S. Bala et al., INHIBITION OF TUMOR-NECROSIS-FACTOR-ALPHA ALTERS RESISTANCE TO MYCOBACTERIUM-AVIUM COMPLEX INFECTION IN MICE, Antimicrobial agents and chemotherapy, 42(9), 1998, pp. 2336-2341
Increased production of tumor necrosis factor alpha (TNF-alpha) appear
s to play an important role in the progression of human immunodeficien
cy virus disease. One treatment strategy being explored is the use of
TNF-alpha inhibitors. TNF-alpha also appears to be important in confer
ring resistance to infections, and the inhibition of this cytokine may
exacerbate the emergence of opportunistic pathogens, such as Mycobact
erium avium complex (MAC). The present study examines the possibility
that inhibition of TNF-alpha will increase the progression of disease
in mice infected with MAC, C57BL/6 beige (bg/bg) mice have been shown
to be highly susceptible to infection with MAC and are routinely used
for testing of antimycobacterial drugs. However, bg/bg mice are known
to exhibit impaired phagocyte and natural killer cell function, Since
these cell types are important sources of TNF-alpha, the susceptibilit
y of the bg/bg strain to infection with MAC was compared with those of
the heterozygous (bg/+) and wild-type (+/+) strains of C57BL/6 mice.
The susceptibilities of the bg/bg and bg/+ strains of mice infected wi
th MAC were found to be comparable. The +/+ strain was the least susce
ptible, Mycobacterial burden and serum TNF-alpha levels increased over
time in all the strains of mice tested. The bg/+ strain of C57BL/6 mi
ce was then chosen to measure the activity of TNF-alpha antagonists. T
reatment with dexamethasone decreased serum TNF-alpha levels and incre
ased mycobacterial burden. Treatment with anti-TNF-alpha antibody or p
entoxifylline did not significantly alter serum TNF-alpha levels but i
ncreased mycobacterial burden. Treatment with thalidomide neither cons
istently altered mycobacterial burden in the spleens or livers of infe
cted mice nor affected serum TNF-alpha levels.