Earlier generations of Treg therapies face several challenges that limit their therapeutic potential
The broad T-cell receptor (TCR) specificity of Tregs, which can recognise a wide array of self and non-self antigens, presents a significant challenge in their potential application as cell therapy. While this broad specificity is advantageous in maintaining overall immune homeostasis, it becomes a major drawback when considering their use in cell therapy as it could lead to unintended immune suppression.
Addressing the issue of broad TCR specificity is a critical hurdle that must be overcome to harness the full therapeutic potential of Tregs.
Polyclonal Tregs administered via cell therapy often struggle to migrate efficiently to the affected tissues or organs, where their suppressive functions are most needed. This limited migration hinders their ability to exert precise control over the inflammatory responses and may result in reduced therapeutic efficacy.
Addressing the issue of poor homing is crucial to enhance the therapeutic potential of Treg-based cell therapy and maximise their beneficial impact in treating autoimmune diseases.
High Functional Plasticity
Tregs, with their ability to adapt their immune-suppressive functions in response to varying microenvironmental cues, are a critical component of maintaining immune homeostasis. However, this very plasticity becomes a double-edged sword when it comes to cell therapy for inflammatory conditions.
Once introduced into the inflamed tissues, polyclonal Tregs can undergo phenotypic changes, potentially losing their suppressive properties and even converting into pro-inflammatory effector T cells. This phenomenon compromises their intended function of dampening the hyperactive immune responses in inflammatory disorders.
The unpredictability of Treg functional plasticity presents a significant challenge in achieving consistent and reliable therapeutic outcomes. Addressing this issue is crucial to harness the full therapeutic potential of Treg-based cell therapy and to ensure safe and effective treatment of inflammatory disorders.
The short in vivo persistence of polyclonal Tregs poses a significant challenge in utilising them as cell therapy. Once administered, polyclonal Tregs often exhibit limited longevity within the host's body. Their relatively short lifespan diminishes their suppressive potential and restricts the duration of their beneficial effects.
As inflammatory disorders can be chronic and progressive, sustained Treg activity is vital for long-term control of the immune dysregulation. The rapid decline of polyclonal Tregs hampers their ability to provide lasting immunosuppression, potentially leading to disease relapse and inadequate therapeutic outcomes.
Overcoming the issue of persistence is critical to enhancing the durability and efficacy of Treg-based cell therapy, offering a promising strategy to effectively treat inflammatory disorders
While Tregs hold tremendous promise as a potent immunosuppressive tool to control and resolve inflammatory responses, their efficacy can be hindered by several factors.
First, the complex and dynamic nature of inflammatory disorders often requires precise and targeted immune regulation, which polyclonal Tregs may struggle to achieve due to their broad antigen specificity and heterogeneity. Second, the harsh inflammatory microenvironment can lead to Treg dysfunction, impairing their suppressive capabilities and rendering them less effective in controlling the exacerbated immune responses. Lastly, the overall frequency of naturally occurring Tregs in the body is relatively low, limiting the number of cells that can be isolated and expanded for cell therapy purposes.
These limitations collectively undermine the ability of polyclonal Tregs to provide robust and consistent suppression of inflammation, reducing their potential as a stand-alone therapeutic approach for inflammatory disorders.
Addressing the issue of limited efficacy requires innovative strategies to enhance Treg function and potency, or alternative approaches to improve their specificity and targeting, in order to fully harness their therapeutic benefits in treating inflammatory disorders.