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Analysis of innate defences against Plasmodium falciparum in immunodeficient mice.

Arnold L, Tyagi RK, Mejia P, Van Rooijen N, Pérignon JL, Druilhe P - Malar. J. (2010)

Bottom Line: The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery.The innate responses towards the murine parasite Plasmodium yoelii were used as a control.Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, 28, rue du Dr Roux, 75015 Paris, France.

ABSTRACT

Background: Mice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed.

Methods: NOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control.

Results: Results show that 1) P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2) in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3) human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4) macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role.

Conclusions: Despite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

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Related in: MedlinePlus

HuRBC, clo-lip and NIMP-R14 antibody are pro-inflammatory. HuRBC (full circle, plain line), clo-lip (open circle) and NIMP-R14 antibody (full circle, dotted line) were injected once in the peritoneum at hour 0, at doses identical to those used for the whole immunomodulation protocol. Leukocyte number (A), CD43- CD62L+ Ly-6C+ inflammatory monocytes (B) and inflammatory cytokines/chemokine (C-E) were assessed in mouse peripheral blood by FACS. Results are the means ± SD. from groups of 4 mice.
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Figure 4: HuRBC, clo-lip and NIMP-R14 antibody are pro-inflammatory. HuRBC (full circle, plain line), clo-lip (open circle) and NIMP-R14 antibody (full circle, dotted line) were injected once in the peritoneum at hour 0, at doses identical to those used for the whole immunomodulation protocol. Leukocyte number (A), CD43- CD62L+ Ly-6C+ inflammatory monocytes (B) and inflammatory cytokines/chemokine (C-E) were assessed in mouse peripheral blood by FACS. Results are the means ± SD. from groups of 4 mice.

Mentions: Considering the indications that inflammation was related to the clearance of the parasite, it was decided to examine whether HuRBC, clo-lip and NIMP-R14 antibody also induce inflammation. The effects of each component, injected i.p. upon 1) the number and phenotype of blood leukocytes, and 2) cytokines serum levels, were examined. The inflammatory effect of HuRBC was not unexpected, as it represents a heterologous graft. The i.p. injection of HuRBC induced an increase in leukocyte numbers (Figure 4A) (P < 0.003 between day 0 and day 3) mainly PMN and to a lesser extent MO and NK cells (data not shown). The inflammatory MO subset increased transiently to peak at 76% of total MO 10 hours post infection (P < 0.009), and then progressively decreased to basal level (Figure 4B). HuRBC grafting also led to a transient secretion of IL-6 (732 ± 51 vs 47 ± 14.7 pg/ml; P < 0.003) and TNFα (216 ± 51 pg/ml vs 75 ± 79 pg/ml; P < 0.1) (Figures 4C and 4E), without substantial modifications of MCP-1, IL-10, IL-12p70 or IFNγ.


Analysis of innate defences against Plasmodium falciparum in immunodeficient mice.

Arnold L, Tyagi RK, Mejia P, Van Rooijen N, Pérignon JL, Druilhe P - Malar. J. (2010)

HuRBC, clo-lip and NIMP-R14 antibody are pro-inflammatory. HuRBC (full circle, plain line), clo-lip (open circle) and NIMP-R14 antibody (full circle, dotted line) were injected once in the peritoneum at hour 0, at doses identical to those used for the whole immunomodulation protocol. Leukocyte number (A), CD43- CD62L+ Ly-6C+ inflammatory monocytes (B) and inflammatory cytokines/chemokine (C-E) were assessed in mouse peripheral blood by FACS. Results are the means ± SD. from groups of 4 mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914061&req=5

Figure 4: HuRBC, clo-lip and NIMP-R14 antibody are pro-inflammatory. HuRBC (full circle, plain line), clo-lip (open circle) and NIMP-R14 antibody (full circle, dotted line) were injected once in the peritoneum at hour 0, at doses identical to those used for the whole immunomodulation protocol. Leukocyte number (A), CD43- CD62L+ Ly-6C+ inflammatory monocytes (B) and inflammatory cytokines/chemokine (C-E) were assessed in mouse peripheral blood by FACS. Results are the means ± SD. from groups of 4 mice.
Mentions: Considering the indications that inflammation was related to the clearance of the parasite, it was decided to examine whether HuRBC, clo-lip and NIMP-R14 antibody also induce inflammation. The effects of each component, injected i.p. upon 1) the number and phenotype of blood leukocytes, and 2) cytokines serum levels, were examined. The inflammatory effect of HuRBC was not unexpected, as it represents a heterologous graft. The i.p. injection of HuRBC induced an increase in leukocyte numbers (Figure 4A) (P < 0.003 between day 0 and day 3) mainly PMN and to a lesser extent MO and NK cells (data not shown). The inflammatory MO subset increased transiently to peak at 76% of total MO 10 hours post infection (P < 0.009), and then progressively decreased to basal level (Figure 4B). HuRBC grafting also led to a transient secretion of IL-6 (732 ± 51 vs 47 ± 14.7 pg/ml; P < 0.003) and TNFα (216 ± 51 pg/ml vs 75 ± 79 pg/ml; P < 0.1) (Figures 4C and 4E), without substantial modifications of MCP-1, IL-10, IL-12p70 or IFNγ.

Bottom Line: The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery.The innate responses towards the murine parasite Plasmodium yoelii were used as a control.Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de Parasitologie Bio-Médicale, Institut Pasteur, 28, rue du Dr Roux, 75015 Paris, France.

ABSTRACT

Background: Mice with genetic deficiencies in adaptive immunity are used for the grafting of human cells or pathogens, to study human diseases, however, the innate immune responses to xenografts in these mice has received little attention. Using the NOD/SCID Plasmodium falciparum mouse model an analysis of innate defences responsible for the substantial control of P. falciparum which remains in such mice, was performed.

Methods: NOD/SCID mice undergoing an immunomodulatory protocol that includes, clodronate-loaded liposomes to deplete macrophages and an anti-polymorphonuclear leukocytes antibody, were grafted with human red blood cells and P. falciparum. The systematic and kinetic analysis of the remaining innate immune responses included the number and phenotype of peripheral blood leukocytes as well as inflammatory cytokines/chemokines released in periphery. The innate responses towards the murine parasite Plasmodium yoelii were used as a control.

Results: Results show that 1) P. falciparum induces a strong inflammation characterized by an increase in circulating leukocytes and the release of inflammatory cytokines; 2) in contrast, the rodent parasite P. yoelii, induces a far more moderate inflammation; 3) human red blood cells and the anti-inflammatory agents employed induce low-grade inflammation; and 4) macrophages seem to bear the most critical function in controlling P. falciparum survival in those mice, whereas polymorphonuclear and NK cells have only a minor role.

Conclusions: Despite the use of an immunomodulatory treatment, immunodeficient NOD/SCID mice are still able to mount substantial innate responses that seem to be correlated with parasite clearance. Those results bring new insights on the ability of innate immunity from immunodeficient mice to control xenografts of cells of human origin and human pathogens.

Show MeSH
Related in: MedlinePlus