Research - Prognostic Biomarkers

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 CD8+ TEMRA cells accumulates in the fracture hematoma and are locally the major of pro-inflammatory cytokines. The healing process of long bone fracture is usually divided into different phases. Beginning with a pro-inflammatory response and an initial hematoma formation, subsequently new blood vessels grow into the fracture area and fibrocartilaginous callus followed by a bony callus will be formed. During this final remodeling phase, the original bone structure will be restored. The pro-inflammatory CD8+ TEMRA cells are thought to inhibit this process. These cells were recruited from the peripheral blood into the hematoma and are locally the major producer of interferon-γ and tumor necrosis factor–α (orange dots), which inhibit the differentiation of MSCs (green) and induce their apoptosis (dark purple).

The process of endogenous bone fracture repair restores prefractured properties and functions under optimal conditions. However, under certain constraints such as severe trauma, enhanced age, steroid therapy, or diabetes, this process can be delayed and may even result in incomplete healing and poor long-term outcome. About 5 to 15% of patients suffer from such complications after a fracture. These patients require additional surgery, which is associated with prolonged hospitalization and rehabilitation time and results in a high socioeconomic impact.

Currently, no reliable methods exist to prospectively identify patients at risk of impaired fracture healing. This may be a result of the wide interindividual variability in the degree of the injury, the associated soft tissue trauma, the patient’s compliance, the differences in anatomical reconstruction, and the inflammatory response at the onset of healing.

In addition to mesenchymal cells, immune cells are crucial for the endogenous regeneration of mesenchymal tissues even in the absence of infection. We previously found a relation between individual’s immune reactivity, the function of bone precursor cells (Mesenchymal Stromal Cells, MSCs) and disturbed fracture healing in humans. Our study revealed that compromised fracture healing is significantly correlated with enhanced levels of circulating terminally differentiated CD8+ effector memory T (TEMRA) cells. These cells were enriched in the hematoma and are major producers of TNF-α and IFN-γ, which inhibit osteogenic differentiation and survival of human MSCs (Fig.). To further investigate a causal relation between the enrichment of TEMRA cells, compromised MSC function, and the pathogenesis of poor bone fracture healing, we specifically depleted CD8+ T-cells in vivo by an antibody therapy. This treatment resulted in an enhanced endogenous fracture repair, whereas a transfer of CD8+ T-cells impaired the healing process. Our current data are the foundation of two ongoing studies (i) prospective validation of the biomarker CD8+ TEMRA cells in a large clinical (multi-center) trial, and (ii) the pharmacologically blocking the circulating CD8+ TEMRA cells or their cytokines to enhance fracture healing.

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Dr. rer. medic. Simon Reinke

Wissenschaftlicher Mitarbeiter

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