T cells and not antibodies are responsible for the loss of full-protective immunity to blood-stage fullbloodPlasmodium chabaudi AS malaria

Ana Paula Freitas do Rosrio NIMR 8 July 2008

Introduction - General Aspects of Malaria

- Endemic disease in tropical and subtropical regions

- Estimated 350-500 million clinical cases / year (WHO, 2005) 350-

- 1 to 3 million deaths (children under 5 years)

Introduction - Immunity Against Malaria

- CD8+ T dependent (liver phase), antibodies and CD4+ T dependent (blood stage) CD8 CD4 - Immunity acquired after a long period of exposure to the parasite - Short-lived Short- Why is it so hard to induce long-term protection? long- Apoptosis (Toure-Balde et al., 1996, Helmby et al., 2000, Sanchez-Torres et al, 2001) ToureSanchez- Elliott et al (2005): limited exposure to the parasite avoid apoptosis

Introduction Influence of Antigenic Load in Immunity Generation

-Lower antigenic loads induced protection with strong cellular response

(Shata et al (2003): HCV; Bretscher et al (1992): Leishmania) 2003) HCV; 1992)

- Very low doses of P. falciparum induced strong cellular response in volunteers

(Pombo et al (2002))

- Important for immunization protocols in vaccine pre-clinical trials pre-

Question

What effect does different parasitemia have on the generation and maintenance of memory immune response to Plasmodium chabaudi AS?

Experimental Design
Untreated Infection

Days
Day 0
Days after infection

Analysis

20 60 120

C57BL/6

106 pRBC

DrugDrug-treated Infection

200

Challenge

108 pRBC

Days after infection

Drug-treated mice have less T cell death and activation

Day 7
(CD4 T cells)

Drug-treated mice produce more IgG2a parasite-specific antibody

Parasite-specific T cell proliferation goes down during infection

Is it an APC problem???

Incubation of T cells with different APCs

20 days

200 days

CD11b+, CD11c+ and B220+ T APC T APC

+ pRBC

There isnt a problem in APC but in T cells

To Remember Before challenge

- Drug-treated infection induced less T cell death and activation; Drug-

- Drug-treated mice produced higher levels of parasite-specific IgG2a; Drugparasite-

- The parasite-specific proliferation goes down with time; parasite-

- At day 200 p.i. the lack of proliferation is due to the incapacity of T cells to respond to the APC stimulation;

- At day 200 p.i. the APC are still able to stimulate T cells.

And after challenge?

Protective immunity decreases with time

Days post-challenge

before challenge

Increasing levels of specific IgG2a after challenge

Days post-challenge

T cell activation decreases with time

Are CD4+T cells still important for immunity against the challenge?
Control mice 200 days

anti-CD4

Untreated mice

total

total -CD4+

only CD4+

Elias et al (2005)

CD28ko

CD28ko

106 pRBC

106 pRBC

35 days
(chloroquine)

108 pRBC

CD4+ T cells are necessary for antibody production and protection after challenge

To Remember After challenge

- Protective immunity decreases after 120 days of infection; - Higher levels of parasite-specific IgG2a after challenge; parasite- The decrease in protection seems to be due to the lack of CD4 T cell response and not absence of Ab; - Despite the fact that CD4 T cell do not proliferate at day 200, they help the Ab production and also guarantee protection against challenge;

Final Conclusion

What effect does different parasitemia have on the generation and maintenance of memory immune response to Plasmodium chabaudi AS?

- Mice from both groups were able to generate and maintain the protective immunity against P. chabaudi independent of the initial parasitemia

Thanks to
University of Sao Paulo - Brazil - Institute of Biomedical Sciences - Dept. Immunology

Prof. Dr. Maria Regina DImperio Lima - Sandra Muxel - Claudia Zago - Sergio Malaga

Prof. Dr. Jose Maria Alvarez Mosig - Luiz Sardinha

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