Immune-activated cellular therapies for osteoarthritis and the role of immune recognition of joint antigens

Abstract

Osteoarthritis (OA) is a progressive, degenerative condition that affects over 550 million people worldwide – a 113% increase since 1990. Despite this high prevalence, there remains a lack of effective treatment options that improve quality of life without risk of adverse effects. Recent evidence supports that OA is a multifactorial condition in which the immune system plays a key role to perpetuate chronic inflammation. Cellular therapies to treat OA have emerged as an option, with mixed results reported in terms of efficacy. Heterogeneity within stromal cell populations has been proposed to be partially responsible for the observed variability in therapeutic responses, particularly in the context of variably inflamed recipient environments such as that seen in OA. Pre-activation, or 'inflammatory licensing' of mesenchymal stromal cells (MSC) through priming their respective ligands has been proposed as a means to generate a homogeneous population of immunomodulatory MSCs – thereby potentially improving their therapeutic consistency in the inflammatory environment of OA. The work in this defense addresses three primary aims: 1) to further investigation the role of the adaptive immune system in OA, investigating autoantibody production to synoviocytes and chondrocytes in OA progression, 2) to evaluate further mechanistically how innate immune pathway activation of mesenchymal stromal cell therapy modulates interactions of MSC with synovium and cartilage to mitigate OA progression, and 3) to examine alternate connective tissue sources of MSC for cell expansion as regenerative therapies. With the lifetime likelihood to develop symptomatic knee OA currently 45% and increasing, the need to develop improved strategies towards disease-modification is critical.