CHANGING THE COURSE OF INFECTION

[Jeffrey Shaw]

>Sender: owner-tdr-scientists at who.ch
>Precedence: bulk
>
>Herewith an other item of TDR Newsletter 52 (will be issued in March 97).
>
>Jocelyne Bruyere
>TDR Communications
>(bruyerej at who.ch)
>
>
>
>------- Forwarded message
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>Posted: Tue, 18 Feb 97 23:00:01 -0100
>Date: Wed, 19 Feb 97 08:01:01 -0100
>Author: "who tdrnews"
>Subject: CHANGING THE COURSE OF INFECTION
>
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>(TDR NEWSLETTER 52 - MARCH 1997) 
> 
>Changing the course of infection 
> 
>New evidence from the world of mice and leishmanias indicates that a 
>lone antigen might be responsible for orchestrating the entire response 
>of a host to a parasite. Making mice tolerant to a single leishmanial 
>antigen can completely change the course of infection - from one of 
>susceptibility to one of resistance.  
>
>Sub-sets and secretions 
>
>Each year, more subsets of T cells seem to be described. Th1 (T 
>helper 1) and Th2 cells are subsets of T cells which were first 
>described nearly ten years ago.  Each of these subsets secretes a 
>different repertoire of cytokines; for instance, Th1 cells produce 
>interferon-g (IFN-g), amongst others, while Th2 cells produce 
>interleukin-4 (IL-4). The outcome of an infection can be determined 
>by the balance between these different cells and their cytokine 
>secretions.  
>After infection, a boost in Th1 cells and IFN-g occurs in mice that are 
>resistant to Leishmania major, whereas a boost in Th2 cells and IL-4 
>occurs in mice that are susceptible to L.major. If the activity of IFN-g 
>is suppressed in a resistant mouse, the mouse is no longer able to 
>resist the progression of the disease. Conversely, if the activity of IL-4 
>in a susceptible mouse is suppressed in the first week of infection, the 
>Th2 response is prevented and a healing Th1 response emerges.  
>IL-4 appears to be the main inducer of the Th2 response and, at the 
>same time, the main inhibitor of the Th1 response. An early burst of 
>IL-4 production occurs in the lymph nodes of infected susceptible 
>mice, and a study by Valrie Julia, Minoo Rassoulzadegan and 
>Nicolas Glaichenhaus (Resistance to Leishmania major induced by 
>tolerance to a single antigen. Science, 1995, 274:421-423) was 
>directed at identifying which parasite antigens trigger this early burst 
>of IL-4 and at how to lessen the Th2/IL-4 response.  
>
>The LACK antigen 
>
>The authors found evidence that a single leishmania antigen, known 
>as LACK (leishmania homolog of receptors for activated C kinase), 
>triggers the early burst of IL-4 and plays a pivotal role in determining 
>whether or not a mouse is susceptible to infection with Leishmania 
>major. When susceptible mice were made tolerant to LACK prior to 
>infection (by transgenic expression of LACK in the thymus), they 
>responded to L.major with Th1 cells rather than Th2 cells and were 
>resistant to infection.  
>Thus there was a reversal of the normal process after mice became 
>tolerant to the single antigen. The authors hypothesize that 
>susceptibility to murine leishmaniasis is determined by the ability of 
>the infected host to mount a strong Th2 response against one or a few 
>antigens (as well as by the loss of ability to generate a Th1 response - 
>an earlier hypothesis).  
>
>
>
>Implications for vaccine development 
>
>The study indicates the importance of choosing which immunogen(s) 
>to include in a vaccine. Whole leishmania parasites will induce a Th2 
>response if given alone subcutaneously. However, if given with IL-12 
>(which enhances the Th1 response and IFN-g), a protective response 
>will emerge. Hence both the immunogen and the secondary stimulus 
>are important. 
>
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