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1782
CORRESPONDENCE
increase in fungal infections. This strategy can be used in high-risk
transplant recipients, including unrelated and HLA mismatch-related
transplant recipients. Based on the data presented here, ganciclovir
should be given for antigenemia at any level and be continued until day
100 in allogeneic transplant recipients.
ACKNOWLEDGMENT
Supported by the American Cancer Society (RD-361) and the
National Cancer Institute (CA-18029). We thank Terri Cunningham and
Maggie Hoyle for chart review, and Chris Dorling for data services.
Michael Boeckh
Raleigh A. Bowden
Ted Gooley
David Myerson
Lawrence Corey
Fred Hutchinson Cancer Research Center
University of Washington
Seattle, WA
REFERENCES
1. Boeckh M, Gooley T, Myerson D, Cunningham T, Schoch GH,
Bowden RA: Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic
marrow transplant—A randomized double-blind study. Blood 88:4063,
1996
2. Einsele H, Ehninger G, Hebart H, Wittkowsky KM, Schuler U,
Jahn G, Mackes P, Hertes M, Klingebiel T, Löffler J, Wagner S, Müller
CA: Polymerase chain reaction monitoring reduces the incidence of
CMV disease and the duration and side effects of antiviral therapy after
BMT. Blood 86:2815, 1995
3. Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell
SR: Recovery of HLA-restricted cytomegalovirus (CMV)-specific
T-cell responses after allogeneic marrow transplant: Correlation with
CMV disease and effect of ganciclovir prophylaxis. Blood 83:1971,
1994
Cimetidine Activates Interleukin-12, Which Enhances Cellular Immunity
To the Editor:
Patients admitted to the intensive care unit (ICU) are generally in a
critical condition and are at risk of developing acute gastric mucosal
lesions caused by various types of stress. They also become immunosuppressed as their illness is prolonged. We usually treat these patients with
histamine-2 receptor antagonists (H2 RAs) to prevent acute gastric
mucosal lesions. Cimetidine, one of the H2 RAs, has recently been
reported to promote cell-mediated immunity and to decrease susceptibility to infection.1 Cimetidine promotes cellular immunity by activating
natural killer (NK) cells,1 by increasing interleukin-2 (IL-2)2 production, and by inhibiting suppressor T lymphocytes,3 but it is unclear why
it has these actions. In this study, we investigated the effect of
cimetidine on IL-12, which enhances cellular immunity.
We analyzed changes of IL-12 p35 subunit mRNA expression by the
reverse transcriptase-polymerase chain reaction4 to investigate whether
cimetidine increased IL-12 production in human mononuclear cells
obtained from our ICU patients. From immediately after admission,
patients received continuous intravenous infusion of cimetidine at 800
mg/d for upward of 8 days. Blood samples were taken on admission
(day 1) and on day 8. Patients treated with 40 mg/d of famotidine were
used as a control.2 Upregulation of IL-12 p35 mRNA was greater after
treatment with cimetidine compared with after famotidine therapy
(Fig 1).
On this basis, we designed a prospective clinical study. Eighteen
patients admitted to our ICU were divided randomly into two groups.
From immediately after admission, group A received continuous
intravenous infusion of cimetidine at 800 mg/d and group B was
administered 40 mg/d of famotidine as a continuous intravenous
infusion. Blood samples were taken on admission (day 1) and on days 2,
4, and 8. Serum IL-12 levels were measured soon after sampling with an
enzyme-linked immunosorbent assay (ELISA) kit (Genzyme Corp,
Cambridge, MA). The Mann-Whitney U test and two-way analysis of
variance (ANOVA) were used for comparison of the groups, and results
were expressed as the mean and the standard error of the mean.
There were no significant differences in age (group A: 46.3 ⫾ 5.29
years, group B: 54.7 ⫾ 4.46 years), sex ratio (group A: seven males and
two females, group B: four males and five females), and APACHE II
score (group A: 17.6 ⫾ 2.58, group B: 21.7 ⫾ 3.15) between the two
groups. There was also no difference in IL-12 levels between groups A
and B at admission and on day 2. However, IL-12 was significantly
higher in group A compared with group B on day 4 (group A
140.41 ⫾ 26.06 pg/mL v group B 65.11 ⫾ 13.26 pg/mL; P ⫽ .0203 by
Mann-Whitney U test) and day 8 (group A 277.26 ⫾ 71.85 pg/mL v
group B 91.19 ⫾ 16.15 pg/mL; P ⫽ .0225 by Mann-Whitney U test).
Moreover, IL-12 levels on day 8 were above those on admission in 7
patients from group A (77.8%) but were decreased in 8 patients from
Fig 1. Reverse transcriptase-polymerase chain reaction analysis of IL-12 p35 subunit mRNA expression by human mononuclear cells obtained from ICU
patients. Specific fragments of IL-12 p35 were evident on Southern blotting (arrow), and upregulation
was detected on day 8 in patients receiving cimetidine. Such fragments were not found in cells from
patients treated with famotidine. Lanes 1 and 2 are
cimetidine treatment on day 1 and day 8. Lanes 3 and
4 are negative controls for lanes 1 and 2, respectively.
Lanes 5 and 6 are ␤-actin for lanes 1 and 2, respectively. Lanes 7 and 8 are famotidine treatment on day
1 and day 8. Lanes 9 and 10 are negative controls for
lanes 7 and 8, respectively. Lanes 11 and 12 are
␤-actin for lanes 7 and 8, respectively. Lane M contains size markers of 123 bp.
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CORRESPONDENCE
1783
study of this issue could help to determine whether continuous
administration of cimetidine to ICU patients is of clinical benefit.
Hiroyasu Ishikura
Hisanori Fukui
Naoshi Takeyama
Takaya Tanaka
Department of Emergency and Critical Care Medicine
Kansai Medical University
Osaka, Japan
REFERENCES
Fig 2. Concentration-time profile of IL-12 levels. Serum IL-12
levels were significantly higher in group A (䊏) compared with group B
(䊊) on days 4 (*P ⴝ .0203) and 8 (**P ⴝ .0225). Group A showed
significant increase of IL-12 compared with group B (***P ⬉ .01).
Error bars ⴝ SEM, *P and **P: Mann-Whitney U test; ***P: two-way
ANOVA.
group B (88.9%). Cimetidine significantly increased the IL-12 level
(P ⬉ .01 by two-way ANOVA) (Fig 2).
Although we only studied a few patients, our results suggested that
cimetidine may promote the release of IL-12 from macrophages or
monocytes,5 leading to the enhancement of NK activity as well as IL-2
and interferon-␥ production, thus increasing cellular immunity. Further
1. Katoh J, Tsuchiya K, Sato W, Nakajima M, Iida Y: Cimetidine and
immunoreactivity. Lancet 348:404, 1996 (letter)
2. Hahm KB, Kim WH, Lee SI, Kang JK, Park IS: Comparison of
immunomodulative effects of the histamine-2 receptor antagonists
cimetidine, ranitidine and famotidine on peripheral blood mononuclear
cells in gastric cancer patients. Scand J Gastroenterol 30:265, 1995
3. Sahasrabudhe DM, McCune CS, O’Donnell RW, Hanshaw EG:
Inhibition of suppressor T lymphocytes (Ts) by cimetidine. J Immunol
138:2760, 1987
4. Fan X, Sibalic V, Niederer E, Wuthrich RP: The proinflammatory
cytokine interleukin-12 occurs as a cell membrane-bound form on
macrophages. Biochem Bioph Res Commun 225:1063, 1996
5. Trinchieri G, Wysocka M, D’Andrea A, Rengaraju M, Aste
Amezaga M, Kubin M, Valiante NM, Chehimi J: Natural killer cell
stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune
response and inflammation. Prog Growth Factor Res 4:355, 1992
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1999 93: 1782-1783
Cimetidine Activates Interleukin-12, Which Enhances Cellular Immunity
Hiroyasu Ishikura, Hisanori Fukui, Naoshi Takeyama and Takaya Tanaka
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