suppressor activit3, ~ hile in the remaining 3 subjects the suppressor acti~ it3 decreased even further. T~ o days following cimetidine ~ ithdra~al suppressor acti~ ity of 13mphoc.vtes increased significantly in all patients I P < 0.0051 and it did not change much during the following 2 ~k of observation: the obtained ~alues ~ere comparable to those before therap3.
5. Discussion l-he presented studies sho~ed that cimetidine decreased the suppressor activity of T-lymphocytes in ~i~o. This was not a non-specific effect of healing duodenal ulcer, because inhibition of suppressor acti~it3 x~as found rapidly alter drug administration, and it ~as persisting throughout the treatment, and returned to the initial ~alues soon after the drug withdra~al. It has alread~ been mentioned that cimetidine also lowers the suppressor acti~ ity tested on lymphoc}te culture in ~itro [27]. The total elimination of suppression and, thus, the appearance of stimulation of I.~mphocyte proliferation m xitro during cimetidine administration are of considerable interest. According to Shou et al. [28], Con A ma3 act by more than one receptor, and one of them is responsible for the enhancement of blastogenic transformation. ~ hile another is responsible for the stimulation of suppressor 13mphoc.vtes. It is also the case that suppressor cells which respond to Con A do not represent the entire suppressor cell population [31,32], and it is not kno~n how other subpopulations of I respond to cimetidine treatment.
It is currently assumed that cimetidine acts on H, receptor of T, lymphocytes, an idea that is additionall)' supported by the rapid increase in suppressor actit it,,' after cimetidine withdra~al, an effect that is probably related to scaling of blocked receptor from 13mphocyte surfaces. Most of the lymphocyte separation techniques do not remo~e all of the basophils, and histamine may be released from them as a result of mitogen stimulation [33]. The changes obser~'ed after cimetidine administration may also be due to blockage of hisfamine-dependent inhibition of lymphocytes [ I-5]. To obtain comprehensive picture of the mechanism invoked, it is necessar3' to determine the effect of cimetidine on the generation of interleukine I by macrophages because, h3pothetically, it may give rise to hyperstimulation of r h lymphocytes. Hox~e~er, regardless of the exact mechanism in~olxed, the inhibiting effect of cimetidine on suppressor acti~ it 3' of lymphocytes is unquestionable, albeit short-lived. It is well-known that impaired suppressor activity is the most important disturbance observed in some autoimmune diseases [30.32]. Thus, it seems that caution should be exercised, especiall.v in cases of long-term cimetidine therapy of patients with suspected autoimmune disease or predisposed to it. It is also necessary to monitor some of the parameters of cellular immunity.
Acknowledgements The authors wish to thank M. Luciak, M.D., for his linguistic help in manuscript preparation.
References [I] Rockhn. R E. I19761J. Clin. ln',e,t. 57.1051-11)58 [2] Rocklin. R. E..Gremeder. D K.. Lmman. B. H and Melmon. K L. 119'781 Cell Immunol 3 "r. 162 1"~3 [3] Rockhn, R. E . Greineder. D. K. and Melmon, K. L. (19",91 Cell. Immunol. 44.41)-.1-415. [4] Plaut. M., Lichlen~tem. C M and H e n n e } . C S. II9751J Chn. In'.est 55,856-874. [5] De Cock. ~,~,.. De Cree. J. and k erhaegen. H. I Ig',~l Chn Immunol. lmmunopathol II, I 5 [6] A',ella. J . Mad>en. J. E.. Binder. H. J and A.-,kenase. P. W. 119781 Lancet I. 624 626 ['] J~me',, F. G. C 119"781 Lancet I. ,xsll
287
[8] Jonzzu. J L.. Sam.,,, W. M . Jegasoth), B k and Olan~k~,, A.J. 119801.Ann. lntern Med. 92, 192-195. [9] Daman. L A and Rosenberg. E. W. I lgT') Lancet 2, 108"7'. [I0] Breudlard, F and SzapJro. E 119"7,81Lancet I, "v'26. [ ] I ] Pnmack,~3,.A. llg~'81Lancet I,~24. [12] Zammit. M. and]-oledo-Pere}ra, L H. llg"gtTran~planta(ion 2". 358 359. [13] Rotoh. B., Formi,,ano, S. and Alfinito, F I19"9) Lancel 2, 583. [14] Delaunot~. k. l19'7,9) N. Fngl J Med 300. 121(,. [15] ~,atson, ,~. J. S . Dalbo'0,. M H . Stachura. 1.. Fragola. J ~.. Rubm. M F . ~ A a t , , o n . R M and Bourke. F 11983~N Fngl. J. Med. 30~. 142-145. [16] RoberL, on. A J.. Peden, N. R.. Saunder~. J H B. (,ibb~. J H.. Potty, R C., Bro~n. R. A.. ~orm~,ley, K G and Beck, J. S. 119791 Lancet 2,420 42l [I "7,] Smith. IM D.. Couhig. E., Md[er. J J and Salaman. J R (19v9~ Lancet I, 1406 [I,~] Er~hler. ~,. B, Hacker, M P., Burroughs. B. J . Moore. A L. and M~,ers, C. F 11983) Chn. Immunol Immunopath~q. 26. I0 17 [19] Beet~.J.L and Dale, M M I I9"91Br. J Pharmacol. 06. 365 3"~2 [20] Giffc, rd, R R M , Hatfield, S. M and SchmtdLke. J. R (19801Transplantanon 29. 143 148. [21] McGregor. C G. A..Cochran, A . J . . O ~ g , L . J , . G r a ) , G R.. Snnlh, J. S , Gdle_-,pie. G. and Forre~ter. J ( 19~vl Lancet I, 122 123. [22] Fe_,,ten, H. P. M., Berden. J H M. and PamL B. E. de
288
[23] [24] [25] [26]
[2"]
[2~] [29] [30]
[31] [32] [33]
11%0) m. H,,-receptor antagom,,ts m peptLC ulcer &sea,e and progre++ in hJstamme re,earch(fc, r:oli. A.. Luccheh. P E. and Brimblecombe. R. W.. Ed', J pp. 327 334. Excerpta Medlca. A m,,terdam-Oxford-PrJnceton. Charpentwr. B. and FrLes. D. q l97~) Lancet I. 1265 Rudge. C J.. Jone,L R. H , Be,.~lck, M . We,to, n. M J and Parsom,. ~,. (19781 Lancet I. 1154 Pauv.. B E. de. Lamers. C B H . ~,l,agener. D J ]~. and Fe+ten. H P M. c 19 '''~) Lancet 2. 616. k anrenterghem. ~ . Roels. L. and IMichlel,,en. P ( 19Nh m. H_,-receptor antagontst,, in pept+c ulcer dbea>e and prc, gre,~, m h~_,,tamine research(lor.-,oh, A., Luccheh. P E and Brimblecombe, R ~A.. Ed+.) pp. 159-162, E'.,cerpta Me&ca A m~terdam-Ox ford-Princeton Palacms. R and Alarcon-Sego',ia. D 119~,1) Immunc.I Let( 3.33 3 ~ Shou. L.. Sch',~artz, S A and Good. R A {19"6)J E.xp Med 143. II00 III0. Bo.,,um, .~.(19681Scand J. Chn Lab. ln'.e_,,t 21,~uppl 97. ~? 90 Nouri-Aria. K I , Hegarth,.. J. E , Alexander. (,i J. M . Eddies(on, A. L ~3, F I n d ~,Jliams. R I19921N Engl J Med 30". 1301 1304. Lobo. P I and Spencer. C E. I19"91,I Chn freest, 63. I15"-I[63 Breshmhan, B and Jasm. H E I19"'I .I Chn In,.e,t 59, 106 116 ]-hue,,on. D O , Speck. L S . Letl-Bro',~n. M A. and Grant. J A 119"91J l m m u n o l 123. 026 632
"7.q19841 285-288
E Ise~~er
Imlet 453
THE EFFECT OF CIMETIDINE TREATMENT ON SUPPRESSOR T CELLS IN D U O D E N A L ULCER PATIENTS Henryk T C H O R Z E W S K I , Konstanty M A R K I E W I C Z and Piotr M A L E C 90-549 .E&t~. and
IDel~arttnent o f Internal Me, he me. In~tttute ~?1 Internal .~h,dtc me. 3Ie~h~ a1.4 cademt, td Zeromsklego 113.
Departmetlt ol" Pathol~h.; stoh~gt, htslttttte o[" Bastt .~letht al St tern e~. .~lettit a1.4~ a~h,on. PL 9 Mata I. 90,64" ~c&t-. Poland
(Recmxed 18 Noxember 19831 {Accepted 15 December 19831
I. Summary
Changes in the suppressor T-lymphocyte activity were studied in I I patients with duodenal ulcer during treatment with cimetidine. The drug was administered intravenously, in a dose of 200 mg four times a day for a fortnight. Suppressor T-cell activity was determined by the Shou et al. method using t ~ o stage culture before treatment, after 4 da3 s of the treatment, just before drug withdrawal, and 2 days and 2 wk after the treatment. Suppressor T-cell activity significantly decreased soon after starting the treatment, remained low throughout the treatment. and rapidl3 and significantly increased following drug withdrawal.
2. Introduction
Histamine ma2, affect the immune system by stimulating the H_,-receptors ~ hich ha~e been identified, among others, on T lymphocytes [I-5]. Cimetidine, a selective antagonist of H,-receptors, is therapeutically used to inhibit gastric acid secretion and to facilitate healing of ulceratke lesions in the gastrointestinal tract. In addition, it is also thought to act as an immunomodulator. This ~ iew is based on
he~" ~,ords" cimetidine suppressor T-lymphocxte actn'.Lt.~duodenal ulcer d,sease
H. Tch0rzev,skn. Zaklad Patofiz ologil IN P WAM. Plac 9 Maja I. 90-647-'UrdL Poland Corre~,pondem e to"
0165 247t~ 84 $3.00 ~, ElsexnerScience Publishers B.V.
the Iinding that cimetidine treatment is accompanied by increased skin test reacti~ ity to a number of antigens [6-8], reversion of tolerance to dinitrochlorobenzene (DNCB) during the treatment of alopecia areata [9,10], accelerated rejection of transplanted kidneys [I I, 12], appearance of a u t o i m m u n o h e m o lytic anemia [13], Quincke's edema [14], nephropathy and polymyositis [ 15], and enhanced mitogen responsi~ chess of lymphocytes in vitro [ 16-20]. However. some authors ~ere unable to detect any effect of cimetidine on the immune system [21-26]. Palacios and Alarcon-Segovia [27] obserwed that cimetidine diminished the suppressor T-lymphocyte activity in xitro ~hich may be responsible for immunological disturbances. The aim of the present study was to determine the suppressor activity of Tlymphocytes in duodenal ulcer patients treated with cimetidine. It was found that drug affects the suppressor activity of human I.~mphocytes in ~ ivo.
3. Material and Methods 3. I. M a t e r i a l
The subjects were I I hospitalized patients, 8 males and 3 females, aged 20-55, mean 32.4 ± 10.9 with duodenal ulcer disease. In all cases gastric acid secretion levels ~ere in the upper range of the norm or a b m e it. Cimetidine (Belomet, Podravka-Belupo) was administered in a dose of 200 mg intravenously four times a day for a fortnight. Blood samples for the investigations were taken twice: to induce the suppressors with concanavalin A (Con A) and, 48 h 285
to measure the suppression. This '`'`as performed (I) before d r u g administration, (11) after 4 days of the treatment, (111) before t e r m i n a t i o n of the cimetidine therapy, (IV) 2 days after d r u g withdrav,al, and (V) 2 wk later. In 7 subjects the whole series of 5 investigations x',as performed, in I patient there '`,,'ere 4 in,,estigations, and 3 in the remaining 3 patients. later,
cells '`,,'ere treated u, ith 50 ~g ml n m o m v c i n C ( M C . Sign'm) for 30 min to inhibit proliferation. The cells prepared in this v, a3 ',,,'ere '`xashed fi',e times ,~ith H B S S and reconstituted to I × 10" cells ml in the m e d i u m described above. T h e n fresh a u t o l o g o u s res p o n d e r lymphocytes (R-cells) suspended in m e d i u m described a b o v e '`~ere added to the culture in a rauo I:1: I x 105 S and R ceils as ,,,,ell as C and R cells. respecti'`ely. 4 x 0.2 ml of each culture '`,,ere carried out in round b o t t o m microtiter plates (Linbro) in the presence of 10,ug ml C o n A for another 120 h, adding to each ',~ell I ,uCi of [~H]th3 midine Ispecific activity 25 Ci m M , IRLIR, Prague) 5 h before the cells '`~ere har'`ested in a '`~ater-water s'`>tem u.,,mg S k a t r o n multi-cell harvester. The degree of[~H] th3midine i n c o r p o r a t i o n '`,,as determined as the n u m b e r of isotope desintegrations per minute [ D P M I in an L K B - M a l l a c - 8 1 0 0 liquid scintillation counter using Bre3's scintillator. The single results represent arithmetic means from four measurements. The percentage of suppression '`~as calculated from the formula:
3.2. Determination o/'suppressor T-lymphocyte activitv T h e suppressor acti'` it3' of T-13 mphocytes '`~as determined in t'`',o-stage culture a c c o r d i n g to S h o u et al. [28]. Blood samples '`~ere taken on heparin from the '`enous blood at 10 12 a.m. The 13mphocytes ',~ere isolated on the F i c o l l - P a q u e density gradient ( P h a r m a c i a ) a c c o r d i n g to B 6 y u m [29]. M o n o n u clears from the interphase ',,,'ere '`',ashed with Hanks" balanced salt solution ( H B S S ) and brought to a c o n c e n t r a t i o n of I × 10t' ml in a Parker's m e d i u m enriched with 20c~ heat-inactivated calf serum. 2 / u m o l ml L-glutamine ( F l o w Laboratories) and 10 ~ug' ml gentamycin. T h e suppressor 13 mphocytes IS-cells) '`,,'ere stimulated '`~ith 20 p.g ml C o n A (Sigma): the control cultures '`',ere set up parallel without an~ C o n A (C-cells). In both cases the lymphocytes were cultured 48 h at a '`olume of 3 \ I ml at 37 ° C in humidified 5% C O , incubator. Next, the
"~ ,uppre,slondpm R-cell~cultured m the pre,.ence ol b-cell,, II
b • I0()
dpm R-cell>cultured m the pre,ence
ol
C-cell,,
The statistical significance of obtained results ',xas scored x',ith W i l c o x o n R a n k signs test.
Table I The acti', it) c,f suppre>.,or I.'.mphocx tesm duodenal ulcer pattent> during c~meudme treatment No.
Patient
.Age
Sex
Percent suppresston I
II
III
IV
I
.I.R.
22
m
_4.,
I0 O
0 5
6 4
2 3
P D S U.
20 52
m m
39 6 12 1
13 4 22
222.5 3"2
I I ,', 4"11
4
.I.M.
34
I
62 O
I" 4
2g 0
55. ~
5 6 " 8 9
KB K.M G.A. K.S SE ~,~, Z. B P.
54 22 24 55 23 24 26
f m m m I m m
16 3 19 75 4 ~0 36.3 4.0 40.5
31 3 I1.1 39.3 150 2 22 l) 13 6 60 9
4.2 4" ".9 138. I 14.4 94." 331.8
21 x "q3 20 6 4 .7
IO
II
Arithmetic means and SD
28.8 ± Ils "
31.2 ±440
e,7.7 ± 114.~
36 3 ± 23 5
\
34 3 221 40 4i 11.4 51 44
I" I + 15 3
Inxe,qigauons: I. before therap.~. II. alter 4 da~.--,o1 therap.,.: Ill. belore termination of therap,.: I\. 2 daxs alter eJmetidme +~lthdrax~al. x. 2 v.k after cimetidme w~thdrav,al. . not done 286
4. Results The results are presented in Table I. Individual percentages of suppression range widel3, which is in agreement with the results of other authors [30]. The general direction of individual changes ~as identical in all cases. After 4 da3s of cimetidine treatment all patients exhibited the decreased suppressor activity of lymphocytes t P < 0.005) and almost all of them sho~ed negative suppression, i.e. instead of suppression of proliferation measured as incorporation of tritium-labelled th.~ midine, they sho~ed stimulation. .At the end of second ~eek of the therap3 I! mphoc~tes from 8 patients had slightly increased suppressor activit3, ~ hile in the remaining 3 subjects the suppressor acti~ it3 decreased even further. T~ o days following cimetidine ~ ithdra~al suppressor acti~ ity of 13mphoc.vtes increased significantly in all patients I P < 0.0051 and it did not change much during the following 2 ~k of observation: the obtained ~alues ~ere comparable to those before therap3.
5. Discussion l-he presented studies sho~ed that cimetidine decreased the suppressor activity of T-lymphocytes in ~i~o. This was not a non-specific effect of healing duodenal ulcer, because inhibition of suppressor acti~it3 x~as found rapidly alter drug administration, and it ~as persisting throughout the treatment, and returned to the initial ~alues soon after the drug withdra~al. It has alread~ been mentioned that cimetidine also lowers the suppressor acti~ ity tested on lymphoc}te culture in ~itro [27]. The total elimination of suppression and, thus, the appearance of stimulation of I.~mphocyte proliferation m xitro during cimetidine administration are of considerable interest. According to Shou et al. [28], Con A ma3 act by more than one receptor, and one of them is responsible for the enhancement of blastogenic transformation. ~ hile another is responsible for the stimulation of suppressor 13mphoc.vtes. It is also the case that suppressor cells which respond to Con A do not represent the entire suppressor cell population [31,32], and it is not kno~n how other subpopulations of I respond to cimetidine treatment.
It is currently assumed that cimetidine acts on H, receptor of T, lymphocytes, an idea that is additionall)' supported by the rapid increase in suppressor actit it,,' after cimetidine withdra~al, an effect that is probably related to scaling of blocked receptor from 13mphocyte surfaces. Most of the lymphocyte separation techniques do not remo~e all of the basophils, and histamine may be released from them as a result of mitogen stimulation [33]. The changes obser~'ed after cimetidine administration may also be due to blockage of hisfamine-dependent inhibition of lymphocytes [ I-5]. To obtain comprehensive picture of the mechanism invoked, it is necessar3' to determine the effect of cimetidine on the generation of interleukine I by macrophages because, h3pothetically, it may give rise to hyperstimulation of r h lymphocytes. Hox~e~er, regardless of the exact mechanism in~olxed, the inhibiting effect of cimetidine on suppressor acti~ it 3' of lymphocytes is unquestionable, albeit short-lived. It is well-known that impaired suppressor activity is the most important disturbance observed in some autoimmune diseases [30.32]. Thus, it seems that caution should be exercised, especiall.v in cases of long-term cimetidine therapy of patients with suspected autoimmune disease or predisposed to it. It is also necessary to monitor some of the parameters of cellular immunity.
Acknowledgements The authors wish to thank M. Luciak, M.D., for his linguistic help in manuscript preparation.
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