Background/Purpose:

Type 1/type 2 T helper (Th1/Th2) cells and their cytokines are implicated in the pathogenesis of autoimmune diseases^[1]; however, their roles in antiphospholipid antibody-associated recurrent pregnancy loss (APA-RPL) remain unclear^[2,3]. Low molecular weight heparin (LMWH) and aspirin combination therapy is a first-line treatment for APA-RPL, but its mechanism remains unclear^[4]. This study aimed to investigate the effect of combination therapy with LMWH and aspirin on Th1/Th2 cells and their cytokines in pregnant patients with APA-RPL.

Methods:

Pregnant patients with a history of APA-RPL (n=89) were enrolled in this study.After confirming a positive pregnancy test result, the patients were treated with LMWH and aspirin combination until 35–37 weeks of pregnancy or up to the time of miscarrige.Blood was drawn before starting and after stopping treatment. The therapeutic outcome was evaluated by using live-birth as an efficacy measurement.31 age matched healthy pregnant women who delivered in our hospital were used as a control group. ELISA was conducted to detect serum levels of the Th1 cytokines interleukin (IL)-2 and tumor necrosis factor alpha (TNF-α) and the Th2 cytokines IL-4 and IL-10. The percentages of CD4⁺-interferon gamma (INF-γ)+ and CD4⁺-IL-4+ cells among the CD4⁺ T cells in peripheral blood were assessed by flow cytometry, and the expression of T-bet and GATA 3 was determined by quantitative real-time PCR.

Results:

Of the 89 patients receiving LMWH-aspirin combination therapy, 72(80.9%) had a live birth and the remaining 17 had miscarriages. At 5-7 weeks of gestation in patients with APA-RPL, serum IL-2 (P=0.006) and TNF-α P<0.001) levels were significantly higher, while serum IL-4 (P=0.037) and IL-10 (P<0.001) levels were significantly lower compared to healthy pregnant control women( Figure 1).Similarly, the CD4⁺-INF-γ+-labeled Th1 cell subset was also significantly increased (P<0.001), while the CD4⁺-IL-4+-labeled Th2 cell subset was significantly reduced (P<0.001) in patients with APA-RPL( Figure 2). Furthermore, gene expression of T-bet was significantly elevated (P=0.003),while GATA3 mRNA expression was significantly reduced in patients with APA-RPL (P=0.002) ( Figure 3).This Th1-biased pattern was reversed in patients who had live birth while receiving the combination therapy. Patients with miscarriages continued to exhibit Th1-bias.

Conclusion:

Th1/Th2 cell frequencies and the protein and gene expression levels of their cytokines are perturbed in patients with APA-RPL, suggesting a possible role of Th1/Th2 imbalance in the pathogenesis of APA- RPL. Importantly, LMWH and aspirin combination therapy effectively reverse Th1 cell polarization for APA-RPL patients attaining live births, providing a new understanding of potential immunomodulatory mechanism of LMWH and aspirin combination therapy on APA-RPL.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-molecular-weight-heparin-and-aspirin-combination-therapy-modulates-th1-th2-cell-imbalance-in-pregnant-patients-with-antip/