Immunotherapy for Infectious Diseases

100 Kundu-Raychaudhuri and Engleman
toward production of interferon-� (IFN-�), a key immune effector molecule (4). RANTES
is a chemokine that attracts both naïve and memory T-cells (5). Fractalkine has unique
properties as both an adhesion molecule and a chemokine for DCs and T-cells (6). Thus,
RANTES and fractalkine help to increase DC/T-cell conjugate formation and, in turn,
T-cell activation.
Exposure of DCs to foreign antigens does not on its own result in the efficient induction
of IL-12 production (7). In general, IL-12-inducing factors (“danger signals”) such
as lipopolysaccharide, immunostimulatory DNA sequences, double-stranded RNA, or
products of activated T-cells such as CD40 ligand and IFN-� are required to “super
activate” DCs. These factors not only induce IL-12 synthesis by DCs but, in addition,
trigger the development of an activated DC phenotype (increased surface expression
of MHC antigens, costimulatory molecules, and adhesion molecules) such that the cells
become far more efficient at antigen presentation. Importantly, most of these stimuli
are products of infectious organisms. Of particular interest is the recent observation
that certain immunostimulatory DNA sequences (so-called CpG-containing oligonucleotides)
found principally in bacterial DNA are extraordinarily potent stimulators of
the immune system (8). At least part of this stimulatory effect appears to be owing to
direct activation of DC by these sequences (9). Most recently, double-stranded RNA
from influenza virus has been reported to activate DCs in a manner somewhat analogous
to that mediated by CpG-containing oligonucleotides (10). Whether or not other
viral RNAs also activate DCs is not yet known.
As noted above, IL-12 is an important mediator of DC function, and abnormal production
of this cytokine during infection can be associated with a poor clinical outcome.
Abnormalities in IL-12 production by APCs have been reported in a variety of
infections, including Leishmania major, Trypanosoma cruzi, influenza virus, and HIV
infection (11–16). Addition of IL-12 to T-cells in vitro restores recall responses to antigen
(17). Genetic differences in cytokine-mediated responses may also influence disease
progression following infection. For example, the genetic background of
T-lymphocytes affects the development of the Th phenotype, resulting in either resistance
or susceptibility of different mouse strains to pathogens such as Leishmania
major (18). Almost certainly, genetic differences contribute to the variable response to
pathogens commonly observed in clinical practice. In this regard, Holland et al. (19)
have reported rare patients who have refractory disseminated nontuberculosis mycobacterial
infections without HIV infection and have abnormal IL-12 regulation. IFN-� has
been used successfully in combination with antimycobacterials in the treatment of
these patients (19).
DENDRITIC CELLS IN HIV INFECTION
The induction of antigen-specific immune responses is certainly the most pertinent
function of DCs, and this function has been amply demonstrated. DCs exposed to
infectious influenza virus or influenza nucleoprotein peptide, sendai, herpes simplex,
Moloney leukemia virus, or HIV induce both proliferative and antiviral CTL responses,
in vitro, in mouse and human systems (20–23). In our earliest studies of human DCs,
we demonstrated that these cells, but not monocytes or B-cells, can sensitize naïve
T-cells to soluble protein antigens, enabling the generation of antigen-specific CD4�
helper and CD8� cytotoxic T-lymphocyte (CTL) lines, in vitro (24,25). Nonetheless,