946
ANTI–IL-6 ANTIBODIES
Marby et al. • ANTI-IL-6 ANTIBODIES IN RAT MENINGITIS
Anti–Interleukin-6 Antibodies Attenuate Inflammation
in a Rat Meningitis Model
D
AVID
ICHARD
M
ARBY, MD, GREGORY R. LOCKHART, MD,
R
R
AYMOND, P D, JAMES G. LINAKIS, P D, MD
H
H
Abstract. Objectives: Interleukin-6 (IL-6) is ele- protein and white blood cell (WBC) count measures
vated in the cerebrospinal fluid (CSF) of humans and were compared using a t-test. Results: Mean CSF
animals with bacterial meningitis. This study’s hy- WBC for the anti-IL-6 treatment group was 2,458/L,
pothesis was that anti-IL-6 antibodies will attenuate versus the PBS controls’ mean of 9,697/L (p = 0.007).
meningeal inflammation in a rat model of bacterial Mean CSF protein for the anti-IL-6 group was 180
meningitis. Methods: 14 male Sprague-Dawley rats mg/dL, versus 296 mg/dL for the controls (p = 0.032).
were inoculated intracisternally (IC) with 0.1 mL of The surgical sham and normal animals had normal
heat-killed pneumococci. At one hour post-inocula- CSF WBC and protein values. Conclusions: In this
tion, the rats received intraperitoneal doses of either rat meningitis model, systemic treatment with anti-
1.0 mL phosphate-buffered saline (PBS treatment IL-6 antibodies after the induction of meningitis sup-
group, n = 7) or 70 g anti-IL-6 antibodies in 1.0 mL pressed both CSF WBC count and CSF protein level,
PBS (anti-IL-6 antibody treatment group, n = 7). two important indices of meningeal inflammation.
Nine rats (normal group, n = 9) had no inoculation, Key words: anti-interleukin-6 antibodies; inflamma-
and four rats (surgical sham group, n = 4) had IC tion; rats; meningitis. ACADEMIC EMERGENCY
inoculations of saline. At six hours post-inoculation, MEDICINE 2001; 8:946–949
all the animals had CSF removed via IC tap. The CSF
ACTERIAL meningitis is a serious central initiation of the inflammatory cascade in menin-
B
nervous system infection that carries signif-
icant mortality (5–40%) and neurologic morbidity,
including hearing loss, hydrocephalus, mental re-
tardation, and seizures.1,2 The pathogenesis of this
infection involves invasion of the cerebrospinal
fluid (CSF) either through the blood–brain barrier
by hematogenous pathogens, or by inoculation via
direct extension from a parameningeal focus of in-
fection. This invasion is followed by the induction
of an intense inflammatory response mediated by
a cascade of hormone-like proteins called cyto-
kines. The morbidity of bacterial meningitis is due,
in part, to damage from cytokine-mediated release
of proteolytic enzymes, toxic free-radicals, and al-
terations in cerebral metabolism and blood flow.1
It has been demonstrated that bacterial cell
walls stimulate the release of interleukin-1 (IL-1)
and tumor necrosis factor–alpha (TNF-␣), which
are thought to play important early roles in the
gitis, including opening of the blood–brain barrier
and cellular toxicity. Both IL-1 and TNF-␣ are
found in high levels in bacterial meningitis in both
animals and humans. They, in turn, induce the re-
lease of other inflammatory cytokines such as in-
terleukin-6 (IL-6) and interleukin-8. Interleukin-6
is a product of monocytes, endothelial cells, and
astrocytes, and is responsible, in part, for comple-
ment activation and release of acute phase pro-
teins, as well as inhibition of TNF-␣ and IL-1.1,3
Current treatment of acute bacterial meningitis
includes parenteral antibiotics and sometimes cor-
ticosteroids to reduce the host’s inflammatory re-
sponse. Recent therapeutic investigations in sev-
eral different animal models have focused on
treatment of various infectious diseases with anti-
cytokine therapies, using monoclonal antibodies
directed against a particular inflammatory cyto-
kine to attenuate the inflammatory cascade.4,5
The present study used a pneumococcal men-
ingitis model in rats to assess the effects of a se-
lective modification of the immunologic response
by neutralizing one particular cytokine, IL-6. The
activity of IL-6 can be suppressed by the injection
of anti-IL-6 antibodies.4 Our hypothesis was that
systemically administered anti-IL-6 antibodies
would attenuate meningeal inflammation, as mea-
sured by CSF total white blood cell (WBC) count
and CSF total protein (TP) level.
From the Section of Emergency Medicine and Department of
Pediatrics (DM, GRL, RR, JGL), Brown University School of
Medicine, Providence, RI.
Received March 1, 2001; revision received June 7, 2001; ac-
cepted June 21, 2001. Presented at the SAEM annual meeting,
San Francisco, CA, May 2000.
Address for correspondence and reprints: Gregory R. Lockhart,
MD, Hasbro Children’s Hospital, Department of Emergency
Medicine, 593 Eddy Street, Providence, RI 02903. Fax: 401-
444-4569; e-mail: glockhart@lifespan.org