Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate...

Area of Science:

• Immunology
• Pharmacology
• Toxicology

Background:

• Antisense oligonucleotides (ASOs) are promising single-stranded DNA drugs.
• Thrombocytopenia (TCP) is a rare side effect of ASO treatment in nonhuman primates (NHPs).
• Mauritian-sourced NHPs exhibit higher susceptibility to ASO-induced TCP compared to Asian-sourced animals.

Purpose of the Study:

• To investigate the immune-phenotypic and functional changes associated with ASO therapy in NHPs.
• To identify potential immune mechanisms underlying ASO-induced thrombocytopenia (TCP).
• To compare immune responses between ASO-treated and control groups in susceptible and less susceptible NHP populations.

Main Methods:

• Utilized mass cytometry and intracellular cytokine staining on cryopreserved peripheral blood mononuclear cells (PBMCs).
• Analyzed samples from Cambodian and Mauritian monkeys over 8 time points during ASO therapy (ISIS 405879).
• Employed unsupervised clustering for immune cell identification and longitudinal analysis to track changes.

Main Results:

• Significant differences in immune cell populations were observed between Mauritian and Cambodian monkeys prior to treatment.
• Mauritian monkeys had lower levels of IFNγ- and TNF-producing T cells and higher levels of MIP1β-producing monocytes and DCs.
• ASO treatment led to increased IL-17- and GM-CSF-producing T cells and IgM-producing B cells in Mauritian monkeys.

Conclusions:

• Differential immune cell abundance and treatment-induced changes in Mauritian monkeys may explain their higher susceptibility to ASO-induced TCP.
• Identifying these immune subsets could elucidate mechanisms of ASO-related toxicity in humans.
• This study provides a foundation for understanding and potentially mitigating ASO-induced thrombocytopenia.