CD28 Monoclonal Antibody Improve Sepsis Mortality by Amending Th17/Treg Balance

Abstract

Background: Sepsis is still developing exorbitantly high mortality. In response to microbial molecules, T cell activation plays a crucial role in sepsis’s initial innate immune reactions. The imbalance between CD4+IL-17+ T helper cells (Th17) and CD4+CD25+ regulatory T cells (Treg) participates in sepsis progression. CD28 signaling pathway was essential for the expression of inflammatory cytokines related to Th17, and play a crucial role in the maintenance of Treg. We investigated the correlations of the balance between Th17 and Treg to prognosis in sepsis patients and influence of anti-CD28 antibody on the ratio of Th17 to Treg in sepsis mice.Methods: 60 sepsis patients' baseline conditions were recorded, and the expressions of inflammatory factors in the peripheral blood and levels of procalcitonin (PCT) were detected. Peripheral blood mononuclear cells (PBMCs) were separated, subtypes of T cells and related biomarkers were measured by Fluorescence-activated cell sorting (FACS). Furthermore, the relationship between the above indicators and patients’ condition scoring (APACHEⅡand SOFA) and ICU hospitalization time were analyzed. To investigate effects of CD28 on the balance of Th17 between Treg, anti-CD28 antibody was intraperitoneal administrated to cecal ligation and puncture (CLP) mice. Results: Compared with septic patients who stay in ICU more than 14 days, the Th17/Treg ratio of patients with ICU hospitalization of fewer than 14 days was significantly lower. The sepsis patients with higher expression of CD28 in peripheral blood lymphocytes have lower APACHE II and SOFA scores. Moreover, the expression of CD28 was significantly higher in sepsis patients than that of healthy donors. After administration of CD28 monoclonal antibody, 7-day mortality and clinical score were significantly improved in septic mice, with splenocyte Th17/Treg ratio decreased. CD28 antibody alleviates the expression of pro-inflammatory factors and spleen injury related to apoptosis. Conclusions: Th17/Treg ratio revealed septic patient severity and can be used as a predictor of ICU stay. CD28 monoclonal antibody could improve 7-day mortality of septic mice by decreasing T cell apoptosis and amending the ratio of Th17/Treg.Trial registration: CHEC2019-133, CTR20191855. Registered 27 August 2019