Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis

Abstract

<jats:sec><jats:title>Objectives</jats:title><jats:p>To clarify the key role of circulating interferon-γ (IFN-γ) and to improve the clinical efficacy of mesenchymal stem cell (MSC) transplantation (MSCT) in patients with rheumatoid arthritis (RA).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Study of wild-type or IFN-γR<jats:sup>-/-</jats:sup> MSCT was first evaluated in a murine model of collagen-induced arthritis (CIA) following which a phase 1/2 randomised controlled study was conducted in 63 patients with RA who responded poorly to regular clinical treatments. Subjects were randomly assigned to an MSCT monotherapy group (n=32) or an MSCT plus recombinant human IFN-γ treatment group (n=31), with 1 year of follow-up. The primary end points consisted of efficacy as assessed as good or moderate EULAR response rates and the proportion of patients at 3 months attaining American College of Rheumatology 20 (ACR20) response rates.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the murine studies, wild-type MSCT significantly improved the clinical severity of CIA, while IFN-γR<jats:sup>-/-</jats:sup> MSCT aggravated synovitis, and joint and cartilage damage. Transitioning from the murine to the clinical study, the 3-month follow-up results showed that the efficacy and ACR20 response rates were attained in 53.3% patients with MSCT monotherapy and in 93.3% patients with MSCT combined with IFN-γ treatment (p&lt;0.05). No new or unexpected safety issues were encountered in 1-year follow-up for either treatment group.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The results of this study show that IFN-γ is a key factor in determining the efficacy of MSCT in the treatment of RA, and that an MSC plus IFN-γ combination therapeutic strategy can greatly improve the clinical efficacy of MSC-based therapy in RA patients.</jats:p></jats:sec>

Correspondence to: ‘Combination of human umbilical cord mesenchymal (stromal) stem cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis’

“…We read with great interest the article by He et al, which the authors reported that mesenchymal stem cell (MSC) transplantation (MSCT) plus interferon-γ (IFN-γ) combination therapy may realise clinical efficacy featuring good or moderate EULAR responses in patients with rheumatoid arthritis (RA) who responded poorly to conventional therapeutics including disease-modifying antirheumatic drugs. 1 MSC-based therapies have become novel therapeutic approaches for RA through immunomodulation, including the induction of T regulatory cells (Treg). 2 We agree with the authors that IFN-γ-primed MSCs may bring about improved immunomodulation in vitro (as suggested in Figure 2 by He et al 1 ), and propose that the results based on studies in patients could be juxtaposed with further evidence on the protocol of IFN-γ treatment, serum levels of IFN-γ in patients and gating strategies for flow cytometry (FC) analysis.…”

“…1 MSC-based therapies have become novel therapeutic approaches for RA through immunomodulation, including the induction of T regulatory cells (Treg). 2 We agree with the authors that IFN-γ-primed MSCs may bring about improved immunomodulation in vitro (as suggested in Figure 2 by He et al 1 ), and propose that the results based on studies in patients could be juxtaposed with further evidence on the protocol of IFN-γ treatment, serum levels of IFN-γ in patients and gating strategies for flow cytometry (FC) analysis.…”

“…As the therapeutic effect of MSCT for RA is regulated by endogenous IFN-γ level, 3 the clinical protocol of IFN-γ treatment in this study involved intramuscular infusion of IFN-γ. 1 On the contrary, the protocol adopted in vitro was IFN-γ priming using MSCs pretreated with IFN-γ for 24 hours (as mentioned in the MSC and T cell co-culture section in Supplementary Materials by He et al 1 ), which would allow for potentiated immunomodulatory functions of MSCs. However, compared with transplanting MSCs primed with IFN-γ, the intramuscular infusion of IFN-γ may initiate further immune reactions 4 5 that have yet been pinpointed in this study.…”

“…However, compared with transplanting MSCs primed with IFN-γ, the intramuscular infusion of IFN-γ may initiate further immune reactions 4 5 that have yet been pinpointed in this study. 1 From a translational standpoint, interpreting the safety of IFN-γ-primed MSC protocols as that of recombinant IFN-γ monotherapy, should be not appropriate. As a result, the discrepancy between these protocols could attribute to underestimated complications of the combination therapy.…”

Response to: ‘Correspondence to: ‘Combination of human umbilical cord mesenchymal stem cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis’’ by Maet al

“…We thank Ma et al 1 for their interest in our recent report titled 'Combination of human umbilical cord mesenchymal stem (stromal) cell transplantation with IFN-γ treatment synergistically improves the clinical outcomes of patients with rheumatoid arthritis'. 2 Ma et al 1 brought up an important issue regarding the safety profile of intramuscular infusion of interferon (IFN)-γ, which may initiate further immune reactions. 3 4 As previously described, recombinant human IFN-γ monotherapy is known to be safe but ineffective in treating rheumatoid arthritis.…”