Poster Presentation Lorne Infection and Immunity 2022

Novel immunotherapeutic strategies for bronchopulmonary dysplasia (#204)

Ina Rudloff 1 2 , Jason C Lao 1 2 , Christine B Bui 1 2 , Merrin A Pang 1 2 , Steven X Cho 1 2 , Kirstin D Elgass 3 , Jan Schröder 4 5 6 , Anton Maksimenko 7 , Niamh E Mangan 8 9 , Malcolm R Starkey 10 11 , Elisabeth M Skuza 1 2 , Yu BY Sun 5 6 , Friederike Beker 12 13 , Clare L Collins 13 , Omar F Kamlin 14 15 16 , Kai König 17 , Atul Malhotra 1 2 18 , Kenneth Tan 2 18 , Christiane Theda 14 15 16 , Morag J Young 19 20 , Catriona A McLean 21 22 , Arvind Sehgal 2 18 , Philip M Hansbro 10 23 , James T Pearson 24 25 , Jose M Polo 4 5 6 , Alex Veldman 1 2 26 , Philip J Berger 1 2 , Claudia A Nold-Petry 1 2 , Marcel F Nold 1 2 18
  1. Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Paediatrics, Monash University, Melbourne, VIC, Australia
  3. Monash Micro Imaging, Monash University, Melbourne, VIC, Australia
  4. Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
  5. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Melbourne, VIC, Australia
  6. Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
  7. Imaging and Medical Beamline, Australian Synchrotron, Melbourne, VIC, Australia
  8. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  9. Department of Molecular and Translational Sciences, Monash University, Melbourne, VIC, Australia
  10. Priority Research Centres for Healthy Lungs & GrowUpWell, Hunter Medical Research Institute & University of Newcastle, Newcastle, NSW, Australia
  11. Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia
  12. Mater Research Institute, University of Queensland, Brisbane, QLD, Australia
  13. Neonatal Services, Mercy Hospital for Women, Melbourne, VIC, Australia
  14. Department of Newborn Research, Royal Women's Hospital, Melbourne, VIC, Australia
  15. University of Melbourne, Melbourne, VIC, Australia
  16. Murdoch Children's Research Institute, Melbourne, VIC, Australia
  17. Medicum Wesemlin, Department of Paediatrics, Lucerne, Switzerland
  18. Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia
  19. Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Melbourne, VIC, Australia
  20. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
  21. Department of Anatomical Pathology, Alfred Health, Melbourne, VIC, Australia
  22. Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia
  23. Centre for Inflammation, Centenary Institute & University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, Ultimo, NSW, Australia
  24. Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
  25. Cardiovascular Disease Program, Monash Biomedicine Discovery Institute & Department of Physiology, Monash University, Melbourne, VIC, Australia
  26. Department of Pediatrics, Dr. Horst Schmidt Hospital, Wiesbaden, Germany

The postnatal maturation of the immune system is poorly understood; as is its impact on illnesses afflicting preterm infants, such as bronchopulmonary dysplasia (BPD), a chronic lung disease. BPD affects up to 65% of very preterm infants and is characterized by inflammation and arrested development of alveoli and pulmonary blood vessels, leading to compromised lung function. The dysangiogenesis causes marked reduction in cross-sectional area, abnormal pulmonary vascular tone and elevated pressure in the pulmonary vasculature, resulting in pulmonary hypertension secondary to BPD (BPD-PH). BPD-PH occurs in up to 39% of severe BPD cases and represents its most significant complication. If not halted, BPD-PH can progress to right heart failure and up to 50% mortality. Currently, safe and effective treatments for BPD/BPD-PH are not available.

Investigating 51 preterm infants (blood obtained longitudinally at birth, day 1, weeks 1&2, and 36 weeks gestational age), 20 healthy term infants (birth, 3-16 weeks) and 5 healthy adults, we observed strong associations between type 2-polarization in circulating CD4+T cells and BPD (odds ratio up to 24). Unexpectedly, maternal magnesium sulfate therapy and delayed hepatitis B vaccination were associated with weaker type 2-polarization (e.g., up to 91% fewer type 2-polarized cells with hepatitis B-vaccination on d4-6 versus soon after birth), potentially conferring protection against BPD/BPD-PH. In a murine model of neonatal BPD/BPD-PH, blocking the type 2-mediators STAT6 or IL-4, IL-5 and/or IL-13 ameliorated lung inflammation and protected alveolar and vascular integrity: BPD-triggered increases in IL-1β and IL-13, and losses of pulmonary capillaries were prevented.

Our work advances knowledge on developmental immunology and its impact on early life diseases such as BPD. We identify maternal magnesium sulfate therapy, delayed hepatitis B vaccination and inhibition of type 2 mediators as promising therapeutic avenues that may lead to effective treatments for BPD/BPD-PH, relieving inflammation-driven suffering in our youngest patients.