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 Recent
Articles
Tsenova L, Mangaliso B, Muller G, Chen Y, Freedman VH, Stirling
D, Kaplan G.
Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy
for ExperimentalTuberculous Meningitis.
Antimicrob Agents Chemother 2002 Jun;46(6):1887-95
PMID: 12019105
Tuberculous meningitis (TBM), the most severe form of Mycobacterium
tuberculosis
infection in humans, is associated with significant morbidity and
mortality
despite successful treatment with antituberculous drugs. This is
due to the
irreversible brain damage subsequent to the local inflammatory response
of the
host to M. tuberculosis. Corticosteroids have been used in conjunction
with
antituberculous therapy in an attempt to modulate the inflammatory
response, but
this strategy has been of limited success. Therefore, we examined
whether
combining antituberculous drugs with the immunomodulatory drug thalidomide
or
with a new thalidomide analog, immunomodulatory drug 3 (IMiD3),
would be
effective in reducing morbidity and mortality in an experimental
rabbit model of
TBM. Intracisternal inoculation of 5 x 10(4) CFU of Mycobacterium
bovis Ravenel
in rabbits induced progressive subacute meningitis characterized
by high
cerebrospinal fluid (CSF) leukocytosis, protein influx, release
of tumor
necrosis factor (TNF), substantial meningeal inflammation, and mortality
by day
28. Treatment with antituberculous drugs or with antituberculous
drugs plus
thalidomide improved the clinical course of disease somewhat and
increased
survival to about 50%. In contrast, treatment with antituberculous
drugs in
combination with IMiD3 limited pathological neurologic changes and
resulted in
marked improvement (73%) in survival. IMiD3 treatment was also associated
with
reduced leukocytosis in the CSF and significantly lower levels of
TNF in CSF and
plasma. Histologically, the meningeal inflammation in animals treated
with
antituberculous drugs plus IMiD3 was considerably attenuated compared
to that of
the other treatment groups. These results suggest a potential role
for IMiD3 in
the management of TBM in patients.
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