Dry eye disease (DED) is a multifactorial condition in which tear film instability, hyperosmolarity, and ocular surface inflammation causes symptoms such as ocular discomfort and pain [1]. The clinical diagnosis of DED is difficult due to the complex etiology and the poor association between signs and symptoms. This leads to DED being underdiagnosed and undertreated [2]. DED can be categorized into two main types: primarily evaporative dry eye (EDE) and primarily aqueous-deficient dry eye (ADDE). However, patients often have a combination of both [3]. A common cause of ADDE is the autoimmune disorder Sjögren's syndrome (SS). In SS, a lymphocytic infiltration of the lacrimal and salivary glands causes glandular hypofunction leading to dryness of the eyes and mouth [4]. The diagnosis of primary SS is based on the “2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for primary Sjögren's syndrome”: positive anti-SSA antibodies (3 points), focal lymphocytic sialadenitis (3 points), abnormal ocular surface staining (1 point), a Schirmer test score of ≤5 mm/5 min (1 point), and a reduced unstimulated salivary flow rate (1 point). A total score ≥4 for these items fulfills the diagnostic criteria for primary SS [5]. Some patients may have SS related to another autoimmune disorder such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), which is classified as secondary SS [6].

In research on novel treatment options for DED, the underlying inflammation is a frequent treatment target. By reducing the inflammation, the vicious circle of DED can be broken, eventually alleviating the signs and symptoms of DED [7]. Topical treatment with ciclosporin A eye drops for DED has been approved in both the US and the EU and is widely used. The subjective and objective results in many clinical trials, however, are inconsistent and may not be significantly different from vehicle or lubricating eye drops alone [8]. Surgical treatments such as salivary gland and amniotic membrane transplantation have also been investigated with varying effects [9]. Further, other lacrimal gland targeted therapies for severe ADDE are currently being investigated [10]. Mesenchymal stem (or stromal) cells (MSCs) have been shown to possess anti-inflammatory and immunomodulatory capabilities, making them suitable candidates for research on inflammatory diseases such as ADDE due to SS. Numerous pre-clinical studies in different animal models have investigated MSCs as a treatment of ADDE [11]; however, only one study investigating injection of MSCs into the lacrimal gland (LG) in humans has been published. In 2021, our research group published the results of the first clinical trial demonstrating the safety and feasibility of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the LG in patients with ADDE [12]. The results of this open-label safety study indicated that injection of ASCs into the LG, in a volume corresponding to maximally 50 % of the LG volume, was a safe treatment. Furthermore, within 4 months after treatment, we found a 40 % decrease in dry eye symptoms measured with the Ocular Surface Disease Index (OSDI) and a significant improvement in fluoresceine tear break up-time (FTBUT), tear osmolarity, and Schirmer test scores. We hypothesize that injection of allogeneic ASCs into the LG reduces inflammation, resulting in decreased ocular discomfort and increased tear film stability in patients with ADDE as compared to injection of vehicle or observation only.