Apresenta

1
Universidade Federal do Rio de Janeiro Centro de
Ciências da Saúde Instituto de Biofísica Carlos
Chagas Filho
The importance of apoptosis for immune
regulation in Chagas disease
George A. DosReis
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Fabrício Montalvão. IBCCF-UFRJ Landi V.
Guillermo. IBCCF-UFRJ Geisy M. de Almeida.
IBCCF-UFRJ Elizabeth M. Silva. IBCCF-UFRJ Marise
P. Nunes. IOC-Fiocruz-RJ Juliana de Meis.
IOC-Fiocruz-RJ Christina M. Takiya. Dept.
Histologia-UFRJ Richard Siegel. NIAID-NIH,
USA Celio Freire-de-Lima. IBCCF-UFRJ Marcela F.
Lopes. IBCCF-UFRJ
3
Phagocytosis of apoptotic cells (efferocytosis)
inactivates macrophages and exacerbates parasite
replication through TGF-ß, ODC and polyamine
synthesis
X
Efferocytosis
Lopes MF et al. Immunol. Today 21 489-494,
2000 Freire-de-Lima CG et al. Nature 403
199-203, 2000
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T. cruzi infection Consequences of apoptosis
Efferocytosis
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Apoptosis in T. cruzi infection
Modify efferocytosis by 1. Caspase
inhibition 2. Anti-FasL treatment 3. Antibodies
to apoptotic cells
Efferocytosis
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Blocking apoptosis in T. cruzi infection
Caspase inhibition
Efferocytosis
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Caspase inhibition reduces lymphocyte apopotosis
in vivo
Silva, E. M. et al. Caspase inhibition reduces
lymphocyte apoptosis and improves host immune
responses to Trypanosoma cruzi infection. Eur.
J. Immunol. 2007, 37 (3), 738-746.
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Treatment with zVAD reduces parasitemia
Silva, E. M. et al. Caspase inhibition reduces
lymphocyte apoptosis and improves host immune
responses to Trypanosoma cruzi infection. Eur.
J. Immunol. 2007, 37 (3), 738-746.
9
Treatment with zVAD in vivo increases macrophage
activation
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• The general caspase inhibitor zVAD
• reduces apoptosis of T lymphocytes in vitro
• and in vivo
• Treatment with zVAD increases immunity
• to T. cruzi infection

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Blocking apoptosis in T. cruzi infection
Anti-FasL
Efferocytosis
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Increased immunity to T. cruzi after treatment
with anti-FasL in vivo
Guillermo, L.V. et al. The Fas death pathway
controls coordinated expansions of type 1 CD8
and type 2 CD4 T cells in Trypanosoma cruzi
infection. J. Leukoc. Biol. 2007, 81, 942-951.
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Anti-FasL in vivo accelerates and increases type
1 cytokine responses
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Anti-FasL reduces apoptosis of CD4 and CD8 T
cells Anti-FasL increases type 1 cytokine
responses, increases macrophage NO production
and reduces parasitemia Lymphocyte apoptosis is
deleterious for T. cruzi Infection in vivo
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Modifying immune regulation through opsonization
of apoptotic cells
Antibodies
Efferocytosis
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Differential reaction of chagasic IgG with
apoptotic lymphocytes
Cha
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Opsonization of apoptotic cells with chagasic
IgG reduces the effect of efferocytosis on
replication of T. cruzi
IgG purified from T. cruzi infection (90 days) or
age matched serum
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Apoptotic cells opsonized with chagasic
IgG increase TNF-a production
Control of parasite replication is mediated by
increased TNF-a production
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Control of parasite replication requires
engagement of Fc?Rs
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Previous immunization with apoptotic cells
reduces parasitemia in vivo
Dm28c
dpi
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Conclusions Chagasic IgG opsonizes apoptotic
cells and reduces the effect of
efferocytosis on parasite replication The
protective effect is mediated by increased TNF-a
production The protective effect requires
Fc?Rs Generation of autoantibodies against
apoptotic cell antigens could play a protective
role against parasite infection