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Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes
Rami Yossef1, Chamutal Gur2, Avishai Shemesh1
1The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Abstract:
Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.
Insights
Blocking the NKp46 receptor in mice significantly reduced type 1 diabetes development. This NKp46 antibody treatment offers a potential new strategy for preventing early insulitis and type 1 diabetes.
Area of Science:
- Immunology
- Endocrinology
- Autoimmunity
Background:
- Natural killer (NK) cells are innate lymphoid cells regulating cytotoxic activity via activating and inhibitory signals.
- NKp46 is a primary activating receptor on NK cells, previously implicated in type 1 diabetes (T1D) development.
- A hypothesis was formed that blocking NKp46 could prevent or hinder T1D progression.
Purpose of the Study:
- To investigate the therapeutic potential of blocking the NKp46 receptor in T1D.
- To develop and test monoclonal antibodies targeting murine NKp46 (Ncr1).
Main Methods:
- Developed a monoclonal antibody, NCR1.15, targeting the murine NKp46 homologue (Ncr1).
- Administered NCR1.15 in vivo to down-regulate NKp46 surface expression and cytotoxic activity.
- Evaluated T1D incidence in non-obese diabetic mice and low-dose streptozotocin models following NCR1.15 treatment.
Main Results:
- NCR1.15 treatment successfully down-regulated NKp46 expression and activity on murine NK cells.
- A significantly lower incidence of T1D was observed in NCR1.15-treated groups compared to controls.
- The study confirmed NKp46's role in T1D pathogenesis.
Conclusions:
- NKp46 plays a direct role in the development of type 1 diabetes.
- Targeting NKp46 with antibodies like NCR1.15 presents a promising novel therapeutic strategy for early insulitis and T1D prevention.
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