645 - Anakinra (IL1 Receptor Antagonist) and Immune Dysfunction in Infants with Neonatal Encephalopathy

Neonatal encephalopathy (NE) is a clinical condition describing abnormal neonatal neurological function and incorporating multiple diverse aetiologies. Despite routine use of therapeutic hypothermia (TH), there is a significant burden of mortality and morbidity, especially in low- and middle-income countries. Therefore, there is an urgent need for the development of both stand-alone therapies and adjunctive treatments for TH. The pathophysiology of NE is based on immune dysregulation and inflammasome and interleukin 1 activation have been implicated. Anakinra (interleukin-1 receptor antagonist) is a short acting recombinant interleukin receptor antagonist, blocking both IL-1α and IL-1β activity, and has been safely used in neonates.

Objective:

To assess the impact of anakinra (IL1RA) on ex-vivo immune function of infants with NE as a potential therapeutic agent.

Design/Methods:

We performed a prospective multicentre cohort study. Term infants with a diagnosis of NE undergoing TH were recruited. Blood samples were taken on days 1, 3, and 7 of life and compared with healthy neonatal controls. Innate immune function was analyzed by flow cytometry for CD11b (cell activation, migration) and Toll-like receptor (TLR)-4 (recognition of lipopolysaccharide, LPS) in neutrophils (CD66b+) and subpopulations of monocytes (CD14/CD16) stimulated with and without LPS, treated with and without ILRA. Samples were assessed by reverse transcription–polymerase chain reaction for markers of inflammasome activation (NLRP3), downstream signaling of TLR4 (MyD88), and proinflammatory cytokines (IL1β).

Results:

Thirty-eight infants were recruited (NE =28; controls =10; total samples =60). In the NE group, 82% were Sarnat grade 2 encephalopathy and 36% had an abnormal MRI.

There were no differences in innate immune function when assessed by CD11b or TLR4 after treatment with anakinra. Neutrophil CD11b, although initially suppressed, increased to baseline by day 7, indicating dysregulated immune responses. Neutrophil TLR4 was increased at all time points in infants with NE compared to control. PCR analysis showed a significant increase in IL1β in infants with NE, both at baseline and after stimulation, which was not decreased by ILRA.

Conclusion(s):

Ex-vivo treatment with anakinra does not alter immune function in infants with neonatal encephalopathy, and may not be a useful adjunctive therapy to TH.