CpG-ODN Motifs for Rabbit TLR9 Activation
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Solution Overview
Problem
Current CpG-oligodeoxynucleotides (CpG-ODNs) developed for human and mouse cells have low activity on rabbit TLR9, necessitating the development of a CpG-ODN with high activity to facilitate antibody response in rabbits, as they have a broader ligand recognition profile but existing CpG-ODNs are not effective in activating rabbit TLR9.
Innovation Solution
A method involving the administration of a CpG-ODN comprising specific nucleotide sequences, such as GACGTT or AACGTT motifs in 12-14 nucleotides, optimized for rabbit TLR9 activation, which includes subcutaneous injection and the use of aluminum hydroxide gel as an adjuvant, to enhance the TLR9-activated immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CpG-ODNs developed for human and mouse cells are used, then they show high immunostimulatory activity in human and mouse, but they have low activity on rabbit TLR9
Solution Approach 1:
The patent applies local quality by modifying specific nucleotide motifs within the CpG-ODN sequence to match rabbit TLR9 recognition patterns. The invention identifies that rabbit TLR9 responds differently to CpG motifs compared to human and mouse TLR9, and optimizes the local nucleotide sequence (specifically using GACGTT or AACGTT motifs) to achieve species-specific activation while maintaining the overall CpG-ODN structure
Solution Approach 2:
The patent changes key parameters of the CpG-ODN including nucleotide sequence composition, motif type (GACGTT or AACGTT), and length (12-14 nucleotides) to optimize activation of rabbit TLR9. These parameter modifications transform the CpG-ODN from being ineffective in rabbits to highly immunostimulatory in this species while preserving the desired immune response outcomes
2Reliability
If conventional adjuvants like CFA/IFA are used, then they can enhance immune response, but they cause significant adverse effects
Solution Approach 1:
The patent converts the harmful inflammatory effects of conventional adjuvants into beneficial immune activation by using CpG-ODN as an alternative immunostimulatory agent. The CpG-ODN sequence specifically activates TLR9 to induce cytokine production and humoral immune responses without the severe adverse effects associated with CFA/IFA, thereby transforming the problem of adjuvant toxicity into a solution using a safer immunomodulator
Solution Approach 2:
The patent introduces CpG-ODN as an intermediary substance that mediates immune response enhancement without the harmful properties of conventional adjuvants. The CpG-ODN acts as a TLR9 agonist that bridges the gap between antigen presentation and immune activation, providing the necessary immunostimulatory effect while avoiding the tissue damage and inflammation caused by traditional adjuvants
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method effectively activates TLR9-mediated immune responses, inducing cytokine production and humoral immune responses with reduced adverse effects compared to conventional adjuvants, such as CFA/IFA, and demonstrates strong antibody production in rabbits.
Implementation Method 1
CpG-oligodeoxynucleotides (CpG-ODN) are potent immune stimuli and toll-like receptor 9 (TLR9) is their cellular receptor. Activation of TLR9 by CpG-ODN can result in a number of immunological effects including increasing of a T helper (Th) 1 polarized cytokine productions
Implementation Method 2
the use of aluminum hydroxide gel as an adjuvant, to enhance the TLR9-activated immune response
Data Source
AI summary
A method of stimulating a TLR9-activated immune response or enhancing a TLR9-activated immune response to an antigen is disclosed herein. TLR9 is the cellular receptor for CpG-ODN, and current developed CpG-ODN has low activity to rabbit TLR9. Here, the method of stimulating TLR9-activated immune response by administering an effective amount of immunogenic composition comprising an antigen and a CpG-ODN comprising GACGTT or AACGTT motif was demonstrated to have potent immunostimulatory activity to rabbit TLR9, and capable of boosting a less toxic and potent antibody response in rabbits.