Background/Purpose: Current treatment strategy of polymyositis/dermatomyositis calls for administration of high dose glucocorticoids and additional immunosupressants when necessary. These options are based largely on successful experiences in treatment of other systemic autoimmune disorders. This is partly because no appropriate animal models were available for basic and preclinical studies. We have developed a new polymyositis model, C-protein induced myositis (CIM) of mice, and disclosed that muscle-reactive killer CD8 T cells and activation of muscular innate immunity are both critical therapeutic targets specific for myositis. To develop a new treatment that addresses specific pathology, CD226 (DNAM-1), which expressed on T cells to promote killer cell function upon interaction with its ligands, was investigated as a candidate therapeutic target.

Methods: Expression of CD112 and CD155, both of which are ligands of CD226, was studied with RT-PCR and immunostaining. In vitro effects of CD226 ligation on CD8 T cells were studied by stimulating mouse splenic CD8 T cells with monoclonal anti-CD226 antibodies (Tx42) and anti-CD3 antibodies immobilized onto microtiter wells. IFNγ in the culture supernatants was quantified with specific ELISA. Mice were immunized with recombinant skeletal muscle C-protein fragments/complete Freund’s adjuvant for CIM induction and treated with intact Tx42, F(ab’)2 of Tx42, or controls. Treatment was initiated before or after the myositis onset.

Results: C2C12 myoblasts and C2C12-derived myotubes expressed CD155 but not CD112 at the mRNA and protein levels. Mouse muscle tissues expressed CD155 mRNA. In vitro treatment of splenic CD8 T cells with immobilized Tx42 augmented IFNγ secretion when the T cells were stimulated with anti-CD3 antibodies. The augmentation was more obvious when the CD3 antibody concentration was low. CIM was ameliorated when immunized mice were treated with F(ab’)2 of Tx42 both in preventive and therapeutic protocols. Intact Tx42 was not effective in either protocol.

Conclusion: Muscles express CD155, which is a ligand of CD226. Blockade of CD226 with Tx42 F(ab’)2, but not with intact Tx42, suppressed CIM. In vitro agonistic effects of immobilized Tx42 in CD8 T cell activation suggested that abrogation of Fc mediated cross-linking by F(ab’)2 preparation is essential for the therapeutic effects of the anti-CD226 antibodies. Killer cell inhibition by CD226 blockade should be a new therapeutic approach that addresses specific pathology of polymyositis and possibly dermatomyositis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/killer-t-cell-inhibition-by-cd226-blockade-for-treatment-of-inflammatory-myopathy/