Nasal administration of a fully human anti-CD3 monoclonal antibody modulates T cell inflammatory responses in COVID-19

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In a recent study published in the Proceedings of the National Academy of Sciences, researchers assessed the impact of an anti-CD3 monoclonal antibody (mAb) called Foralumab in coronavirus disease 2019 (COVID-19) treatment.

Study: Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19. Image Credit: Kateryna Kon/Shutterstock
Study: Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19. Image Credit: Kateryna Kon/Shutterstock

Background

In the early phases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, T cells are present and play a crucial role in illness prognosis and long-term immunity. In moderate COVID-19 cases, nasal delivery of a completely human anti-CD3 monoclonal antibody called Foralumab decreased lung inflammation as well as blood interleukin (IL)-6 and C-reactive protein.

About the study

In the present study, researchers evaluated the immunological alterations noted in Foralumab-treated individuals.

To assess the transcriptomic alterations in immune cells after treatment with nasal Foralumab in SARS-CoV-2-infected patients, the team obtained CD3+ (T cells), CD14+ (monocytes), and CD19+ (B cells) from Foralumab-treated as well as untreated SARS-CoV-2-infected patients at baseline and day 10. Samples were also collected from healthy subjects. Then, CD3+ cells obtained from COVID-19-infected individuals were compared with those from healthy controls.

The team then examined the impact of nasal Foralumab on gene expression associated with B cells, T cells, and monocytes by comparison of pre-treatment (day-2) to follow-up (day-10) in Foralumab-treated and untreated patients. Furthermore, gene expression of total CD3+ T cells pre-treatment was compared to that on day 10 for Foralumab-treated as well as untreated COVID-19 individuals.

Results

Ingenuity pathway analysis (IPA) of the most differently expressed genes (DEGs) revealed that coronavirus pathogenesis pathways were upregulated in the three immune cell groups. The team also noted increased expression in activation markers such as CD69, CD83, Regulator of G-protein signaling 1 (RGS1), inducible T-cell costimulator (ICOS), and other stress-related genes such as activating transcription factor 4 (ATF4), hypoxia-inducible factor 1-alpha (HIF1A), nuclear factor NF-kappa-B (NFKB1), and PR1. Moreover, genes associated with T cell responsiveness, including IL21R, IL4R, and CXCR4, were increased in COVID-19-infected individuals.

COVID-19 patients exhibited elevated IL-18 and vascular endothelial growth factor A (VEGFA)-VEGF receptor-2 signaling pathways, as determined by an enrichment study of DEGs. Also, NLRP3 inflammasome activation by SARS-CoV-2 and host-pathogen interaction between human coronavirus interferon induction canonical pathways were elevated in T cells of COVID-19 patients compared to healthy controls.

Inflammatory pathways, like interferon and hypercytokinemia signaling pathways, were downregulated in treated and untreated groups based on the IPA of DEGs noted before and after therapy. Moreover, the team found a coronavirus pathogenesis pathway that exhibited downregulation in the Foralumab cohort but not in the untreated group.

Notably, Caspase-1 was downregulated in T cells, B cells, and monocytes in Foralumab-treated versus untreated patients. Caspase-1 is linked to immune-related COVID-19 pathogenicity and a poorer prognosis. The coronavirus pathogenesis pathway was marginally downregulated in monocytes collected from Foralumab-treated people compared to untreated persons.

Although the team identified alterations in genetic expression in B cells, like the downregulation of IL-4 and IL-15 signaling in treated participants, these differences were statistically less significant than those observed in T cells. Furthermore, the reported in vivo impacts of nasal Foralumab on monocytes and B cells were indirect, as neither B cells nor monocytes express CD3 on their cell surface.

Nasal treatment with Foralumab resulted in the downregulation of genes involved in inflammation as well as coronavirus pathogenesis with its immunomodulatory effects being most prominent in CD3+ T cells. However, the team also noted indirect evidence of alterations in monocytes and B cells. Furthermore, patients treated with Foralumab recover substantially from the naive CD4+ decrease observed on day -2 in SARS-CoV-2 patients.

In Foralumab-treated patients, effector function genes such as NKG7, IL32, CCL5, cystatin F (CST7), granzyme B (GZMB), GZMH, GZMA, CCL4, and PRF1 were significantly downregulated. Foralumab-treated participants exhibited a decrease in IL32 in CM and EM CD8+ cells along with a decline in gamma delta T cells. GZMH was downregulated in CD4+ effector cells, while PRF1 was downregulated in CD8+ CM. The data indicated a loss in effector characteristics in various T cell subsets among Foralumab-treated subjects relative to untreated controls.

Compared to baseline, downregulation of NKG7 was noted in CD8+ EM, CD8+ TEMRAs, VD2 gamma deltas, and non-VD2 gamma delta T cells in COVID-19-treated participants but not in untreated controls. TGFB1 was elevated in many CD3+ subsets, such as CD4+ TEMRA, CD8+ EM, CD8+ TEMRA, VD2 gamma-delta, and nonVD2 gamma-delta T cells, in comparison to healthy controls as well as untreated COVID-19 participants following Foralumab treatment. Increased expression of the TGFB1 gene was seen in cell types with established effector roles other than traditional Treg cells.

Conclusion

The study findings showed that nasal Foralumab alters T-cell inflammatory responses in SARS-CoV-2 infections by inhibiting effector characteristics in several CD3+ T-cell subsets. The most important discovery of the present study is the recognition of a unique mechanism linked with nasal Foralumab, which will assist the progress of the use of Foralumab as adjuvant therapy for COVID-19 and guide its long-term usage in autoimmune disorders.

Journal reference:
Bhavana Kunkalikar

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.

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