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Abstract: PO2042

Elevation of Serum IL-8 in Patients with Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Kasinath, Vivek, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Yilmaz, Fazilet, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Aksu, Hamza, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Walt, David R., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Abdi, Reza, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for several different hematopoietic malignancies and disorders. However, HSCT-associated thrombotic microangiopathy (TA-TMA) represents a major obstacle to the success of this procedure in transplant recipients, and rapid progression to end-stage renal disease is a major complication of this disorder, affecting nearly 1 in 3 patients. Here, we sought to Identify a serum biomarker for the detection of TA-TMA and investigate its role in the pathogenesis of this severe disease.

Methods

We measured the concentrations of several different cytokines and vasoactive peptides in the sera of 14 adult human HSCT recipients at the time of transplantation and again at 5-6 weeks following HSCT. Levels of IL-1β, IL-6, IL-8, TNF-α, IFN-γ, VEGF-B, HIF1α, and GM-CSF were measured, using the highly sensitive ELISA single molecule array (Simoa) method.

Results

Statistical analysis of the change in each of the cytokines revealed that IL-8 was the sole marker that increased significantly over time in the TMA group. Next, we found that co-culture of irradiated peripheral blood mononuclear cells (PBMCs) with human umbilical vein endothelial cells (HUVECs) resulted in increased IL-8 expression by the PBMCs. Furthermore, in vitro treatment of HUVECs with IL-8 increased platelet adhesion and vWF expression. Treatment of platelets independently with IL-8 also increased their adhesion in vitro to HUVECs. Finally, treatment of HUVECs with IL-8 also induced senescence, and platelets were found to adhere more readily to senescent HUVECs in vitro. Moreover, exposure of these HUVECs to a senolytic agent abrogated the platelet adhesion.

Conclusion

These findings implicate IL-8 as a potentially important thrombogenic and pathogenic factor in TA-TMA. In addition, these data highlight senescence of endothelial cells for the first time as a possible mechanism for the microvascular thromboses observed in TA-TMA patients, suggesting that modulation of IL-8 could be an effective therapeutic pathway for this severe disease.

Funding

  • NIDDK Support