Children are more susceptible to developing allergic asthma than adults. An estimated 6 million children have allergic asthma, making asthma one of the most common long-term diseases of childhood.
Asthma is potentially life-threatening, yet there is no cure, rather only management of symptoms.
Progress in understanding the disease was reported in the Dec 17, 2019, issue of Immunity. Investigators at Massachusetts General Hospital discovered that the T-cell-specific dopamine receptor DRD4 controlled Th2 specification and associated inflammation that ultimately influenced susceptibility to allergic asthma in mouse models.
Principal investigator Xinbing Ai, assistant professor of pediatrics, Harvard, Massachusetts General Hospital, told BioWorld that the “key finding here is to link how the nervous system develops in the lung and how the lung acquires [an] allergic phenotype… and then the practical finding is that we are trying to move forward to see whether we can identify first of all the gene signatures in kids with asthma to truly validate our findings because, currently, most of the findings are just validated by histology, looking at how the human lung is innervated. We didn't have any T-cell-related work directly from humans."
Ai and her team investigated the developing nervous system with respect to asthma and discovered that sympathetic nerves innervating the lung produced dopamine in early postnatal life, but neurotransmitter norepinephrine as adults. Similarly, they observed that the lungs and lymph nodes of children up to 13 years of age primarily produce dopamine, while adults ranging from 40 to 65 years produced mainly norepinephrine.
Moreover, Ai and her colleagues observed that dopamine released by sympathetic nerves would bind to the CD4+ T-cell-specific DRD4 receptors to promote differentiation into Th2 cells, increasing lung inflammation. However, norepinephrine production in the adult lung does not specify delineation to Th2 lineage and does not promote inflammation.
The next step will be to look at how the T cells look in children with asthma, and identify downstream pathways or transcription factors they may be able to target.
Ai said she does not think the dopamine pathway is likely to be the best target since dopamine is so important for brain development as well.
However, Ai pointed out that, in fact, the DRD4 dopamine receptor that T cells use is unique so it is possible that it is targetable, especially if compounds can be delivered locally, such as with an inhaler. The lung doesn’t normally express DRD4; DRD4 is very T-cell-specific. By contrast, knockout of DRD1 is embryonic lethal. There are five dopamine receptors in mice and humans, where DRD1 and 5 represent a subclass, while DRD2, 3 and 4 are another subclass that Ai said she believes to be functionally redundant.
Ai cautioned that there has not been enough work with the DRD4 inhibition in humans yet, so it is too early to say. Nonetheless, there are specific DRD4 inhibitors the investigators used after adoptive transfer to determine that DRD4 inhibitors caused a reduction in Th2 inflammation independently of the mouse genotype.
Ai’s research has focused first on how the nervous system develops in the lung because while much is known about the developmental innervation of the gastrointestinal tract, the skin and other organs, the developmental innervation of the lung has been less studied. An additional research focus is to map out what each nerve type is doing. For example, the sympathetic nerves appear to be mostly regulating early Th2 and vascular tone, because norepinephrine is a powerful bronchial constrictor. Sensory nerves appear to be predominantly controlling neuroendocrine cells and the sensing of the lung environment, while the cholinergic nerves are likely regulating airway smooth muscle contractility.
Next, Ai plans to move beyond the initial allergen exposure. Children with allergic asthma have an initial early event, but when they reencounter the same allergen, the patient will develop recurrent exacerbation. Ai and her team are moving their focus to memory T cells, a small subset of persistent T cells formed in response to the initial insult. Upon reencountering an allergen, the memory T cells proliferate dramatically.
The investigators plan to test whether the gene signature they identified in this study in mouse T cells can be identified similarly in human T cells collected from patients with asthma. They will be particularly interested in determining whether DRD4 and associated transcription factors are expressed at higher levels in asthmatic patients.
The team also plans to test whether DRD4 inhibitors can be delivered locally to prevent either the early phases of allergic response or progression of the response in asthmatics.
Ai emphasized the asthma field tends to follow adult asthma samples, probably because it's easier to get patient consent. However, asthma develops in the majority of asthmatics very early on. So she stressed that the field should start to move the study window to a younger age, since these are the individuals that are more vulnerable to the disease.