Immunotherapy for Infectious Diseases

124 Matthews
and heart. Interestingly, the Duffy antigen is a factor in infections with Plasmodium
vivax in which the parasite utilizes this receptor to invade erythrocytes (22). In people
of African descent, this receptor may not be expressed on red blood cells, and they are
resistant to infections with P. vivax. Chronic exposure to P. vivax may have exerted
selection pressure for gene expression in different cells since this receptor may be
expressed on other tissue cells. In addition to P. vivax, some herpes viruses and HIV-
1 are also able to use chemokine receptors as factors in their pathogenesis. Human
cytomegalovirus (CMV) has genes that encode a functional chemokine receptor that
can bind MIP-1�, MIP-1�, RANTES, and MCP-1 (23, 24). The mechanism by which
expression of a chemokine receptor is advantageous to the virus is not clear (21).
The signaling of cellular response to chemokines occurs through G proteins (guanine
nucleotide binding regulatory proteins) coupling to initiate phosphoinositide
hydrolysis. The resultant increase in diacylglycerol and cytosolic Ca 2� leads to activation
of protein kinase C (25). The ability of some chemokines such as RANTES and
MIP-1� to activate Stats suggests that the signaling pathways of Stats and G proteins
may act with some communication.
CYTOKINES IN IMMUNE RESPONSE TO INFECTIONS
As discoveries and comprehension of cytokine biology continue to increase, the
complexity of the cytokine network has become overwhelming. Despite the complexity
of cytokine activity, it is important to appreciate the role of the interplay of the
cytokines with their various target cells in the immune response to an inflammatory
agent. The immune response during the early stages will either eradicate the infectious
agent or set the stage for the type of chronic immune response. When the control mechanism
for the type of cytokine response is dysfunctional, the result may be the development
of a chronic or progressive infection rather than eradication or containment of
the infectious agent, e.g., the development of miliary tuberculosis, lepromatous leprosy,
visceral leishmaniasis, and sepsis. The host’s genetic background is also a factor in the
development of chronic inflammatory response and pathology. Autoimmune diseases
result from perturbation of the immune system either intrinsically for unknown reasons,
(e.g., systemic lupus, juvenile rheumatoid arthritis) or in response to an infectious
agent, (e.g., type I diabetes mellitus).
The purpose of this section is to provide a background sketch of the role of the
cytokine network in the responses of the immune system to an infectious agent prior
to its commitment to the appropriate immune protective mechanism, i.e., the development
of antibody by B-cells, macrophage activation, or cytolysis by T-cells. Two
aspects of the immune response that have been the focus of immunomodulators of
cytokines to treat infections will be discussed: the initial leukocyte response and the
differentiation of the CD4� T-cells into the Th1 and Th2 subsets.
Initial Inflammatory Response and Leukocyte Migration
The body’s innate immune response to an invading organism results in the recruitment
of leukocytes and phagocytosis of the organism. Numerous factors, including bacterial
components, will stimulate migration of the leukocytes. Bacterial endotoxin or lipopolysaccharide
(LPS) stimulates the release of chemokines and cytokines from the surrounding
tissue cells and macrophages. Immunotherapies that are intended to interfere with the