| Summary: | 碩士 === 國立臺灣大學 === 免疫學研究所 === 96 === Systemic lupus erythematosus is an autoimmune disease caused by multiple but elusive pathogenic factors. Different immune components play diverse roles in varied stages and aspects. Previous studies upon SLE-prone murine models demonstrated that the removal of B-1 cells by either hypotonic shock or IL-10 deprivation was beneficial to relieve the disease flare. However, these experimental approaches possess ominous potentials to cause immense damages and side-effects and thus are not considerable for further clinical indications. Knock-out or dominant-negative model against p110δ, a leukocyte-specific catalytic subunit of PI3Ks, are proved to be able to abrogate the maturation of B cell lineages, especially the marginal zone B cell and B-1 cell populations. Thus, we look for a more specific approach to remove B-1 cells through targeting p110δ. At first, we proved that PI3Ks are not only important for the development of B-1 cells but still essential for the maintenance of their population after birth. We then designed shRNAs carried by either retroviral or lentiviral systems and validated that several among them can sufficiently knock down the expression of p110δ. We introduced either pan-specific inhibitors against all PI3Ks or p110δ-targeting shRNAs into an SLE-prone animal model, NZB/W F1 mice, for therapeutic purposes. We found salutary effects in our preliminary data. One inhibitor, LY294002, significantly delayed the accumulation of anti-dsDNA IgG auto-antibody. shRNAs delivered by low dose of lentivirus exhibited certain potential to retard the rising of anti-dsDNA IgG auto-antibody, too. Our findings are not only promising for developing treatments against SLE. Knowing that PI3Ks are critical for the maintenance of B-1 cell populations also shed light on dealing with other diseases associated with B-1 cells, such as certain melanoma, lymphoma, or leukemia.
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