Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
5) Pleiotropic roles of type I IFN
(a) Impact on the global immune response
Type I IFN are currently approved for use as the treatment of several diseases, including solid
and hematologic cancers, multiple sclerosis, as well as chronic viral hepatitis. In patients
chronically infected with HCV, it is known that endogenous type I IFN are produced, but the
infection is not cleared. However, treatment with exogenous IFNα can lead to the resolution
of infection in approximately 50% of patients (Mihm et al., 2004). These data strongly
suggest that there is a differential effect of endogenous versus exogenous injected IFN on
viral clearance. Of note, for this treatment regimen, IFNα is stabilized by its conjugation to
polyethylene glycol, which confers an increased half-life upon injection and also a lag in
clearance from the patient’s system. In contrast, IFNβ is used for the treatment of multiple
sclerosis patients, in order to inhibit their autoreactive immune response. These two examples
of the contrasting effects of type I IFN treatments in clinical settings suggest the vast
complexicity of its action.
Studies examining the secondary side effects of IFNα treatment in cancer patients have
demonstrated that this treatment may have further differential effects on the immune response
(Gogas et al., 2006). Several autoimmune disorders induced by treatment have been
described. DC-derived monocytes obtained following IFNα treatment have been shown to be
fully matured, able to engulf apoptotic bodies and capable of trigerring an anti-tumor T cell
response. One explanation for the development of autoimmune disorders during the course of
IFNα treatment could be that DCs are stimulated and take up apoptotic bodies derived from
normal host cells and present self-antigens, leading to a robust anti-self immune response
(Rizza et al., 2010).
Pleitropic functions of type I IFN have also been described for infectious diseases (Decker et
al., 2005). Type I IFN favor infection by Listeria monocytogenes or Chlamydia muridarum,
probably by sensitizing effector cells to death (Qiu et al., 2008). However, in the case of
infection by Streptococcus pneumoniae or Salmonella typhimurim, type I IFN protect the host
by enhancing antibody production or inducing IFNγ production, respectively.
(b) Factors influencing type I IFN action
The pleiotropic effects of type I IFN observed at the systemic level are not at all well
understood. Nevertheless, recent studies have offered some new insight into the parameters
that regulate the function(s) of type I IFN at cellular and molecular level, which may be able
to explain these differential functional observations. Importantly, it has been observed that
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