M. Jacobs et al., Correction of defective host response to Mycobacterium bovis BCG infectionin TNF-deficient mice by bone marrow transplantation, LAB INV, 80(6), 2000, pp. 901-914
Tumour necrosis factor-alpha (TNF) plays a central role in the recruitment
and activation of mononuclear cells in mycobacterial infection. In the abse
nce of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Guerin (B
CG) infection of mice is not contained, leading to fatal disease. Because t
ype 1 TNF receptor binds both TNF and lymphotoxin-alpha, we used TNF-defici
ent mice to determine the specific role of TNF in the host resistance to BC
G infection. The bacterial burden of the lungs of TNF-deficient mice was su
bstantially increased and the mice succumbed to pneumonia between 8 and 12
weeks with a defective granuloma response. Atypical granulomas developed by
4 weeks expressing tow levels of MHC class II, intracellular adhesion mole
cule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activati
on and had low levels of acid phosphatase activity and inducible nitric oxi
de synthase (INOS) expression. Despite the defective cellular recruitment,
the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage i
nflammatory protein-1 (MIP-1 alpha), were increased in broncho-alveotar lav
age fluid of TNF-deficient mice. The defective host response was corrected
by the transplantation of normal bone marrow cells into irradiated TNF-defi
cient mice. These results demonstrate that TNF derived from hemopoietic cel
ls rather than from mesenchymal origin are essential for a normal host resp
onse to BCG infection. Furthermore, TNF dependent expression of adhesion mo
lecules may be essential for the recruitment of mononuclear cells for the f
ormation of bactericidal BCG granulomas.