# Season-dependent low basal CD86 expression promotes immune cell activation upon treatment with plasma-derived factor Ⅷ products

## TL;DR

This study found that immune cell activation in response to factor VIII treatment depends on the season due to changes in CD86 expression.

## Contribution

The study identifies season-dependent CD86 expression as a novel determinant of immune cell activation in hemophilia A treatment.

## Key findings

- Immune activation by plasma-derived FⅧ plus LPS was time point-dependent, not donor or product-specific.
- Low basal CD86 expression on dendritic cells correlates with immune activation and cytokine secretion.
- Seasonal variations in CD86 expression influence the probability of immune cell activation.

## Abstract

The most serious complication in treatment of hemophilia A is the development of factor (F)Ⅷ anti-drug antibodies (ADAs), while immunological danger signals seem to play a critical role in ADA development. Accordingly, we have shown in previous studies that plasma-derived (pd) FⅧ in presence of the bacterial danger signal lipopolysaccharide (LPS) synergistically activates dendritic cells (DCs), which in turn induce proliferation of (FⅧ-specific) CD4+ T helper cells. However, our in vitro assays using DC and T cells from healthy donors revealed that only cells from some donations can be synergistically activated upon treatment with pdFⅧ plus LPS, while cells from others cannot.

Therefore, we investigated a data pool of 160 donations for DC activation and 265 donations for T-cell proliferation from healthy donors collected by 3 different experimenters between 2012 and 2023 to determine parameters that correlate with pdFⅧ plus LPS-induced immune cell activation.

Human immune cells from healthy donors are synergistically activated by pdFⅧ plus LPS. However, neither DC activation nor T-cell proliferation depended on a specific pdFⅧ product, did not correlate with the donor’s biological sex, and was not donor- but rather time point-dependent. Analyses of different activation markers revealed seasonal differences in CD86 expression, and low expression correlated with DC activation and tumor necrosis factor-α expression.

In fact, we could demonstrate that the meteorological season correlates with the basal CD86 expression on DC. This, in turn, determined the capability of synergistic DC activation and cytokine secretion, as well as partially impacted T-cell proliferation.

•Some patients with hemophilia A develop inhibitors reducing effectiveness of infused FⅧ products.•Up to 265 donations from healthy volunteers were analyzed to define parameters correlating with immune cell activation.•Immune activation was independent from product, sex, or donor but rather time point-dependent.•Season-dependent CD86 basal expression on DC determines the probability of immune activation.

Some patients with hemophilia A develop inhibitors reducing effectiveness of infused FⅧ products.

Up to 265 donations from healthy volunteers were analyzed to define parameters correlating with immune cell activation.

Immune activation was independent from product, sex, or donor but rather time point-dependent.

Season-dependent CD86 basal expression on DC determines the probability of immune activation.