Study the Immune Modulatory Mechanisms of Anti-CD4 Moab-Induced Regulatory T Cells in Asthma Animal Model

Bronchial asthma is a chronic inflammatory disorder of the airways with high serum allergen specific IgE and eosinophil infiltration in lung. Despite intensive effort designed to develop pharmacological agents to block inflammatory mediators, the treatment suffers from a number of limitations and serious side effects. Although it has been well established that cytokines produced by Th2 type cells are responsible for asthmatic pathology; the chronic inflammation evident in asthma might arise as a consequence of a defect in immune regulation. Recently, the importance of the regulatory T (Treg) cells in immune responses has been observed in a number of experimental models. Due to the heterogeneous phenotypes, the mechanisms for the generation of Treg cells are still poorly understood. With the use of non-depleting anti-CD4 monoclonal antibody (MoAb), YTS177, we are currently studying whether this MoAb is able to generate regulatory T cells and whether it will suppress the allergic inflammation in chicken ovalbumin (OVA)-immunized asthmatic mice model. The preliminary results indicate that the injection of YTS177 into mice before OVA-sensitization is capable to suppress allergic lung inflammation, eosinophil infiltration and cytokine production from OVA-activated splenocytes. In addition, CD4+CD25+ from YTS177-treated mice inhibited the OVA-activated proliferation of CD4+CD25- T cells isolated from sensitized mice. Thus, we would like to explore the cellular and molecular mechanisms of how YTS177 induces Treg cells and the suppressive function in our asthmatic animal model. We will first test whether the YTS177 enhance the proliferation of pre-existing CD4+CD25+ Treg cells or to convert the CD4+CD25- T cells to have regulatory function. It is also important to examine whether YTS177-induced Treg cells relieve the hyper-responsiveness by the inhibition the function of allergen-activated Th2 cells and the function of Th2-related transcription factors. Since TGF-芻and IL-10 are two important cytokines for Treg function, we would like to test whether the anti-TGF-芻or anti-IL-10 antibodies could block the Treg function. Whether YTS177-induced Treg cells from IL-10 or TGF-芻knockout mice still possess suppressive function may provide some clues for the regulatory mechanisms. We will examine whether the expression of some Th2 regulatory molecules, such as SOCS3 or TSLP, is enhanced with YTS177 or Treg cells. Finally, we will also like to test whether tissue specific expression of small interfering RNAs (siRNAs) that target IL-10 or TGF-芻genes will block the suppressive function of YTS177-induced Treg cells. The results obtained in this study will offer a better understanding of the role and functional mechanisms of regulatory T cells in allergic diseases. Some novel vaccine or therapeutic approaches might be developed based on the information obtained from this study.

Project ID:PC9706-0156
External Project ID:NSC95-2320-B182-043-MY3