Immunotherapy for Infectious Diseases

102 Kundu-Raychaudhuri and Engleman
However, infection of immature DCs with T. cruzi profoundly inhibits the ability of
DCs to produce IL-12 and TNF-�. Moreover, infection of such cells prevents their maturation.
Thus, by altering DC function, T. cruzi may escape the host immune responses,
leading to persistent infection (50,51).
Leishmania major appears to infect both macrophages and DCs. However, DC are
the sole source of IL-12 production following infection with Leishmania organisms.
The likely explanation for this phenomenon is that whereas both life cycle stages (promastigotes
and amastigotes) infect macrophages, only amastigotes can infect DCs and
do so without inhibiting IL-12 production by the cells. In contrast, infected macrophages
do not produce IL-12 (52).
During Toxoplasma gondii infection, host immunity is mediated by CTLs as well as
IFN-�, which is induced by IL-12. DCs stimulated with T. gondii tachyzoites or soluble
antigens derived from this organism fail to produce IL-12. However, when DCs are
cocultured with T-cells from Toxoplasma-seropositive individuals, they produce IL-12.
These observations demonstrate that signals from contact between primed lymphocytes
and DCs are essential for the induction of immunity to this parasite (53).
Several viruses have evolved mechanisms that compromise the ability of DCs to
mount an immune defense. DCs infected by measles virus are reported to lose their
immunostimulatory functions and become immunosuppressive (54)! Human cytomegalovirus
(CMV), a ubiquitous pathogen that is normally benign in healthy individuals,
is a serious cause of morbidity and mortality in immunocompromised hosts. This virus
and its closely related immune murine counterpart employ many diverse strategies to
avoid detection by the host immune system. Among these are their ability to interfere
with MHC class I and II expression on APCs (55). Both human and murine CMV
infect APCs, including macrophages and DCs, downregulate IFN-�, and induce IL-10
production, leading to decreased expression of MHC class I and II, which in turn
causes immunosuppression.
Human papillomavirus (HPV) is causally associated with cancer of the urogenital
tract (56). HPV-associated proliferative skin lesions expressing abundant viral protein
can persist for years in immunocompetent subjects, a property that distinguishes HPV
infection from that of the lytic RNA viruses. The fact that no antibody to viral capsid
proteins is detectable for 6–12 months following infection confirms the idea that HPV
infection does not generate a conventional immune response. One mechanism by
which this virus may suppress the generation of immunity appears to be related to their
infection of Langerhans cells (DCs of the epidermis). Thus, Langherhans cells expressing
the E7 protein of papillomavirus have been shown to be poor stimulators of E7specific
T-cells. Precisely how HPV inhibits DC function is unknown.
Chlamydia trachomatis is a common cause of sexually transmitted diseases and a
leading cause of preventable blindness worldwide (57). Host defense against chlamydial
infection is mediated by both cellular and humoral immune responses (58). Ex
vivo DCs pulsed with killed or live chlamydiae and reinfused into mice have been
reported to induce strong protective immunity to vaginal infection (59,60). Similar protective
effects have been observed for Borrelia bergdorfei, lymphocytic choriomeningitis,
Toxoplasma, Leishmania major, and equine herpesvirus.
As noted earlier, double-stranded RNA from influenza virus can increase the ability
of DCs to process and present antigen. Presumably this is responsible for the observa-