GATOT SOEGIARTO, 090710149 (2013) Mekanisme Diferensiasi Limfosit T CD4+ Pada Sensitisasi dan Paparan Alergen Der p1 Dosis Berbeda Melalui Perubahan Ekspresi Heat Shock Protein 70 dan Ligand Notch Oleh Sel Dendritik. Disertasi thesis, Universitas Airlangga.

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Abstract

Objective: To elucidate the mechanisms of differential CD4+ T lymphocyte response after stimulation (sensitization and exposure) to differential (high vs. low) doses of allergen, we stimulate (sensitize and expose) groups of male Balb/c mice with high or low doses of Der p1 allergen. Methods: The mice were randomly allocated to 9 different groups of intervention, i.e. sham, or low dose (10 g), or high dose (1000 g) intraperitoneal Der p1 allergen sensitization, and subsequent 7 days of sham, or low dose (15 g), or high dose (1500 g) Der p1 allergen inhalation. Levels of Hsp70 expression, IL-12 secretion, Notch ligands (Jagged1/Jagged2 and Delta1/Delta4) expression by lung dendritic cells, Notch receptors (Notch1, Notch2, Notch3), and transcription factors (GATA-3, T-bet) expression by mediastinal lymph nodes CD4+ T lymphocytes, cytokines secretion in bronchoalveolar lavage fluid (IL-12, IL-4, IFN- ) and in serum (IL-4, IFN- ) were measured and analyzed. Results: Low dose Der p1 allergen stimulation (sensitization and exposure) caused low level of Hsp70 expression, low level of IL-12 secretion, and low levels of Notch ligands (Jagged1/Jagged2 and Delta1/Delta4) expression by lung dendritic cells, which in turn induce GATA-3 transcription factor expression in mediastinal lymph nodes CD4+ T lymphocytes and lead to the secretion of Th2 specific cytokines (IL-4). On the contrary, high dose Der p1 allergen stimulation (sensitization and exposure) caused high level of Hsp70 expression, high level of IL-12 secretion, and high level of Notch ligands (Jagged1/Jagged2 and Delta1/Delta4) expression by lung dendritic cells, which in turn induce T-bet transcription factor expression in mediastinal lymph nodes CD4+ T lymphocytes and lead to the secretion of Th1 specific cytokines (IFN- ). Allergen sensitization doses turn out to have more significant influence compared to allergen exposure dose. Hsp70 expression play a central role in driving the behavior of lung dendritic cells as an antigen presenting cells in such a way that enable them to change the polarization of CD4 T lymphocyte from Th2 to Th1 type of immune response. Conclusion: The mechanisms of CD4+ T lymphocytes differentiation after different doses of Der p1 allergen stimulation (sensitization and exposure) occured through changes in levels of: Hsp70 expression, IL-12 secretion, Notch ligands (Jagged1/Jagged2 and Delta1/Delta4) expression by lung dendritic cells, which in turn induce differential expression of transcription factors (GATA-3 or T-bet) in mediastinal lymph nodes CD4+ T lymphocytes, and lead to differential cytokines synthesis and secretion of Th2 (IL- 4) or Th1 (IFN- ) specific cytokines.

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