探討間質幹細胞對自體免疫疾病病人之T細胞的免疫調控能力及其機制

Study on the Immunoregulatory Effect of Mesenchymal Stem Cells on T Cells From Patients with Autoimmune Diseases and Its Mechanism

韋登元(Teng-Yuan Wei)

指導教授 ： 莊雅惠

國立臺灣大學/醫學院/醫學檢驗暨生物技術學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201702381

摘要

自體免疫疾病是一種慢性發炎的疾病，且第一型輔助性T細胞與第十七型輔助性T細胞在其致病機轉中扮演不可或缺的角色。間質幹細胞具有免疫抑制的功能，並且被廣泛地研究作為許多自體免疫疾病療法的可能性。在本篇論文中，我們研究分離自新來源的胎盤絨毛膜褪膜間質幹細胞(pcMSC)是否具有抑制自體免疫疾病病人之T細胞功能的能力。我們也進一步探討pcMSC免疫調控能力的機轉，並研究IL-33是否在其中扮演一定的角色。我們發現pcMSC無法抑制小兒自體免疫疾病病人之T細胞。重要的是，pcMSC可以顯著地抑制多發性硬化症與視神經脊髓炎病人之完全活化的T細胞，不過它也意外地對低度活化之T細胞表現免疫促進的效果。我們更進一步證明pcMSC的促進效果不須依靠細胞之間的接觸，且經IFN-前處理後亦無法避免此現象的發生。再者，pcMSC的抑制與促進能力皆與IL-33無關。總結來說，pcMSC具有治療多發性硬化症與視神經脊髓炎的潛能，但其免疫促進的效果必須被審慎評估。

關鍵字

自體免疫疾病 ； 間質幹細胞 ； T細胞 ； 免疫調節 ； IL-33

並列摘要

Autoimmune disease is a type of chronic inflammatory disease, and T helper 1 (Th1) and T helper 17 (Th17) cells play a crucial role in its pathogenesis. Mesenchymal stem cells (MSC) possess immunosuppressive function and are widely studied as a potential cell therapy to many autoimmune diseases. Here, we investigated the therapeutic potential of the newly isolated placenta choriodecidual membrane-derived MSCs (pcMSCs) on T cell function of various autoimmune diseases. We also investigated the mechanisms of the immune-modulatory effects of pcMSCs, and evaluated whether IL-33 plays a role in them. We found that pcMSCs could not inhibit the T cells derived from pediatric autoimmune patients. Of note, pcMSCs significantly suppressed high-reactive T cells from adult multiple sclerosis (MS) and neuromyelitis optica (NMO) patients, although they displayed an unexpected enhancing effect on low-reactive T cells. We further demonstrated that the enhancing effect of pcMSCs is not dependent of cell-cell contact, and may not be prevented by IFN- pretreatment. Also, the suppressive and promoting function of pcMSCs were not mediated by IL-33. In conclusion, pcMSCs may have the potential to remedy MS and NMO, but their immune-enhancing effect should be carefully considered beforehand.

並列關鍵字

autoimmune disease ； mesenchymal stem cells (MSCs) ； T cells ； immunomodulation ； IL-33

參考文獻

1. Ermann, J. and C.G. Fathman, Autoimmune diseases: genes, bugs and failed regulation. Nat Immunol, 2001. 2(9): p. 759-61.

2. Wahren-Herlenius, M. and T. Dorner, Immunopathogenic mechanisms of systemic autoimmune disease. Lancet, 2013. 382(9894): p. 819-31.

3. Yang, J., et al., Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum, 2009. 60(5): p. 1472-83.

4. Shivakumar, S., G.C. Tsokos, and S.K. Datta, T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis. J Immunol, 1989. 143(1): p. 103-12.

5. Crispin, J.C., et al., Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J Immunol, 2008. 181(12): p. 8761-6.