Impairment of the Immune Response to Vaccination After Acute Malaria

Williamson, W.A.; Greenwood, Brian

doi:10.1016/s0140-6736(78)92403-0

Cited by 190 publications

(106 citation statements)

References 5 publications

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“…However, systemic DC maturation induced by sepsis or malaria infection depletes the immune system of DCs capable of responding to new infections and thus causes immunosuppression. Such an effect might contribute to poor vaccination outcomes, and to the prevalence of Burkitt's lymphoma, in malariaendemic areas (40,41), the latter thought to be a consequence of compromised control of Epstein-Barr virus infection. We could reverse this effect in our experimental system by injecting the immunocompromised mice with DCs presenting the antigen.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Young

Wilson

Schnorrer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro. Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs. Here, we show that DCs matured in vivo could still capture and process soluble antigens, but were unable to present peptides derived from these antigens. Furthermore, presentation of viral antigens synthesized by the DCs themselves was also severely impaired. Indeed, i.v. injection of pathogen mimics, which caused systemic DC activation in vivo, impaired the induction of CD4 T cell responses against subsequently encountered protein antigens. This immunosuppressed state could be reversed by adoptive transfer of DCs loaded exogenously with antigens, demonstrating that impairment of CD4 T cell responses was due to lack of antigen presentation rather than to overt suppression of T cell activation. The biochemical mechanism underlying this phenomenon was the down-regulation of MHC IIpeptide complex formation that accompanied DC maturation. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to the understanding of the mechanisms causing immunosuppression during systemic blood infections. 2). In their immature state, DCs are highly endocytic and express low amounts of MHC II molecules on their plasma membrane. Pathogenassociated compounds such as those recognized by Toll-like receptors (TLRs) activate immature DCs, which then undergo dramatic phenotypic changes that culminate in the acquisition of a ''mature'' phenotype. Mature DCs down-regulate macropinocytosis and phagocytosis, although they retain their micropinocytic activity (3, 4). Mature DCs accumulate long-lived surface MHC II-peptide complexes, derived from antigens contained within the endosomal compartments at the time of activation (5-10, 55). Such antigens correspond to proteins captured from the extracellular medium (exogenous), or those synthesized by the DCs themselves (endogenous). The latter include components of the endocytic route, plasma membrane proteins, and even cytosolic proteins transferred to endosomal compartments by autophagocytosis (1). Down-regulation of MHC II-peptide complex turnover allows long-term presentation of antigens captured, or synthesized, at the time of activation (''antigenic memory'') (2).Once DCs mature, they lose their capacity to present newly encountered antigens (2). This is usually attributed to downregulation of endocytosis, but it is unclear whether other factors downstream of antigen uptake also contribute to poor presentation of new antigens. It is also i...

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Section: Discussionmentioning

confidence: 99%

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Young

Wilson

Schnorrer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Several studies on human and mice infection with malaria indicate that T cell responses against malaria and non-malaria antigens are inhibited by the disease [5,7,10,53,54]. Using a mouse malaria model, we have characterized two immune mediators that are generated in response to blood-stage infection: TGF-b and PGE 2 , which play an essential role in T cell inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…A number of epidemiological studies suggest the existence of malaria-induced immune suppression. In endemic areas, an association of malaria with a higher incidence of other infectious diseases [3][4][5] and reduced immune responses to vaccination during malaria infections [6,7] is found.…”

Section: Introductionmentioning

confidence: 99%

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

et al. 2007

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During an acute blood-stage malaria infection, T cell responses to malaria and other bystander antigens are inhibited. Plasmodium infection induces strong cytokine responses that facilitate parasite clearance but may interfere with T cell functions, as some of the soluble immune mediators induced are also general inhibitors of T cell responses. Using a malaria mouse model, we have analyzed the cytokines produced by dendritic cells in response to P. yoelii infection that have potential T cell inhibitory activity. We found that during acute infection DC migrate to the spleen and secrete TGF-b, prostaglandin E 2 (PGE 2 ) and IL-10. We have analyzed the role of these general T cell inhibitors in a particular T cell response of evident importance in malaria infections: the CD8 + T cells generated against the liver-stage of the disease. During blood-stage infection, inhibition of the activity of TGF-b and PGE 2 restores the CD8 + T cell responses generated by sporozoites, increasing protection against re-infection. Our findings suggest that the strong cytokine response induced by blood-stage P. yoelii infection affects host T cell responses, inhibiting protective CD8 + T cells against the liver-stage of the disease.

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“…** , P Ͻ 0.01. (48)(49)(50). Nevertheless, T-cell-dependent humoral immune responses are clearly induced during acute malaria, and adults living in endemic areas often show high levels of antimalarial IgG (51), although antibodies against individual parasite antigens frequently seem to be short-lived (52,53).…”

Section: Discussionmentioning

confidence: 99%

A role for CD36 in the regulation of dendritic cell function

Urban

Willcox

Roberts

2001

Proc. Natl. Acad. Sci. U.S.A.

269

223

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Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-␣, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.A daptive immune responses are initiated by antigenpresenting cells, among which dendritic cells (DC) are crucial because they are most efficient in activating naïve T cells. Immature DCs reside in almost all tissues and continually sample antigens. Proinflammatory cytokines as well as bacterial products provide strong stimuli provoking their maturation and migration into the T-cell areas of draining lymph nodes and spleen. During maturation, the DCs cease phagocytosis and up-regulate the surface expression of costimulatory molecules, adhesion molecules, and stable HLA͞peptide complexes that allow them to prime naïve and boost memory T cells (reviewed in ref. 1). Depending on the local cytokine environment and progression in their maturation, DCs can induce both Th1 and Th2 T-cell responses (2, 3). However, DCs also play an important role in the induction of CD8 ϩ T-cell and B-cell function (4, 5).Recent studies have shown that tissue injury provides an endogenous maturation signal for DCs. Necrotic cells derived from primary fibroblasts in mice, or from established cell lines in humans, stimulated DC maturation, whereas apoptotic cells did not (6, 7). On the basis of these and other studies, it has been hypothesized that DCs that have ingested apoptotic bodies in the absence of maturation stimuli might induce T-cell tolerance directly or transfer antigens to other bystander DCs (8, 9). If, however, DCs receive inflammatory signals while ingesting apoptotic cells, they might cross-present apoptotic cell-derived peptides within MHC class I molecules and so activate CD8 ϩ T cells, promoting immune responses to the activating insult (10). Thus, depending on the local environment and the signals they receive, DCs seem to be pivotal not only for the induction of immune responses to invading pathogens but also for the regulation of harmful immune responses directed against environmental or self-antigens. However, the precise signals and pathways determining whether DCs activate or dampen immune response...

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Impairment of the Immune Response to Vaccination After Acute Malaria

Cited by 190 publications

References 5 publications

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection

A role for CD36 in the regulation of dendritic cell function

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Impairment of the Immune Response to Vaccination After Acute Malaria

Cited by 190 publications

References 5 publications

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens

Role of TGF‐β and PGE2 in T cell responses during Plasmodium yoelii infection

A role for CD36 in the regulation of dendritic cell function

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Role of TGF‐β and PGE₂in T cell responses during Plasmodium yoelii infection