Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications

ABSTRACT

Introduction: Heat-labile enterotoxins (HLTs) and their cognate ganglioside receptors have been extensively studied because of their therapeutic potential. Gangliosides play arole in modulating effector cells of the immune system, and HLTs provide a novel means for stimulating ganglioside-mediated responses in immunocompetent cells.

Areas covered: To evaluate the mechanisms of HLT adjuvanticity, a systemic literature review was performed using relevant keyword searches of the PubMed database, accessing literature published as recently as late 2020. Since HLTs bind to specific ganglioside receptors on immunocytes, they can act as regulators via stimulation or tapering of immune responses from associated signal transduction events. Binding of HLTs to gangliosides can increase proliferation of T-cells, increase cytokine release, augment mucosal/systemic antibody responses, and increase the effectiveness of antigen presenting cells. Subunit components also independently stimulate certain immune responses. Mutant forms of HLTs have potent immunomodulatory effects without the toxicity associated with holotoxins.

Expert opinion: HLTs have been the subject of abundant research exploring their use as vaccine adjuvants, in the treatment of autoimmune conditions, in cancer therapy, and for weight loss, proving that these molecules are promising tools in the field of immunotherapy.

KEYWORDS:

• A subunit
• adjuvants
• B-pentamer
• cancer therapeutics
• enterotoxins
• gangliosides
• immunomodulation
• toll-like receptors
• vaccines

Article highlights

• Type I and type II heat-labile enterotoxins (HLTs) are potent adjuvants that can significantly augment systemic and mucosal immune responses to co-administered antigens.

• Binding of HLTs to gangliosides on the surface of immunocompetent cells leads to ganglioside crosslinking, initiating signal transduction pathways that result in immunoregulation. The presence of unique binding affinities for specific gangliosides results in distinct immunoregulatory profiles for each HLT.

• Characteristics of HLTs can be classified as functions of the holotoxin, the A subunit, or the B-pentamer subunit. These distinctions are relevant to adjuvant potential as toxicity is primarily associated with cAMP production mediated by the A subunit. When separated from their holotoxins, B pentamers of certain HLTs interact with toll-like receptors to independently elicit immune responses.

• Mutant forms of HLTs are promising adjuvants due to their variable capacity to elicit an immune response to specific antigens while minimizing or avoiding entirely the toxic effects of the wildtype holotoxins.

• Pre-clinical and clinical trials utilizing HLTs in vaccine models have demonstrated varying levels of success. Studies have also been conducted demonstrating a role for HLTs in cancer, autoimmune disease, and obesity research.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.