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Dissection of the mechanisms leading to the selective triggering of protective and non protective T cell responses following infection with Leishmania : relevance for the induction and detection of human protective immunity

Objective



Leishmaniasis is a public health problem world-wide.
Indeed, transmission of Leishmania parasite occurs in more than 80 countries, mainly developping countries, but also in developped countries. The recovery from leishmaniasis - either spontaneously or after chemotherapy - is correlated to the slow development of a T-cell dependent state of immunity to reinfection in the majority of individuals.
Thus, vaccination should represent an effective mean of controlling the infectious and disease processes.
The use of animal models of cutaneous leishmaniasis has allowed to demonstrate that T cells triggered during infection either express a TH1 (type 1) protective phenotype or a TH2 (type 2) nonprotective phenotype and may be committed either along a TH1 protective phenotype or along a nonprotective TH2 phenotype.
Such a situation may also be exemplified in the human responses to the parasite Leishmania braziliensis.

The most common clinical form of the disease caused by L.braziliensis is localized cutaneous leishmaniasis (LCL) characterized by single or multiple ulcerated dermal lesions that usually heal spontaneously.
However, in 2-5% of LCL patients in Brazil and Colombia, a chronic mucocutaneous form arises later leading to progressive (2) destruction of the nasal, oral and/or pharyngeal tissues.
Therefore, the rational design of an effective vaccine against american leishmaniasis depends upon (5) the ability to selectively trigger protective responses and to identify parasite molecules which are able to elicit and to be the targets of protective effectors.

The aims of the present project are to investigate the priming conditions that control the preferential expansion and differentiation of Leishmania specific precursor T cells towards type 1 or type 2 cells.
In vitro studies using naive/virgin mouse or human T cells will be performed to specify the priming conditions that determine whether T cells will produce interleukins IL4, IL10 and IL13 or interferon y (IFNv) upon subsequent rechallenge (teams of Cali, Lausanne, Rio de Janeiro). If a peculiar combination of cytokines and antigen-presenting cells is recognized as critical, a logical consequence will be to ask whether such priming conditions will be rapidly set in motion in vivo in both the skin site of infection and the draining Iymph nodes.
A new method devised by the team in Paris allows to have access to such an in situ analysis.

Indeed ears are optimal sites where to inject Leishmania sP. and from which it is possible to recover all the cells thought to be critical for T cell priming namely dendritic leucocytes, mononuclear phagocytes, mast cells, NK cells, keratinocytes.
Results from the experiments proposed in the present application will allow a definition of the conditions leading to the development and maintenance of a protective response.
Once these conditions are defined, studies aimed at the identification of parasite molecule targets of protective effector T cells will be initiated using Listeria monocvtoqenes of attenuated virulence and expressing L.braziliensis genes as a screening system.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Institut Pasteur
Address
28 Rue Du Docteur Roux
75724 Paris
France

Participants (3)

Centro Internacional de Entrenamientoe Investigaciones Medicas
Colombia
Address
3-03,Avenida L Norte
0344406 Cali - Valle
Fundação Oswaldo Cruz
Brazil
Address
4365,Av.brasil
21040 Rio De Janeiro
UNIVERSITY OF LAUSANE
Switzerland
Address
155,Chemin Des Boveresses 155
1066 Epalinges