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and Primed Lymphocytes
Cornell University Medical College, Division of International Medicine and Infectious Diseases, Department of Medicine, New York, NY 10021
Mycobacterium tuberculosis (Mtb) is the
world’s leading infectious cause of mortality. Despite the
overwhelming data supporting the critical role of cellular immunity,
little is known of the early microbial and immune cell interactions and
whether human macrophages can be activated to express
anti-Mtb activity. We report the reconstitution of an
in vitro system whereby human macrophages express
anti-Mtb activity only in coculture with PBL and with
IFN-
. Omission of IFN- in the cocultures or Mtb
lysate/IFN--primed lymphocytes was associated with high growth of
Mtb, high IL-10 and IL-12 p40, nearly undetectable IL-12
p70 levels, and the highest percentages of CD4 and CD8 T cells. In
contrast, IFN- treatment of cocultures containing Mtb
lysate/IFN--primed PBL reduced bacilli count by 
2.5 log,
decreased the production of IL-10 by 5.7-fold, increased IL-12 p70 by
50-fold, and reduced the percentages of CD4 and CD8 T cells.
Activation of anti-Mtb activity was time and dose
dependent. At 2000 U/ml of IFN-, bactericidal activity was achieved
(10-fold reduction from initial inoculum). Anti-Mtb
activity against several strains of M. tuberculosis (H37Ra
and H37Rv, and C, a clinical isolate) was observed and was associated
with expression of inducible nitric oxide synthase. These data suggest
that induction of human macrophage anti-Mtb activity
required dual signaling from PBL and IFN-. Thus, the development of
an in vitro human system may greatly facilitate studies to delineate
immune cells, cytokines, and effector functions/genes critical in
controlling Mtb. Defining the mechanisms may also provide
novel treatment strategies for tuberculosis.
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