News Release
Histio UK Grant Award November 2024
The 2024 Grant has been made to Dr Claire Shannon-Lowe, The University of Birmingham.
For her research into: Understanding the role of Myeloid derived suppressor cells in the
pathogenesis of Epstein Barr virus-associated Haemophagocytic lymphohistiocytosis.

The aims of the research:
Epstein Barr virus (EBV) usually establishes a harmless lifelong infection in up to 90% of the
human population. However, on occasion, EBV infection can cause secondary (non-genetic)
HLH.

Secondary HLH can be caused by infections, malignancies, metabolic disease and
immunopathologies. EBVHLH accounts for nearly 70% of all infection-associated HLH and up
to 40% of all HLH without malignancy. The clinical outcomes of EBV-HLH are significantly worse
than for non-EBV-HLH, yet our understanding of how EBV causes HLH remains poor. A greater
understanding of the disease is required to identify more effective treatment.

We have shown EBV-HLH is most frequently associated with EBV infection of T-cells and natural
killer cells, and with large expansions of myeloid-derived suppressor cells (MDSCs) that inhibit
our antiviral immunity, allowing the uninhibited growth of infected cells. We have also shown
the production of MDSCs is driven by ‘factors’ released by the EBV-infected cells, but we don’t
understand what they are or how they work.

We therefore aim to:
1. Identify factors released from EBV-infected T/NK cells that trigger the production of
MDSCs.
2. Understand the unique markers expressed by MDSCs.
3. Determine how MDSCs inhibit our cellular immunity to EBV.

Describing the describe the relevance of this project and how it fits with Histio UK research
goals and objectives.

This project intimately aligns with the objectives of Histiocytosis UK; (i) scientific research into
the pathology of histiocytocytic diseases, and (ii) development of more accurate means of
diagnosis.

EBV-associated HLH is diagnosed using the HLH diagnostic criteria together with high blood
EBVDNA loads. However, this does not differentiate between HLH driven by EBV-associated B
cell malignancies or HLH driven by EBV infection of T-cells and natural killer (NK) cells. This
differentiation is critical because B-cell malignancies are managed completely differently to
T/NK cell infections, and diagnostic delays frequently result in poor clinical outcomes.

We have developed an assay that aids diagnosis of EBV-HLH by identifying and enumerating the
EBV-infected lymphocyte subset in patient blood, enabling rapid and appropriate treatment.
Importantly, this assay has revealed significant insights into the pathogenesis of EBV-HLH.

We have demonstrated the EBV-infected T/NK cells drive the hypercytokinemia observed in patients
and drive the production of myeloid-derived suppressor cells that create an immune
suppressive microenvironment and inhibit antiviral T-cells.

Furthermore, we have shown
HLH2004 therapy clears overt HLH symptoms but actually exacerbates the underlying disease
in T/NK-cell infections by further inhibiting the antiviral T-cells, resulting in uncontrolled
outgrowth of infected T/NK cells and frequent relapse.