Ebrahimi Rezvan, Asghari Kimia Motlagh, Alamdary Sina Janbaz, Kamrani Amin, Soltani-Zangbar Mohammad Sadegh, Danaii Shahla, Aliasgharzadeh Akbar, Heris Javad Ahmadian, Aghebati-Maleki Leili, Hojjat-Farsangi Mohammad, Yousefi Mehdi
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Hum Immunol. 2025 Mar;86(2):111229. doi: 10.1016/j.humimm.2024.111229. Epub 2025 Jan 10.
Recurrent pregnancy loss (RPL) remains a complex and challenging reproductive issue often associated with immunological abnormalities. This study investigates the immunomodulatory effects of intradermal lymphocyte therapy in RPL patients, exploring cellular, molecular, and cytokine changes, with specific attention to individuals with positive anti-thyroid peroxidase antibodies (Anti-TPO).
The study included 105 patients with RPL, divided into Anti-TPO positive RPL patients (n = 25), Anti-TPO negative RPL patients (n = 38), and RPL patients without lymphocyte immunotherapy (LIT) (n = 42). LIT was administered according to a standardized protocol, and various immune parameters including flow cytometry analysis of Th1/Th2, Th17, Treg, and NK cells, real-time PCR analysis of gene expression levels, and ELISA analysis of cytokine levels were assessed before and after LIT. Clinical outcomes including clinical miscarriage rates, delivery or pregnancy rates, and live birth rates were also evaluated.
Flow cytometry analysis revealed significant decreases in Th1/Th2 and NK cell percentages post-LIT in both Anti-TPO positive and negative RPL patients. Real-time PCR analysis showed significant alterations in gene expression levels of FoxP3, T-bet, GATA3, RORγt, IL-17, TGF-β, IFNγ, and IL-4 post-LIT in both groups. ELISA analysis demonstrated significant changes in levels of IL-17, TGF-β, IFNγ, and IL-4 post-LIT in both groups. Anti-TPO negative RPL patients with LIT had a lower miscarriage rate (10.53 %) compared to Anti-TPO positive RPL patients with LIT (40 %). Also, the pregnancy rate and the live birth rate were higher (89.47 %) in Anti-TPO negative RPL patients with LIT compared to Anti-TPO positive RPL patients with LIT (60 % and 56 % respectively). Moreover, the average pregnancy rate and live birth rate were significantly higher in RPL patients with LIT than in those without LIT (30.95 %).
These findings suggest that while LIT may confer benefits in improving pregnancy outcomes, its efficacy may be influenced by the presence of Anti-TPO Abs. These findings highlight the complex interplay between immune dysregulation and pregnancy outcomes in RPL patients and underscore the need for personalized treatment approaches.
复发性流产（RPL）仍然是一个复杂且具有挑战性的生殖问题，常与免疫异常相关。本研究调查皮内淋巴细胞疗法对RPL患者的免疫调节作用，探索细胞、分子和细胞因子的变化，特别关注抗甲状腺过氧化物酶抗体（Anti-TPO）阳性的个体。
该研究纳入105例RPL患者，分为Anti-TPO阳性RPL患者（n = 25）、Anti-TPO阴性RPL患者（n = 38）和未接受淋巴细胞免疫疗法（LIT）的RPL患者（n = 42）。LIT按照标准化方案进行，在LIT前后评估各种免疫参数，包括Th1/Th2、Th17、调节性T细胞（Treg）和自然杀伤（NK）细胞的流式细胞术分析、基因表达水平的实时聚合酶链反应（PCR）分析以及细胞因子水平的酶联免疫吸附测定（ELISA）分析。还评估了包括临床流产率、分娩或妊娠率以及活产率在内的临床结局。
流式细胞术分析显示，Anti-TPO阳性和阴性RPL患者在LIT后Th1/Th2和NK细胞百分比均显著降低。实时PCR分析表明，两组在LIT后FoxP3、T-bet、GATA3、RORγt、白细胞介素-17（IL-17）、转化生长因子-β（TGF-β）、干扰素-γ（IFNγ）和白细胞介素-4（IL-4）的基因表达水平均有显著变化。ELISA分析显示，两组在LIT后IL-17、TGF-β、IFNγ和IL-4水平均有显著变化。接受LIT的Anti-TPO阴性RPL患者的流产率（10.53%）低于接受LIT的Anti-TPO阳性RPL患者（40%）。此外，接受LIT的Anti-TPO阴性RPL患者的妊娠率和活产率（分别为89.47%）高于接受LIT的Anti-TPO阳性RPL患者（分别为60%和56%）。而且，接受LIT 的RPL患者的平均妊娠率和活产率显著高于未接受LIT的患者（30.95%）。
这些发现表明，虽然LIT可能在改善妊娠结局方面有益，但其疗效可能受Anti-TPO抗体的存在影响。这些发现突出了RPL患者免疫失调与妊娠结局之间复杂的相互作用，并强调了个性化治疗方法的必要性。
