Influence of HLA Matching on the Efficacy of Allogeneic Mesenchymal Stromal Cell Therapies for Osteoarthritis and Degenerative Disc Disease

Abstract

BackgroundThe necessity for more effective therapies for chronic osteoarticular diseases has led to the development of treatments based on mesenchymal stem cells (MSCs), the natural precursors of musculoskeletal tissue. Treatments with autologous MSCs yielded excellent results, with nearly 70% improvement of pain and disability in osteoarthritis and degenerative disc disease. Using allogeneic MSCs is logistically more convenient and would widen the pool of eligible patients, but potential immune rejection should be considered. In this context, MSCs are purportedly immune evasive and better tolerated than other cell types.MethodsWe used samples collected during the performance of 2 randomized clinical trials using allogeneic bone marrow MSCs for treatment of osteoarthritis (NCT01586312) and degenerative disc disease (NCT01860417). Serum samples were used to determine anti-HLA antibodies, whereas either blood or MSC samples were used for HLA typing of recipients and donors, respectively. Algofunctional indexes were used as indicators of clinical evolution, and the correlation between the number of donor-host HLA mismatches and the efficacy of treatment was determined.ResultsImmune response was weak and transient, with reactivity decaying during the first year. Consistently, better donor-recipient HLA matching did not enhance efficacy.ConclusionsThis lack of reactivity is presumably due to the cooperation of 2 factors, (1) downregulation of the host immune responses by the transplanted MSCs and (2) effective insulation of these cells inside the articular cavity or the intervertebral disc, respectively. Interestingly, better HLA matching did not enhance efficacy. These observations have medical relevance as they support the clinical use of allogeneic cells, at least as a single-dose administration. Multiple-dose applications will require further research to exclude possible sensitization.

Evaluation of Mesenchymal Stem Cell Therapy for Sepsis: A Randomized Controlled Porcine Study

“…There is the lack of studies comparing effects of matched vs. mismatched MSCs in the large animal model of sepsis. However, the clinical study of the team of Garcia-Sancho (34) showed that better HLA matching of donor MSCs with recipients did not enhance the efficacy of MSCs therapy in osteoarthritis and degenerative disc disease. Furthermore, there are several completed clinical trials applying allogenic MSC without any analysis of donor MSCs and recipient matching (5,(35)(36)(37) indicating that the donor MSCs and recipient matching may not play the role in MSCs potency.…”

Immunomodulatory Effect of Adipose-Derived Stem Cells: The Cutting Edge of Clinical Application

“…In fact, it has been observed that the immunogenicity of ASCs decreases with cell passaging, so that cells at low passages are more immunogenic than those at higher passages (McIntosh et al, 2006), and that ASCs are not fully immune privileged, since they elicit both humoral and cellular immune response in vivo, depending on the microenvironment (Ankrum et al, 2014). Also ASC differentiation may alter their immunogenic phenotype, increasing HLA class-I and HLA class-II expression (García-Sancho et al, 2017), as well as culturing condition (e.g., use of human serum or serum-free conditions) (Patrikoski et al, 2014).…”

Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

“…Four clinical trials have been published that have documented the presence/absence of anti-HLA antibodies in patients after allo-MSC therapy for various disease indications, including osteoarthritis, Crohn’s disease, and Type II diabetes. Results published by Garcia-Sancho et al on the influence of HLA-matching on the efficacy of allogeneic MSC therapy in osteoarthritis and degenerative disk disease ( 43 ), indicated that only a very limited number of patients receiving MSC had developed anti-donor antibodies and, surprisingly, better donor–recipient HLA-matching did not enhance efficacy. In another clinical trial for complex perianal fistulas in Crohn’s disease, Panés et al reported that allogeneic adipose-derived mesenchymal stem cells (Cx601) treated patients developed donor-specific antibodies ( 44 ).…”

“…Alternative cell types could be investigated to replace damaged tissue ( 55 , 56 ), or in-depth studies into the mechanism of action of, e.g., licensed MSC may yield candidate molecules which could replace cell therapy altogether. Investigation of alternative routes of administration (e.g., “inert” locations such as the articular cavity or intervertebral disk ( 43 ) which may lower the “visibility” of the cells to the host immune system. A detailed understanding of how allo-MSC cell death affects their immunogenic or tolerogenic properties and how (or if) allo-MSC cell death regulates ensuing anti-donor immune responses.…”

“…Investigation of alternative routes of administration (e.g., “inert” locations such as the articular cavity or intervertebral disk ( 43 ) which may lower the “visibility” of the cells to the host immune system.…”