Interleukin-1 (IL-1) comprises a family of cytokines implicated in the pathophysiology of many respiratory disorders. This family includes pro-inflammatory IL-1α and IL-1β and anti-inflammatory IL-1 receptor antagonist (IL-1Ra) – all of which have a role in the innate immune response to a pathogen or injury. While IL-1β is the primary driver of inflammation, IL-1Ra has an anti-inflammatory role that moderates the risk of excessive response.

IL-1 Drives Innate Immunity

The IL-1 family has a leading role in the innate immune system where it provides an early response to infection or tissue damage and regulates functions of the adaptive immune response. The key agonists, IL-1α and IL-1β, bind to the IL-1 receptor and promote a multi-step inflammatory process that includes expression of pro-inflammatory IL-6 and IL-8. The process is particularly important in the body’s defense against intracellular pathogens. While typically protective, the inflammatory response, if unchecked, can lead to tissue damage.

Cytokine Storm Syndrome is a hyper-immune response caused by an excessive or uncontrolled release of proinflammatory cytokines. While the etiology of Cytokine Storm Syndrome is unknown, it has been shown to be a driver of acute respiratory failure and can be lethal. Patients who do survive manifest varying degrees of pulmonary fibrosis and restrictive ventilatory impairment.

IL-1Ra, the only antagonist in the IL-1 family, binds competitively to the same IL-1R1 receptor as does IL-1α and IL-1β. Importantly, IL-1Ra does not generate the conformational change that would produce proinflammatory chemokines (Borthwick 2015). In this way, IL-1Ra can attenuate the inflammation mediated by IL-1α and IL-1β and lead to a resolution of the inflammatory response.

IL-1Ra and Bronchiolitis obliterans syndrome (BOS)

Bronchiolitis obliterans syndrome (BOS) remains the major cause of allograft dysfunction following lung transplantation and is associated with poor long-term survival. It may be considered as a form of chronic transplant rejection and manifests as an obstructive pattern on pulmonary functions testing. BOS is the leading cause of death in lung transplant recipients who survive beyond one year and can be found in more than 50% of patients who are alive at 5 years. To date, no effective treatment exists for BOS.

Bronchiolitis obliterans syndrome is characterized by increased IL-1 production and subsequent over-activation of the innate immune response in lung tissue. Treatment with inhaled IL-1Ra has demonstrated the potential to attenuate the innate immune response and improve or prevent further loss of respiratory function.

IL-1ra and Bronchiolitis Obliterans Syndrome (BOS)

IL-1Ra and Chemical Lung Injury

The inhalation exposure from noxious chemicals such as sulfur mustard as well as pollutants or smoke may be associated with an increased IL-1 production and subsequent over-activation of the innate immune response in lung tissue. Experimental models support the potential for an inhaled IL-1Ra to mitigate the innate immune response triggered by inhaled irritants such as sulphur mustard1 those associated with vaping injury2 and ameliorate loss of respiratory function.

Incidence figures are difficult to calculate owing to the diversity of compounds that may cause lung injury and the settings in which such injury may occur (accidental exposure in industrial or home settings or via chemical attack). It has been estimated by the National Occupational Exposure Survey, conducted by the CDC, that at least one million US workers are at risk of exposure to respiratory irritants, with injuries occurring more frequently at home3.

1. Mishra NC, Rir-sima-ah J, Grotendorst GR, Langley RJ, Singh SP, Gundavarapu S, Weber WM, Pena-Philippides JC, Duncan MR, Sopori ML. Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology. Int Immunopharmacol. 2012 May;13(1):101-8. doi: 10.1016/j.intimp.2012.03.010. Epub 2012 Mar 28. PMID: 22465472; PMCID: PMC3340497. 2. Lerner CA, Sundar IK, Yao H, Gerloff J, Ossip DJ, McIntosh S, et al. (2015) Vapors Produced by Electronic Cigarettes and E-Juices with Flavorings Induce Toxicity, Oxidative Stress, and Inflammatory Response in Lung Epithelial Cells and in Mouse Lung. PLoS ONE 10(2): e0116732. https://doi.org/10.1371/journal.pone.0116732 3. Gorguner M, Akgun M. Acute inhalation injury. Eurasian J Med. 2010;42(1):28-35. doi:10.5152/eajm.2010.09

For more information, see also:

  • Publications related to ALTA-2530 here
  • Information on the clinical development of ALTA-2530 here