Monash-led study unveils potential long-term treatment for lupus

By Vijay Kumar MalesuFeb 8 2024Reviewed by Danielle Ellis, B.Sc.

In a recent study published in Nature Communications, a group of researchers assessed Smith (Sm)-specific regulatory T cells (Tregs) efficacy in halting lupus nephritis (LN) by engineering and testing epitope-targeted Tregs for systemic lupus erythematosus (SLE) treatment.

Background 

Tregs play a crucial role in immune balance, with their dysfunction linked to autoimmune conditions like SLE. Treg therapies, especially those targeting specific antigens, have shown promise in controlling autoimmune responses. LN, a critical SLE manifestation, is often associated with the Sm autoantigen and specific human leukocyte antigen (HLA) haplotypes, suggesting a targeted therapeutic approach might be effective.

Further research is needed to optimize Sm-specific Treg therapy for broader clinical application and to understand its long-term efficacy and safety in diverse SLE patient populations.

About the study 

The present study utilized a biophysical affinity binding assay. Researchers screened peptides derived from Sm proteins against HLA-DR15, identifying those with the highest affinity. This thorough approach enabled the calculation of binding affinities and half-life estimations, crucial for selecting epitopes with the potential to evoke a strong T-cell response.

Ethical adherence was paramount, with all procedures conforming to the Declaration of Helsinki and receiving approval from relevant ethics committees. The study's rigorous inclusion criteria ensured that only suitable participants, informed and consenting, contributed to the findings.

Further investigations into the immunogenicity of top-ranking Sm epitopes utilized whole blood from an HLA-DR15 homozygous donor. This approach allowed for the differentiation of monocytes into dendritic cells and the subsequent activation of Cluster of Differentiation 4 (CD4)+ T cells, providing a robust platform for assessing T-cell responses to Sm epitopes.

The process extended to detailed methodologies for expressing and purifying HLA-DR15, crucial for understanding the intricate interactions between Sm epitopes and the immune system. Protein crystallization and structural determination further illuminated the binding mechanisms at play, offering insights that could pave the way for novel therapeutic strategies.

This comprehensive study not only identified potential targets for autoimmune therapy but also set a high standard for methodological rigor and ethical compliance, promising future research in this critical area of medicine.

Study results 

The researchers explored the potential of Tregs, particularly in SLE and its severe manifestation, LN. Tregs, known for their role in maintaining immune equilibrium, become a focus due to their decreased numbers or malfunction in autoimmune diseases. Targeted therapies using Tregs, especially those engineered to be antigen-specific, offer a promising approach to suppress the pathogenic autoactivity inherent in these conditions.

The study embarked on identifying immunodominant Sm protein epitopes, given their association with LN and specific HLA haplotypes. Through a thorough screening process involving 145 overlapping peptides from Sm proteins, researchers identified a set of epitopes with strong binding affinity to HLA-DR15, with SmB/B'_58-72 standing out for its binding stability and capacity to induce T-cell proliferation, marking it as a prime candidate for further exploration.

Diving deeper, the team elucidated the crystal structure of the SmB/B'_58-72 epitope in complex with HLA-DR15, revealing key amino acid residues pivotal for T-cell activation. This structural insight laid the groundwork for identifying high-affinity T-cell receptors (TCRs) specific to the SmB/B'_58-72 epitope. Leveraging high-throughput sequencing and binding assays, they isolated TCRs with potent affinity, notably TCR1, which demonstrated significant clonal expansion and functional activity indicative of its therapeutic potential.

The translational leap involved engineering Tregs with the identified Sm-specific TCRs using lentiviral vectors. These engineered Tregs not only retained their regulatory phenotype but also showcased enhanced specificity and suppressive capacity against Sm epitope-induced pro-inflammatory responses, both in vitro and in a humanized mouse model of LN. This specificity was further evidenced by their ability to form immune synapses upon encountering their target antigen, leading to effective T-cell activation and suppression of autoimmunity.

Moreover, the study highlighted the therapeutic efficacy of these Sm-specific Tregs in suppressing SLE patient-derived autoreactivity, as demonstrated through in vitro cytokine profiling and in vivo models of LN. Mice treated with Sm-Tregs exhibited significantly less renal injury and proteinuria compared to those receiving polyclonal Tregs or no treatment, underscoring the potential of antigen-specific Tregs in restoring immune tolerance and halting disease progression.

This research opens new avenues for targeted immunotherapy in autoimmune diseases, emphasizing the power of precision medicine in addressing complex disorders like SLE and LN. Harnessing the specificity and regulatory capabilities of Tregs presents a promising strategy for developing more effective and personalized treatments, marking a significant step forward in the battle against autoimmune diseases.