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Novel opportunities for tailor-made immunomodulation in atopic diseases - breaking the waves.

By B. Kapitein

Abstract

Treatment and, ultimately prevention of complex diseases such as atopic diseases, should start with the identification of individuals at risk for developing (an) atopic disease(s). Gene expression profiles, that is, whether a gene is expressed as mRNA, can reflect both genetic and environmental factors. We explored gene expression profiles in children with wheezing symptoms. Children who persist to wheeze after the age of three are at risk of developing asthma, but recognition of these persistent wheezers is difficult due to several heterogeneous wheezing phenotypes. Gene expression profiles did not only differentiate between transient and persistent wheezers, but these two distinct wheezing phenotypes also share some common pro-inflammatory genes, such as DUSP2, JunB, TNFAIP3, TNFSF13B and LILRB2. Three genes, STAT1, TLR7 and PTGER2 which appeared to differentiate between the transient and persistent wheezers proved to distinguish these two phenotypes in a prospective cohort study, thereby recognizing those children at risk to develop asthma. Also, when wheezing children were compared with healthy controls, the increased expression of several genes encoding for heat shock proteins (hsp) was found. These stress proteins play an important role in the regulation of inflammatory processes and interestingly, their activation secludes both innate as well as adaptive immune responses. To elucidate the mechanism on how hsp exert a regulatory role we studied the effects of stimulation of CBMCs with human hsp60. The cord blood mononuclear cells are thought to be naive cells, but the immune regulatory capacities of hsp are thought to be innate and might therefore exert certain reactions in CBMCs. Not only did CBMCs proliferate in response to hsp60 but this recognition led to the induction of suppressive, FOXP3 positive T cells. These suppressive FOXP3 positive T cells are referred to as regulatory T cells. This induction of suppressive, regulatory T cells is of great interest when exploring new opportunities for therapeutic strategies in atopic diseases. A cytokine known for its immunosuppressive effect is TGF-Beta. To get more insight in the pathophysiology of the induction of regulatory T cells and the influence of the differentiation status of T cells in this process, a study was performed in which naïve CBMCs of healthy donors were stimulated with TGF-Beta in vitro. The CBMCs were stimulated either unskewed, or skewed towards a TH1 or TH2 type. This skewing process seemed to be of great influence on the effects of TGF-Beta, since CBMCs skewed towards a TH2 profile were far less responsive to the influence of TGF-Beta compared to CBMCs skewed towards a TH1 profile. This implicates that the mechanisms involved in regulation varies, depending at least in part, to the cell type which is targeted. Hsp are also capable of inducing regulatory T cells in CBMCs of healthy donors. The role of hsp in atopic diseases is unclear, but a few studies have shown that increased levels of hsp (hsp70 in this particular study) can be detected in asthma. We were curious whether hsp were also capable of eliciting a response in PBMCs of atopic children with active allergic symptoms. The PBMCs of atopic children recognized hsp which induced pro-inflammatory autoreactive T cells in vitro. The implication for future therapeutic perspectives have to be further investigated

Publisher: Utrecht University
Year: 2008
OAI identifier: oai:dspace.library.uu.nl:1874/31691
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