Mice studies show that the use of an antibody towards NK cells could reduce the development of diabetes in susceptible populations.
It is well known that type 1 diabetes is an autoimmune condition. Studies have shown that natural killer cells (NK cells) have cytolytic (cell death) activities against the insulin-producing beta islets cells of the pancreas. With this knowledge, scientists are exploring mechanisms to blockade NK cells.
NK cells have several activating as well as inhibitory receptors that pick up cues in the form of ligands (signaling proteins) from the microenvironment (nearby cells). One such activation receptor, NKp46, which is present on human NK cells, is known to have a genetic equivalent in mice, mNKp46.
In mice and man, beta islet cells express ligands for the mNKp46 or NKp46 receptors during health and diabetes, thereby stimulating the activation and cytolytic activities of NK cells. Scientists hypothesized that manipulating NKp46 could provide the therapeutic approach that they were seeking for intervention in type 1 diabetes. To this end, they pursued the strategy of antibody-mediated NKp46 function modulation.
Genetically engineered mice lacking mNKp46 were immunized with mNKp46 fusion proteins. Antibody-producing B cells were subsequently collected from the spleen and fused with myeloma cells (tumor cells) in the lab, thereby generating hybridomas, which are a hybrid of B cells and myeloma cells. Hybridomas multiply profusely in tissue culture, and can be used to produce a specific antibody indefinitely.
Several hybridoma clones were tested. One, which generated an antibody that specifically reacted with mouse but not human NKp46 was selected. It was found that inoculating mice with anti-mNKp46 antibody did not lead to a reduction in the fraction of NK cells, but that the mNKp46 levels on NK cells were reduced. The effector function of NK cells from inoculated mice was significantly reduced, meaning these NK cells had lower tendencies for lysing target cells.
An accepted model of experimental autoimmune diabetes in mice is the generation of diabetic mice through chemical treatment with streptozotocin. Even though this practice yields diabetic mice without fail, treating mice with anti-mNKp46 before chemical treatment significantly hindered diabetes development. Furthermore, the anti-mNKp46 antibody treatment also significantly reduced the development of type 1 diabetes in non-obese diabetic (NOD) mice, which have a genetic propensity for spontaneous development of autoimmune diabetes.
This study represents a pinpoint-targeted therapeutic approach that specifically reduces the NKp46 component in NK cells with therapeutic benefit in type 1 diabetes. HemaCare provides NK cells for research and looks forward to the translation of the findings from this study into the clinical setting.
- Yossef R, Gur C, Shemesh A, Guttman O, Hadad U, Nedvetzki S, Miletić A, Nalbandyan K, Cerwenka A, Jonjic S, Mandelboim O, Porgador A. Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes. PLoS One. 2015 Feb 26;10(2):e0118936.