全身性紅斑狼瘡之可能療法—
藉由抑制p110δ訊息傳遞分子干擾B-1細胞之功能

系統性紅斑狼瘡(systemic lupus erythematosus)是多因性的自體免疫疾病，致病因子間的交互作用複雜且並不明確。不同的免疫細胞與分子在疾病發展過程中，扮演了多樣且分歧的角色。在之前的研究中研究者發現，將B-1細胞以低滲透壓環境或移除10型介白質(IL-10)的方式，從系統性紅斑狼瘡的模式小鼠身上移除後，疾病將會得到緩解，換言之，移除B-1細胞是有潛力的治療概念。然而，臨床上於病患腹腔產生低張環境或移除10型介白質都將導致大規模的周邊組織破壞與副作用，因此，移除B-1細胞的概念需要更有應用價值的方式。另一系列的研究發現，在磷酸肌醇-3-激酶(phosphoinositide 3 kinase, PI3K)的催化性次單元中，p110δ具有在免疫細胞中表現的專一性。從胚胎基因體中剔除(knock out) p110δ或是置入p110δ的顯性功能缺陷變異體(dominant negative)，都將阻礙B細胞的發育，其中，B-1細胞幾近完全消失。由此可以推想p110δ與B-1細胞的存在有重要的關聯。因此，我們將透過基因特異性的方法，抑制p110δ的表現，試圖移除B-1細胞，進一步治療系統性紅斑狼瘡。首先，我們發現在成體中，抑制磷酸肌醇-3-激酶的功能仍能顯著降低B-1細胞的數量。接著，我們以兩種反轉錄病毒攜帶我們設計的小干擾型核醣核酸(siRNAs)，發現它們能顯著抑制p110δ的表現。之後，我們將抑制磷酸肌醇-3-激酶的抑制劑與由病毒攜帶的小干擾型核醣核酸，投入系統性紅斑狼瘡的模式小鼠進行活體治療。目前，我們發現抑制劑LY294002與低量給予的小干擾型核醣核酸，會對抗雙股去氧核醣核酸的自體抗體(anti-dsDNA auto-antibody)的發生，產生顯著的抑制作用或抑制趨勢。由於自體抗體的產生是系統性紅斑狼瘡的重要病理指標，因此，針對磷酸肌醇-3-激酶或更精確地針對p110δ的基因特異性調控將有潛力成為系統性紅斑狼瘡的應用療法。此外，證明磷酸肌醇-3-激酶與B-1細胞族群的維持相關也提供嶄新的研究方向，嘗試治療其他與B-1細胞相關的疾病。

關鍵字

系統性紅斑狼瘡； B-1細胞；磷酸肌醇-3-激酶小干擾型核醣核酸

並列摘要

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.

並列關鍵字

Systemic Lupus Erythematosus ； SLE ； B-1 cell ； phosphoinositide 3 kinase ； PI3Ks ； RNAi ； NZB/W F1 ； lentivirus

參考文獻

1. Huggins, J.L. and H.I. Brunner, Targeting B cells in the treatment of childhood-onset systemic lupus erythematosus. J Pediatr, 2006. 148(5): p. 571-3.

2. Rahman, A. and D.A. Isenberg, Systemic lupus erythematosus. N Engl J Med, 2008. 358(9): p. 929-39.

3. Johnson, A.E., et al., The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum, 1995. 38(4): p. 551-8.

4. Buyon, J.P., et al., The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med, 2005. 142(12 Pt 1): p. 953-62.

5. Inui, A., et al., Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Clin Rheumatol, 2007. 26(10): p. 1675-8.

國際替代計量

全身性紅斑狼瘡之可能療法— 藉由抑制p110δ訊息傳遞分子干擾B-1細胞之功能

全文下載

主題瀏覽