parasito 8jul 08

8/3/2019 parasito 8jul 08

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T cells and not antibodies are responsible for theT cells and not antibodies are responsible for the

loss of fullloss of full--protective immunity to bloodprotective immunity to blood--stagestage

Plasmodium chabaudiPlasmodium chabaudi AS malariaAS malaria

Ana Paula Freitas do Rosrio

NIMR 8 July 2008


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Introduction - General Aspects of Malaria

-- Estimated 350Estimated 350--500 million clinical cases / year500 million clinical cases / year (WHO, 2005)(WHO, 2005)

-- Endemic disease in tropical and subtropical regionsEndemic disease in tropical and subtropical regions

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


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Introduction - Immunity Against Malaria

-- ShortShort--livedlived

-- CDCD88++ TT dependentdependent (liver(liver phase),phase), antibodiesantibodies andand CDCD44++ TT dependentdependent (blood(blood stage)stage)

-- Immunity acquired after a long period of exposure to the parasiteImmunity acquired after a long period of exposure to the parasite

-- Why is it so hard to induce longWhy is it so hard to induce long--term protection?term protection?

-- ApoptosisApoptosis ((ToureToure--Balde et al., 1996, Helmby et al., 2000, SanchezBalde et al., 1996, Helmby et al., 2000, Sanchez--Torres et al, 2001)Torres et al, 2001)

-- Elliott et al (2005): limited exposure to the parasite avoid apoptosisElliott et al (2005): limited exposure to the parasite avoid apoptosis


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Introduction Influence of Antigenic Load in Immunity Generation

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

(Pombo et al (2002))(Pombo et al (2002))

--LowerLower antigenicantigenic loadsloads inducedinduced protectionprotection withwith strongstrong cellularcellular responseresponse

(Shata(Shata etet alal ((20032003)):: HCVHCV;; BretscherBretscher etet alal ((19921992)):: Leishmania)Leishmania)

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


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Question

What effect does different parasitemia have on the generation andWhat effect does different parasitemia have on the generation and

maintenance of memory immune response tomaintenance of memory immune response to Plasmodium chabaudiPlasmodium chabaudi AS?AS?


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Day 0Day 0

106 pRBC

Untreated InfectionUntreated Infection

DrugDrug--treated Infectiontreated Infection

2020

6060

120120

200200

108

pRBC

C57BL/6

Analysis

Challenge

Experimental Design

Days

Days after infection

Days after infection


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Drug-treated mice have less T cell death and activation

Day 7(CD4 T cells)


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Drug-treated mice produce more IgG2a parasite-specific antibody


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Parasite-specific T cell proliferation goes down during infection

Is it an APC problem???


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Incubation of T cells with different APCs

20 days 200 days

T

APC

T

APC

+ pRBC+ pRBC

CD11b+, CD11c+ and B220+


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There isnt a problem in APC but in T cells


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And after challenge?


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Protective immunity decreases with time

before challenge

Days post-challenge


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Increasing levels of specific IgG2a after challenge

Days post-challenge


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T cell activation decreases with time


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Are CD4+T cells still important for immunity against the challenge?

200 days

anti-CD4

onlyonlyCD4CD4++

totaltotal--CD4CD4++

totaltotal

Untreated mice

CD28ko

101066 pRBCpRBC

35 days35 days

101088 pRBCpRBC

CD28ko

101066 pRBCpRBC

(chloroquine)

Elias et al(2005)

Control mice


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CD4+ T cells are necessary for antibody production and protectionafter challenge


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To Remember After challenge

-- The decrease in protection seems to be due to the lack of CD4 T cell responseThe decrease in protection seems to be due to the lack of CD4 T cell response

and not absence of Ab;and not absence of Ab;

-- Despite the fact that CD4 T cell do not proliferate at day 200, they help the AbDespite the fact that CD4 T cell do not proliferate at day 200, they help the Ab

production and also guarantee protection against challenge;production and also guarantee protection against challenge;

-- Higher levels of parasiteHigher levels of parasite--specific IgG2a after challenge;specific IgG2a after challenge;

--Protective immunity decreases after

120 days of infection

;Protective immunity decreases after

120 days of infection

;


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Final Conclusion

-- Mice from both groups were able to generate and maintain the protectiveMice from both groups were able to generate and maintain the protective

immunity againstimmunity against P. chabaudiP. chabaudi independent of the initial parasitemiaindependent of the initial parasitemia

What effect does different parasitemia have on the generation andWhat effect does different parasitemia have on the generation and

maintenance of memory immune response tomaintenance of memory immune response to Plasmodium chabaudiPlasmodium chabaudi AS?AS?


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Thanks to

Prof. Dr. Maria Regina DImperio LimaProf. Dr. Maria Regina DImperio Lima

-- Sandra MuxelSandra Muxel

-- Claudia ZagoClaudia Zago

-- Sergio MalagaSergio Malaga

Prof. Dr. Jose Maria Alvarez MosigProf. Dr. Jose Maria Alvarez Mosig

-- Luiz SardinhaLuiz Sardinha

Support:Support:

University of Sao PauloUniversity of Sao Paulo -- BrazilBrazil

-- Institute of Biomedical SciencesInstitute of Biomedical Sciences -- Dept. ImmunologyDept. Immunology

parasito 8jul 08

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