The 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.
We 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.
Immune response was weak and transient, with reactivity decaying during the first year. Consistently, better donor-recipient HLA matching did not enhance efficacy.
This 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.
1 Institute for Molecular Biology and Genetics (IBGM), University of Valladolid and Spanish National Council (CSIC), Valladolid, Spain.
2 Division of Traumatology, Valladolid University Clinic Hospital, Valladolid, Spain.
3 Infection and Immunity Medical Investigation Unit (IMI), Microbiology and Immunology Service, Valladolid University Clinic Hospital, Valladolid, Spain.
Published online 17 August, 2017.
Received 15 June 2017. Revision requested 14 July 2017.
Accepted 15 July 2017.
J.G.-S. and A.S. are members of the Board of Directors of Citospin, a spin-off the University of Valladolid that specializes in Good Manufacturing Practices (GMP)-compliant cell production. No other disclosures are reported.
Funding/Support: Financial support from the Red de Terapia Celular of the Instituto de Salud Carlos III (RD16/0011/0003) and from the Centro en Red de Medicina Regenerativa de Castilla y León are gratefully acknowledged. EU cofinanced these grants through the European Regional Development Fund. The sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the article.
J.G-S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. J.G-S. and M.N. participated in the conception and design of the article. A.V.N. and M.N. were primarily responsible for the clinical and analytical work, and A.S. for the cell production. All authors participated in analysis, discussion, and interpretation of data, revised the report, and gave final approval of the version to be published. J.G-S. assembled all data and wrote the final form of the article.
The authors declare no conflicts of interest.
Correspondence: Javier García-Sancho, MD, PhD, IBGM, University of Valladolid, c/Sanz y Fores, 3; 47003, Valladolid, Spain. (firstname.lastname@example.org).
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