74 ADAPTIVE SKIN CARE
threshold for immune response, meaning that harmless stimuli are increasingly interpreted as threats.15
The Tolerogen: a new cosmetic category A tolerogen is an active ingredient that trains the skin’s immune system to generate tolerance, not suppress responses but educate immune cells to stop over-reacting to harmless stimuli. Tolerance is a skill; a tolerogen teaches it. This tolerogenic active is a biotechnology
ingredient designed to re-educate hyperreactive urban skin by helping restore its natural immune tolerance, comfort and visible resilience. Modern lifestyles have placed sensitive
skin under continuous pressure. Indoor pollution, urban exposure and chronic low- grade environmental stress may contribute to persistent redness, discomfort, tightness, stinging and burning sensations. In this context, sensitive skin is not only a skin type; it can be understood as skin that has lost part of its immune calibration. The tolerogen addresses this challenge by targeting the abovementioned Langerhans cells (LC). The loss of immune tolerance in urban skin is mechanistically linked to the progressive erosion of endogenous Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) signalling, shifting Langerhans cells from tolerance to constitutive inflammation. GM-CSF is a protein produced endogenously by keratinocytes, fibroblasts, and endothelial cells. It governs the differentiation, survival, and functional programming of LC, critical for immune tolerance.16 Inspired by this biology, the company has
developed a recombinant human protein (GM-CSF) produced in a plant biofactory system, combining molecular precision with the advantages of plant-derived biotechnology.
BIOLOGICAL SWITCH ➞ IMMUNOGENIC Chronic inflammation IL-8 · IL-6 · TNF-α CCR7 · CD80 · CD86 REACTIVITY
Mechanism of action: the tolerogenic reset The active binds to the GM-CSF receptor on LC surfaces, it triggers the NF-κB signalling pathway and activates transcription factors RELB and SOX4, which lock LC into a tolerogenic, non- inflammatory phenotype characterised by low expression of co-stimulatory molecules (CD80/86) and the migratory receptor CCR7. These calmed LC secrete TGF-β suppressing
pro-inflammatory cytokines (TNF-α, IL-8, IL-6), preserving a non-inflammatory skin microenvironment, maintaining a tolerogenic state (Figure 3). Chronic exposure to pollution, UV exposure, and ageing progressively depletes this tolerogenic signal.
Toleroxyl TOLEROGENIC Homeostasis
RELB · SOX4 TGF-β · IL-10
RESILIENCE
Figure 2: The biological switch: Langerhans cell phenotypic states and their downstream immune consequences
Biological activity (in vitro) A comprehensive series of in vitro studies were conducted using a reconstructed human epidermis model containing Langerhans cells. The model was exposed to an Indoor Pollution
Challenge (IPC), a mixture of PAHs, heavy metals, pesticides and industrial chemicals, and particulate matter (PM10 and PM2.5), to simulate the real indoor urban environments (Figure 4). Treatments with the active were compared
with untreated controls and dexamethasone, used as a positive control due to its well-established anti-inflammatory properties and its widespread use in inflammatory skin conditions. Inflammatory markers (IL-8, CCR7, CD80, CD86), tolerogenic mediators (TGF-β, RELB, SOX4), and barrier- associated proteins (filaggrin, loricrin, cadherin-1, claudin-4) were analysed.
In vitro 1: the inflammatory reset IPC exposure induced significant upregulation of immune activation markers, driving Langerhans cells towards an immunogenic phenotype. The active ingredient fully normalised all the markers (CCR7: down to 143%; CD80: down to 141%; CD86: down to 135%; IL-8: down to 61% versus stressed baseline), restoring immunogenic LC signalling to physiological levels, whereas dexamethasone suppresses it below baseline.
In vitro 2: tolerogenic reset Beyond the modulation of inflammatory pathways, the restoration of immune tolerance represents a critical component of skin homeostasis. In this context, it is essential to assess not only the anti-inflammatory effects of the active ingredient, but also its ability to actively induce tolerogenic mechanisms. This section evaluates the impact of the
Hyperreactive skin Recalibrated skin Figure 3: Mechanism of action of the active PERSONAL CARE MAGAZINE October 2026
ingredient on key regulators of cutaneous tolerance (RELB, SOX4 and TGF-β) as a readout of restored skin tolerance.
www.personalcaremagazine.com
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