The allergic reaction is the immune system’s exaggerated response to a typically harmless substance, known as an allergen. The body mistakenly identifies the allergen as a threat, triggering a predictable, multi-step sequence of events. While immediate symptoms are often recognized, the immune response frequently involves a second, delayed wave of inflammation. Understanding this “late phase” is important for developing effective treatments that address the full spectrum of allergic disease.
The Biphasic Nature of Allergic Reactions
Allergic responses frequently present as a biphasic, or two-part, event, distinguishing the immediate reaction from the sustained reaction that follows. The first part is the Early Phase (EP), which has a rapid onset, usually beginning within minutes of exposure and peaking around 15 to 30 minutes. This phase is driven by mast cell degranulation, where these cells rapidly release pre-formed chemical mediators like histamine. The immediate effects are classic allergic symptoms, such as hives, sneezing, itching, and acute bronchospasm.
The second part is the Late Phase (LP), a delayed response that typically starts four to 12 hours after the initial allergen exposure, often after the early symptoms have subsided. Unlike the EP, the late phase is characterized by sustained symptoms, including congestion, prolonged airway constriction, and significant tissue swelling. The LP is a focus in research because it can occur even without a severe early reaction, and its persistent inflammatory nature is strongly associated with chronic allergic conditions like asthma.
Cellular and Molecular Drivers of the Late Phase
The difference in timing and symptoms between the two phases is rooted in distinct biological mechanisms. The early phase involves the instantaneous release of stored mediators, but the late phase requires the de novo synthesis and recruitment of additional components. This sustained reaction begins when mast cells and other initial responder cells release signaling molecules called chemokines and cytokines.
These chemical signals recruit a secondary wave of inflammatory cells from the bloodstream to the site of allergen exposure. Among these new recruits are eosinophils, basophils, and T-lymphocytes. Eosinophils are significant because their numbers are often elevated in affected tissues during the late phase, and they release toxic proteins that cause tissue damage and promote structural changes seen in chronic asthma.
Beyond cellular recruitment, the late phase is sustained by a shift in mediator production. While histamine dominates the early response, the late phase is driven by newly synthesized lipid mediators like leukotrienes and prostaglandins, which are more potent at causing prolonged bronchoconstriction and swelling. Specific cytokines, such as Interleukin-5 (IL-5), are released by T-cells and enhance the survival and activation of eosinophils, perpetuating the inflammatory cascade.
Assessing the Late Phase in Drug Trials
The distinct mechanisms of the late phase make it a specific target in drug development, especially for treatments aimed at chronic allergic diseases. Effective therapies must address both the immediate symptoms and the inflammation that drives the delayed response. Many older antihistamines primarily target only the histamine released in the early phase, making them less effective at controlling the persistent inflammation of the late phase.
Researchers frequently use controlled Allergen Challenge Tests to assess a drug’s efficacy against the late phase in clinical trials. For instance, in asthma studies, a patient is exposed to a controlled amount of an allergen through inhalation, and their lung function is measured over the following 24 hours. The decline in forced expiratory volume (FEV1) that occurs hours later confirms the presence of a late-phase reaction.
The measurement of sustained inflammation and symptom recurrence is a metric in demonstrating a new drug’s benefit. Regulatory bodies often require proof that a medication can mitigate the inflammatory components of the late phase, particularly for chronic conditions. This testing methodology helps confirm that modern treatments, such as leukotriene modifiers or biologics that target specific cytokines like IL-5, are effective at interrupting the delayed inflammatory cycle.