Interventional Immunology in Early Life Diseases
Research Group Heads
The Nold Laboratory follows the innovation value chain from basic science to product development; with our main focus in harnessing our expertise in immunology to explore the molecular mechanisms of several poorly understood and currently largely untreatable diseases that affect our tiniest patients, namely babies born prematurely. These diseases include bronchopulmonary dysplasia (BPD) that severely compromises lung function and entails pulmonary arterial hypertension (PAH), which in turn often causes right heart failure; intracranial haemorrhage (ICH) whose survivors commonly require extensive special education; and necrotising enterocolitis (NEC), a disease of the intestine that carries up to 70 per cent mortality (see review #8). Our aim is rapid translation of our findings into clinical medicine, as best exemplified by a planned clinical trial that is based on one of our discoveries (see paper #1 & 2 below) and that may establish the first safe and effective treatment for BPD.
Our laboratory’s second major focus lies on the new interleukin (IL-)1 family cytokines IL-37 and IL 38. Our revelation of the powerful anti-inflammatory properties of IL-37 (see paper #3 below), its signalling mechanisms, cell surface receptor (see paper #4 below) and discovery that homodimerization limits the anti-inflammatory effect of IL-37 (see paper # 5 below) has led to a surge of international interest in these previously largely obscure cytokines and revealed IL-37’s translational potential. Examples of our current work include exploration of the therapeutic potential of IL-37 in NEC (see paper #6 below), and the characterisation of IL-38 in health and disease, including in systemic lupus erythematosus (SLE) (see paper #7 below), an incurable autoimmune disease that affects women during their childbearing age and their unborn children.
- Exploring a new frontier: The immune and coagulation systems of the premature infant and their relevance for the risk of the major diseases of prematurity.
Direct clinical relevance: high. Hands-on learning opportunities: Multi-color flow cytometry, protein arrays, cell culture of primary human blood cells.
- Molecular tracking of the cytokine IL-37 in anti-inflammatory signalling.
Direct clinical relevance: medium/low. Hands-on learning opportunities: Confocal microscopy, molecular engineering (cloning), cell culture of primary human blood cells and cell lines.
- Novel anti-inflammatory approaches for currently untreatable diseases of the preterm baby: IL-1Ra and IL-37 in animal models of bronchopulmonary dysplasia and necrotising enterocolitis.
Direct clinical relevance: high. Hands-on learning opportunities: Various aspects of work with mice, workup of tissues for various downstream applications, flow cytometry, histology, immunohistochemistry, protein detection by ELISA, synchrotron X-ray imaging.
- Molecular characterisation of regulation and mechanism of action of the anti-inflammatory cytokine interleukin 37.
Direct clinical relevance: medium/low. Hands-on learning opportunities: Culture of primary human blood cells and cell lines, protein detection by ELISA, RNA detection by real-time PCR, flow cytometry, immunohistochemistry.
- The first in vivo exploration of IL-38.
Direct clinical relevance: medium/low. Hands-on learning opportunities: Various aspects of work with mice, workup of tissues for various downstream applications, flow cytometry, histology, immunohistochemistry, protein detection by ELISA, RNA detection by real-time PCR.
Our research focus
1 | Nold MF, Mangan NE, Rudloff I, Cho SX, Shariatian N, Samarasinghe TD, Skuza EM, Veldman A, Berger PJ, Nold-Petry, CA (2013) Interleukin 1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia. Proc Natl Acad Sci USA 110(35):14384-89.
2 | Rudloff I, Cho SX, Bui CB, McLean C, Veldman A, Berger PJ, Nold MF, Nold-Petry CA (2017). Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia. J Cell Mol Med. 2017 Jun;21(6):1128-1138. doi: 10.1111/jcmm.13044. Epub 2016 Dec 13. PMID: 27957795; PMCID: PMC5431131.
3 | Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11(11):1014-22.
4 | Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC, Ellisdon AM, Rotter B, Azam T, Mangan NE, Rossello FJ, Whisstock JC, Bufler P, Garlanda C, Mantovani A, Dinarello CA, Nold MF (2015) IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 16(4):354-65.
5 | Ellisdon AM, Nold-Petry CA, D’Andrea L, Cho SX, Lao JC, Rudloff I, Ngo D, Lo CY, Soares da Costa TP, Perugini MA, Conroy PJ, Whisstock JC, Nold MF (2017). Homodimerization attenuates the anti-inflammatory activity of interleukin-37. Sci Immunol. 2017 Feb 10;2(8):eaaj1548. doi: 10.1126/sciimmunol.aaj1548. PMID: 28783685.
6 | Cho SX, Rudloff I, Lao JC, Pang MA, Goldberg R, Bui CB, McLean CA, Stock M, Klassert TE, Slevogt H, Mangan NE, Cheng W, Fischer D, Gfroerer S, Sandhu MK, Ngo D, Bujotzek A, Lariviere L, Schumacher F, Tiefenthaler G, Beker F, Collins C, Kamlin COF, König K, Malhotra A, Tan K, Theda C, Veldman A, Ellisdon AM, Whisstock JC, Berger PJ, Nold-Petry CA, Nold MF (2020). Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities. Nat Commun. 2020 Nov 13;11(1):5794. doi: 10.1038/s41467-020-19400-w. PMID: 33188181; PMCID: PMC7666196.
7 | Rudloff I, Godsell J, Nold-Petry CA, Harris J, Hoi A, Morand EF, Nold MF (2015). Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2015 Dec;67(12):3219-25. doi: 10.1002/art.39328. PMID: 26314375.
8 | Cho SX, Berger PJ, Nold-Petry CA, Nold MF (2016). The immunological landscape in necrotising enterocolitis. Expert Rev Mol Med. 2016 Jun 24;18:e12. doi: 10.1017/erm.2016.13. PMID: 27341512; PMCID: PMC5001507.