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Lieke Reubsaet

Thursday 9 January 2014

Immune development and regulation in young children - potential markers for prediction of health and disease

Promotor: Prof. dr. A.B.J. Prakken
Defence: 09 January 2014

The human immune system is complex and is formed and shaped during life by many triggers. We are continuously exposed to many kinds of antigens derived from microbes, food and airborne substances. Although it is important to neutralize harmful and infectious agents, it is equally important that innocuous antigens do not induce an inflammatory response at first encounter and subsequently later in life. Different subsets of T helper cells are involved in immunity against pathogens, but can also play a role in inflammatory diseases like allergy, asthma and graft-versus-host disease (GvHD). The regulation of these inflammatory responses is mediated by the regulatory T cell (Treg). During our whole life these different T cell subsets try to maintain a balance within the immune system.

Graft-versus-Host disease
Allogeneic haematopoietic SCT (HSCT) may provide a curative therapy for haematological malignancies. The downsides of HSCT are the life threatening early allo-reactive complications of acute GvHD (aGvHD) and the related idiopathic pulmonary syndrome (IPS). Insight into the dynamics of early immune reconstitution after HSCT is essential for unravelling the mechanisms that may be involved in allo-reactive disease. We studied early Treg reconstitution after paediatric HSCT and showed that in children Treg proportions early after HSCT and in the graft were inversely correlated with allo-reactivity. Thus evaluation of FOXP3+ T cell numbers early after HSCT and in the graft may be used to judge the risk of developing allo-reactivity after HSCT.

Allergic disease
In patients with allergic diseases symptoms are caused by aberrant Th2 cell responses to nonpathogenic antigens and regulatory T (Treg) cells play a role in the control of these responses. The development and function of Treg cells are controlled by the transcription factor forkhead box protein 3 (FOXP3), whereas high expression of GATA3 determines Th2 cell differentiation. GATA3 is involved in induction of Th2 cytokines IL4, IL5 and IL13. First we investigated the role of GATA3 and FOXP3 in allergen specific responses in allergen sensitized and non-sensitized children. We showed that in allergic children allergens induce upregulation of GATA3 and FOXP3 partially within the same cell. This FOXP3/GATA3 double-positive cell population were activated Th2 like cells with partial Treg features. They were able to suppress proliferation and Th1 cytokines, while Th2 cytokines were unaffected. Because these FOXP3/GATA3 double positive cells only suppress non-Th2 cytokines they might contribute to the polarization, amplification or both of the allergen specific Th2 response in sensitized subjects instead of controlling it. Next we studied the allergen specific T cell response in young children that were or became sensitized or were non-sensitized and showed that in young children, allergen specific in vitro Th2 responses, characterized by GATA3 expression and production of IL4, IL5 and IL13, precede the detection of allergen specific IgE. Thereby we might be able to predict development of allergic disease even before IgE is detected and provide a window of opportunity to novel therapeutic interventions.

Predicting allergic disease
Assuming individuals are genetically predisposed to allergic diseases and the pathogenic process is initiated early in life, the question is whether we can predict development of allergic diseases such as allergic asthma. In order to find parameters for prediction prospective follow up studies are needed investigating differences between individuals that develop disease and individuals that do not. We prospectively follow a group of early wheezers from age 3 to 6 years and at age 6 they were categorized as having allergic asthma or not. This study showed that plasma levels of Interferon gamma induced protein 10 (IP-10 [CXCL10]), thymus- and activation-regulated chemokine (TARC [CCL17]) and macrophage derived chemokine (MDC [CCL22]) were increased in early wheezers that developed allergic asthma and might thus be able to contribute to the prediction of allergic asthma. A larger prospective follow-up study is needed to validate these results.