Stem Cell Inhibition of Multiple Sclerosis by IDO Induction

Lodz, Poland -

One of the very interesting things is trying to figure out how stem cells mediate their therapeutic effects in conditions such as multiple sclerosis.  In general there are three main ways: 1) Differentiation into neurons/oligodendrocytes; 2) Secrete growth factors; and 3) Immune modulation. 

We are going to discuss a publication (Matysiak et al. Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism. J Neuro Immunol 2008 Jan;193(1-2):12-23) dealing with immune modulation by stem cells in the mouse model of multiple sclerosis.  The mouse model is called experimental allergic encephalomyelitis (EAE).  In this paper they induced EAE by immunization with proteolipid protein peptide. 

Mice were injected on day 0.  Disease severity increases.  Mice recieved 2 million intravenous lineage negative stem cell antigen positive.  Subsequent to injection disease severity decreased in the treated group.  So the question was whether the stem cells were inducing immune modulation. 

To assess immune modulation the authors evaluated recall response and reported that there was suppressed PLP peptide specific recall response in the mice recieving stem cells.  HOWEVER, restimulation of the T cells from mice treated with stem cells resulted in increased interferon gamma production.  Interferon gamma is actually associated with inflammation, so this data was very interesting. 

The investigators then sought to see if interferon gamma could be inducing expression of indolamine 2,3 deoxygenase (IDO).  This enzyme is associated with suppression of T cells by locally "starving" the T cells of tryptophan.  Also IDO is associated with protection of the "fetal allograft" from the maternal immune system.

The investigators performed Western Blot to assess IDO expression in spleens of stem cell treated and control mice.  There was increased basal production of IDO, as well as increase expression in splenocytes of stem cell treated mice subsequent to treatment in vitro with interferon gamma.  Additionally, the investigators demonstrated that IDO expression was restricted to the dendritic cell compartment by showing that IDO was found only in the CD11c positive fraction.

Inhibition of IDO activity by treatment of mice with 1-MT lead to abrogation of the therapeutic effects of stem cell on EAE progress.

This paper suggests that hematopoietic cells actually induce IDO in dendritic cells as a mechanism of immune regulation.  There have been numerous animal models, and early clinical descriptions of stem cells having effects in multiple sclerosis.  This paper suggests some possible therapeutic mechanisms.