SummaryThe immunomodulatory effects of probiotics were assessed following exposure of normal peripheral blood mononuclear cells (PBMC) ,

Dendritic cells (DC) suffer a maturation defect following interaction with erythrocytes infected with malaria parasites and become unable to induce protective malaria liver-stage immunity. Here we show that, by contrast, maturation-arrested DC in vitro are capable of the successful induction of antigen-specific gamma interferon (IFN-␥) and interleukin 4 (IL-4) T-cell responses, antibody responses, and potent protection against lethal blood-stage malaria challenge in vivo. Similar results were found with DC pulsed with intact parasitized Plasmodium yoelii or Plasmodium chabaudi erythrocytes. Cross-strain protection was also induced. High levels of protection (80 to 100%) against lethal challenge were evident from 10 days after a single immunization and maintained up to 120 days. Interestingly, correlation studies versus blood-stage protection at different time points suggest that the immune effector mechanisms associated with protection could change over time. Antibody-independent, T-cell-and IL-12-associated protection was observed early after immunization, followed by antibody and IL-4-associated, IFN-␥-independent protection in long-term studies. These results indicate that DC, even when clearly susceptible to parasite-induced maturation defect effects in vitro, can be central to the induction of protection against blood-stage malaria in vivo.

Recently, there has been a surge of interest in the use of ex vivo antigen-pulsed dendritic cells (DCs) in the immunotherapy for cancer. DCs are powerful adjuvants with the ability to prime naive CD4+ and CD8+ T cells. As antigen sources, various preparations, including peptides, proteins, crude tumor lysates, and DCs transfected or transformed with various viruses, have been used. These procedures that involve the isolation of patient DCs and reintroduction after in vitro manipulation are time-consuming and expensive. The DC populations used frequently in ex vivo clinical studies are IL-4 and GM-CSF cultured DCs that may not represent the in vivo DC populations. An attractive method of targeting in vivo DCs is to utilize various ligands or antibodies that bind discrete populations of DCs. These cell surface receptors will direct the antigen to different antigen processing pathways depending on the targeted receptor to induce cytotoxic T cell or T helper responses. This review will discuss the various approaches and receptors that have been used for antigen targeting that may eventually be translated to alternative DC-based immunotherapies.

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Individuals living in malaria-endemic areas show generally low T cell responses to malaria Ags. In this study, we show murine dendritic cell (DC) interaction with parasitized erythrocytes (pRBC) arrested their maturation, resulting in impaired ability to stimulate naive, but not recall T cell responses in vitro and in vivo. Moreover, within the naive T cell population, pRBC-treated DC were selectively deficient in priming CD8+ but not CD4+ T cells. Indeed, DC that had taken up pRBC were shown for the first time to efficiently prime CD4+ T cell responses to a known protective merozoite Ag, MSP4/5. In contrast, impaired priming resulted in decreases in both proliferation and cytokine production by CD8+ T cells. Deficient priming was observed to both a model and a Plasmodium berghei-specific CD8+ T cell epitope. The mechanisms underlying the inability of parasite-treated DC to prime CD8+ T cells were explored. pRBC treatment of DC from wild-type C57BL/6, but not from IL-10 knockout animals, suppressed DC-mediated T cell priming across a Transwell, suggesting active IL-10-dependent suppression. CD8+ T cells were arrested at the G0 stage of the cell cycle after two cell divisions post-Ag stimulation. The proliferation arrest was partially reversible by the addition of IL-2 or IL-7 to responder cultures. These results suggest that in malaria-endemic areas, priming of CD8+ T cell responses may be more difficult to induce via vaccination than the priming of CD4+ T cells. Moreover, pathogens may selectively target the CD8+ T cell arm of protective immunity for immune evasion.