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Abstract Number: 1080

Effect of Anti-NKG2A Antibody Treatment On NK Cell Receptor Expression in Rheumatoid Arthritis Patients

Joseph Wahle, John Bui and Kristen Bontadelli, Biopharmaceuticals Research Unit, Novo Nordisk, Seattle, WA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Natural killer (NK) cells and rheumatoid arthritis (RA)

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Session Information

Session Title: Innate Immunity and Rheumatic Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose:

This study explored the effect of in vitroblockade of the NKG2A HLA-E interaction on peripheral NK cells from rheumatoid arthritis patients.  To block this interaction we have utilized an anti-NKG2A monoclonal antibody, NNC141-0100, a novel therapeutic mAb designed for the treatment of rheumatoid arthritis.

Natural killer cells are potent members of the innate immune system with both cytotoxic and cytokine producing ability.  NK cells express a myriad of germ line encoded receptors on their surface that provide multiple pathways via which NK cells activity can be regulated.  These receptors include both activating receptors, that recognize stress inducible ligands, and inhibitory receptors that provide protection to self via the recognition of HLA molecules.  One such inhibitory receptor is NKG2A, which functions as a heterodimeric receptor with CD94, in order to recognize HLA-E and thereby block NK cell activation.  Additionally, NK cells express a number of chemokine receptors and other homing related molecules.  The expression of these molecules is crucial for the NK cell to maintain proper lymphoid and non-lymphoid tissue distribution as well as for NK cells to home to and remain at the site of inflammation.

Methods:

A whole blood culture system that allows for up to 48 hours of whole blood culturing was utilized for all experiments.  This technique allowed for exploring the effect of NKG2A blockade in the context of the complex interactions that exist in the periphery with minimal manipulation. 

Results:

The addition of the anti-NKG2A mAb to the whole blood cultures led to alteration of the surface phenotype of NK cells from rheumatoid arthritis patients.  These alterations included the up-regulation of chemokine receptors as well as the modulation of CD27.  This appeared to be a specific pattern of up-regulation as a wide panel of NK related receptors were explored and were not found to be altered.  This up-regulation was also found to be rapid occurring within 24 hours of culture.  Finally the effect was specific to RA patients as similar changes were not seen in normal donors. 

Conclusion:

These results indicate that treatment with an anti-NKG2A mAb may alter the homing potential of an NK cell to the site of inflammation.  Once at the site of inflammation the presence of the anti-NKG2A mAb may skew the inhibitory balance and thus enable the elimination of stressed and/or inflamed cells.  These two activities provide a novel mechanism of action, via the anti-NKG2A mAb, for the treatment of RA.


Disclosure:

J. Wahle,

Novo Nordisk,

3;

J. Bui,

Novo Nordisk,

3;

K. Bontadelli,

Novo Nordisk,

3.

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