Immunotherapy for Infectious Diseases

Cytokines, Cytokine Antagonists, and Growth Factors 125
activity of these cytokines and other inflammatory molecules, e.g., proteins that bind LPS,
TNF-�, IL-1, or inhibitors of nitric oxide production, would be expected to diminish the
pathologic effects of the acute response to infections. In contrast to the acute increase in
serum TNF-� concentrations associated with acute infections, some autoimmune diseases,
e.g., rheumatoid arthritis and Crohn’s disease, are associated with chronic elevations in tissue
TNF-� concentrations. Immunomotherapies that lower levels of TNF-�, such as soluble
TNF receptor and monoclonal antibodies to TNF-�, have shown clinical benefit.
The binding of LPS to macrophages stimulates the release of IL-1 and TNF-�. These
cytokines in turn stimulate their target cells to produce a number of different molecules.
Endothelial cells and macrophages are stimulated by IL-1 and TNF-� (and by
bacterial LPS itself) to produce G-CSF and GM-CSF from endothelial cells and
macrophages, which further enhances the number of leukocytes and the duration of
their recruitment to the site of infection. In response to IL-1, TNF-�, and IFN-�,
endothelial cells will produce prostaglandins, platelet-activating factor, and nitric
oxide. One potential effect of these products could be the production of thrombi. These
inflammatory cytokines can also stimulate endothelial cells to express molecules
involved with leukocyte adhesion and integration through the endothelium including
E-selectin, P-selectin, and ICAM-1. These latter molecules are important in the recruitment
of leukocytes from the circulation to the infected tissue.
With expression of leukocyte adhesion molecules, the leukocytes loosely attach to the
endothelial cells through the oligosaccharides on their membranes. With their movement
slowed by this loose attachment, the leukocytes will begin to roll along the endothelial
surface. The chemokines released from macrophages, the surrounding tissue cells, and
the endothelial cells in response to the bacterial components bind to the endothelium,
where they cause the rolling leukocytes to adhere more firmly to the endothelium through
binding of the integrins to their ligand. Chemokines involved in this process include
MCP-1, RANTES, and MIP-1�. The leukocytes then migrate through the endothelium
and move up a gradient of chemokine concentrations to the inflammatory site.
The types of leukocytes recruited to the inflammatory site can differ depending on
the source of inflammation, (e.g., bacterial, allergen) and the duration and amount of
exposure. The pattern of cytokines produced, i.e., the type and concentration, will
depend on these factors as well as the host’s genetic background. The predominant
cytokines in this pattern (e.g., IL-4, IFN-�, and (IL-12) will then determine the subsequent
T-cell response to chronic infection/inflammation or to immunization (26).
Activation of T-Helper Cells: Th1/Th2 Subsets
When stimulated, T-cells produce different types and amounts of cytokines, which
in turn, characterizes the functional response of the T-cells. According to the pattern of
cytokines produced, the CD4� T-cells can be differentiated into the subsets of Th1 or
Th2 (27, 28). The cytokines produced by each subset regulates the function and development
of the other. IFN-� produced by Th1 cells inhibits Th2 cell production and
function. IL-4 and IL-10 produced by Th2 cells inhibit Th1 cell production and the
killing of bacteria by macrophages. Several immunotherapies for infectious diseases
have focused on the manipulation of the type or degree of T-cell response, e.g., stimulation
of Th1 response by IFN-� to treat mycobacterial infections or visceral leishmaniasis,
and stimulation of CD4� T-cell production by IL-2.