The role of CD30 in atopic allergy

Abstract

The 120 kDa CD30 molecule belongs to the tumour necrosis factor (TNF) receptor superfamily and is expressed by activated lymphoid cells. Small populations of CD30+ cells have been detected in the peripheral lymphoid organs, as well as in the thymus. A subset of CD45RO+, so-called memory T cells, also express CD30 after various kind of stimuli. A role for CD30 in the normal development of T cells in the thymus has been suggested. CD30 expression has also been associated with Th2 related diseases. CD30 ligand (CD30L) is expressed on activated T cells and macrophages. Further, CD30L+ cells have been detected in the thymus. Soluble CD30 (sCD30) is generated when the membrane bound molecule is proteolytically cleaved. Elevated levels of sCD30 can be found in various human conditions characterised by an over-expression of CD30, e.g. Hodgkin's lymphoma and anaplastic large cell lymphoma, but also in infectious diseases such as HIV, hepatitis B, C and infectious mononucleosis.

The general aim of this thesis was to investigate the role of CD30 in atopic allergy. I have analysed the expression pattern of CD30 in allergen-specific human T-cell clones of Th1, Th0 and Th2 type. All three subtypes had the ability to express CD30 after activation, although the CD30 expression was sustained in the clones defined as Th2. In contrast to what has previously been proposed by others, our results show that CD30 cannot be used as a reliable marker to identify the Th2 cell subset.

When sCD30 levels in serum were analysed in a group of atopic dermatitis (AD) patients, elevated levels were observed, compared with non-atopic controls. Although, no correlation with total or specific IgE levels, or disease activity was shown, analysis of sCD30 levels, together with other parameters, may help in the diagnosis of AD. The expression of CD30 and CD30L was assessed in placenta specimens from atopic and non-atopic mothers. As previously shown, CD30 was expressed exclusively on the decidual stromal cells of the placenta. Further, we made the novel observation of CD30L expression on macrophage-like HLA-DR+ cells throughout the mesenchymal chorionic villi. CD30 and CD30L were detected to the same extent in human placenta from atopic and non-atopic mothers. sCD30 levels were significantly higher in the atopic mothers, compared to non-atopic mothers, while the levels in cord blood were relatively high irrespective of maternal atopy. sCD30 levels in cord blood and CD30 expression in the placenta may reflect the Th2 environment surrounding the foetus. In addition, CD30 and CD30L could have important immune-regulatory functions in the placenta. To investigate the function of CD30-CD30L interaction in human T helper cells, we used agonistic anti-CD30 monoclonal antibodies.

Our results indicate an enhanced cytokine production by Th1 and Th2 cells after stimulation with anti- CD30 antibodies, which suggests that CD30 can function as a positive regulator in activated human T cells. N-acetyl-L-cysteine (NAC) and glutathione (GSH) decreased the production of cytokines by Th0 and Th2 clones, with the most pronounced down-regulation of IL-4. Further, our results demonstrate that the low levels of IL-4 can be due to a direct action of NAC on IL4 at the protein level. NAC and GSH also down-regulated the surface expression of CD30 on Th0 and Th2 clones and the levels of sCD30 in their culture supernatants. The results indicate that NAC and GSH might favour a Th1 response by down-regulating Th2 type cytokines. The decrease in CD30 surface expression after NAC/GSH treatment might suggest that CD30 expression is dependent on IL4, or that CD30 is modified directly by NAC. If CD30 and its soluble counterpart are shown to contribute to the pathogenesis of Th2 related diseases like allergy, novel therapies that inhibit CD30 expression, or molecules that are involved in CD30 signal transduction could help treat these diseases.