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Chronic inflammatory diseases represent a massive global health challenge. Asthma affects approximately 262 million people globally—roughly 1 in 31 people. Meanwhile, atopic dermatitis (AD) impacts over 230 million people worldwide, meaning about 1 in 33 individuals currently live with the condition.
Historically, treatment relied on broad immunosuppression, particularly corticosteroids—effective, but blunt tools that suppress the entire immune system and carry significant safety liabilities. Over the past decade, the field has shifted toward a pathway-driven paradigm. Targeted biologics now act more like a scalpel, selectively inhibiting key mediators such as IL-4/IL-13, IL-5, IgE, and TSLP to control inflammation with improved safety profiles.
However, clinical experience has revealed a clear limitation: a ceiling effect in single-node targeting. The Th2 (T-helper 2) inflammatory network is highly redundant and adaptive, and inhibition of one node often leads to compensatory activation of parallel pathways. As a result, even highly successful biologics such as dupilumab leave a subset of patients with incomplete or suboptimal responses, particularly in moderate-to-severe disease.
The Th2 inflammatory network is not linear—it is a dynamic, self-reinforcing system. In AD and asthma, epithelial injury triggers release of alarmins such as TSLP, IL-25, and IL-33, which activate dendritic cells and initiate Th2 polarization. This drives downstream effector pathways mediated by IL-4, IL-5, and IL-13, resulting in IgE production, eosinophilia, barrier dysfunction, and airway hyperresponsiveness.
This cascade is anchored by two sequential control nodes:
While emerging therapies targeting TSLP or downstream cytokines have improved outcomes, single-axis intervention remains insufficient in established disease, where both upstream initiation and T-cell persistence contribute to chronic inflammation.
In contrast, dual blockade of TSLP and OX40/OX40L directly targets both disease ignition and immune amplification, reducing pathway redundancy and enabling deeper, more durable immune reset.
Realizing the full potential of combination strategies requires preclinical systems that faithfully recapitulate human immune network complexity. However, conventional models are limited by species differences in TSLP and OX40 biology, and single-humanized systems fail to capture coordinated multi-axis immune interactions.
To address this, Biocytogen has developed the B-hTSLP/hTSLPR plus/hOX40/hOX40L humanized mice (Catalog No. 113916), enabling simultaneous evaluation of upstream and T-cell–mediated inflammatory axes within a single in vivo system. Our model provides:
To validate its translational value, an OVA-induced airway inflammation (asthma-like) model was established in humanized TSLP/OX40 mouse model. Combination targeting of human TSLP (SHR-1905), IL-13 (lebrikizumab), and OX40L (amlitelimab) demonstrated clear gains in therapeutic depth:
Combination regimens significantly reduced CD45⁺ inflammatory cells and eosinophils in bronchoalveolar lavage fluid (BALF) compared to PBS controls—demonstrating the model’s ability to resolve incremental efficacy across combination strategies.
Mice treated with combination therapies showed markedly lower total serum IgE levels, reflecting robust suppression of systemic type 2 immune activation.
Superior reduction of systemic IgE via triple-pathway blockade in OVA-induced B-hTSLP/hTSLPR plus/hOX40/hOX40L humanized mice. The triple combination (G5) achieved near-complete normalization of serum IgE, significantly outperforming monotherapies and double combinations. This pronounced reduction in IgE—a central biomarker of allergic sensitization—supports enhanced control of B-cell–mediated responses and overall Th2 signaling.
Although current biologics can effectively reduce inflammatory signaling, many patients continue to experience persistent disease activity and long-term tissue remodeling, including airway structural changes and mucus hypersecretion. This highlights a critical gap between immune suppression and true disease modification.
Biocytogen’s B-hTSLP/hTSLPR plus/hOX40/hOX40L humanized mouse model addresses this gap through a uniquely versatile design that recapitulates both immune modulation and tissue-level pathology. In addition to accurately modeling reduced inflammatory responses, it also enables evaluation of tissue protection, airway remodeling, and structural pathogenic improvement—dimensions often missing in conventional or single-axis preclinical models.
This platform provides a more comprehensive translational framework for developing next-generation therapeutics aimed at both immune control and disease modification.
👉 Contact us for model inplementation, study design and more.
Simultaneous targeting of TSLP and OX40/OX40L intervenes at both the source of the immune alarm (the TSLP "ignition switch") and the core amplification axis of T-cell activation (the OX40 "fuel booster"). This dual-target strategy helps overcome the limitations of single-cytokine blockade by reducing pathway compensation and more effectively restoring immune balance for durable disease control.
