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Efficacious MSC treatment for Arthritis

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Original article from Stem Cells Translational Medicine

"Comparison of Drug and Cell-Based Delivery: Engineered Adult Mesenchymal Stem Cells Expressing Soluble Tumor Necrosis Factor Receptor II Prevent Arthritis in Mouse and Rat Animal Models"

Tumor necrosis factor-α (TNFα) is a cytokine that mediates normal homeostatic mammalian processes (Schaible et al and Wajant et al) but has been linked to the systemic autoimmune disease Rheumatoid Arthritis (RA), where a TNFα induced cytokine cascade causes inflammation and joint destruction.   Blocking TNFα function would therefore seem a viable means to treat RA.   Etanercept, a TNF receptor (TNFR) linked to the immunoglobin Fc fragment and two monoclonal antibodies, infliximab and adalimumab are three TNFα inhibitors approved in the United States (Mazza et al), while TNFα blockers certolizumab pegol and golimumab are also utilised  (Wallis and Scallon et al).   However, the necessity for systemic delivery leads to certain unwanted side-effects, and so site-specific drug action is being sought after.   To this end, in a report in Stem Cells Translational Medicine, researchers led by Joseph D. Mosca at Osiris Therapeutics, Inc., Baltimore, Maryland, USA have published the results of their studies on the potential use of mesenchymal stem cell (MSC)-based TNFR delivery and the efficacy of this treatment compared to the use of etanercept (Liu et al).

Primary hMSCs from three donors were isolated, cultivated and transduced with a replication-defective MuLV vector expressing human soluble TNFR (hsTNFR) linked with the human IgG1 Fc and eGFP.   Transduction used a centrifugation step which allowed for an efficacy of 90% as compared to a static transduction protocol.   Subsequent hsTNFR secretion was closely correlated to the percentage of eGFP+ cells, which was stable during cell passaging and furthermore, integration of the transgene was noted not to affect multidifferentiation potential of the MSCs.

Functionality of hMSCs was assessed in vitro and in vivo using a variety of assays.   In vitro assays found that supernatant from hsTNFR-hMSCs could block TNFα-mediated nitric-oxide synthetase activity in bovine articular chondrocytes, while transduced hMSCs did not upregulate the expression of ICAM-1 on the cell surface in response to TNFα (Schultz et al) due to the neutralizing effect of hsTNFR molecule expression.   In vivo analyses in NOD/SCID mice studied the implantation of hsTNFR-hMSCs with or without a bio-scaffold, finding that intramuscular injections of cells alone and sub-cutaneous implanted cells seeded into polyglycolic acid (PGA) felt pads led to the highest systemic levels of hsTNFR, with the PGA pads allowing for sustained expression for 4 weeks.   Efficacy of hsTNFR was shown through the reduction in serum levels of TNFα after transplantation of hsTNFR-transduced hMSCs alongside TNFα-transduced hMSCs.   Further proof of efficacy was shown through the ability of hsTNFR-hMSCs to inhibit cytokine storm (a potentially fatal immune reaction) after lipopolysaccharide (LPS) challenge, an endotoxin that binds the CD14-TLR4-MD2 receptor complex to promote the secretion of proinflammatory cytokines, mediated by blocking TNFα biological activity.   Importantly, this was noted to be more efficient that treatment with etanercept, which did not remove the CD14-TLR4-MD2 receptor complex from circulation.

After confirming expected in vivo and in vitro activity, hsTNFR-hMSCs were tested for their activity in an immune-deficient mouse arthritic model (BalbC/SCID mice), mediated through administration of an anticollagen type II monoclonal antibody cocktail and LPS.   Prior to arthritis-induction, mice were injected intramuscularly with transduced or untransduced hMSCs into the hind limb.   While mice injected with untransduced hMSCs showed signs of arthritis (swelling and redness of paws, severe cartilage destruction and inflammatory cell infiltration), excitingly, animals injected with hsTNFR-hMSCs showed no such signs, and were comparable to naïve paws.    Additional analysis in an immune-competent Fischer rat arthritic model found that etanercept showed a similar anti-inflammatory/efficacy to hsTNFR-hMSCs after collagen-induced arthritis.

In conclusion, this detailed paper details the beneficial effect of hsTNFR-hMSCs in animal models of arthritis; with the cell-mediated delivery mode of hsTNFR delivery being as efficacious as the "drug" form (etanercept) in a rat model.   The combination of this data and the known homing ability of hMSCs to damaged tissues (Hong et al, Karp and Leng Teo and Myers et al) suggests that hsTNFR-hMSCs could be an effective therapeutic alternative to other systemic forms of arthritis treatment.  This could also theoretically lead to a reduction in unwanted side effects from continued drug injection, with drugs requiring to be injected daily as compared to an injection of cells every 3 to 6 months.   Use of hESCs may necessitate additional immunosuppression, although the use of patient-specific induced pluripotent stem cells (iPSCs) may remove this obstacle.

References

Hong HS et al (2012)
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Karp JM, Leng Teo GS (2009)
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Cell Stem Cell 4:206–216

Mazza J et al.
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Dermatol Clin 2010;28:559–575

Myers TJ et al. (2010)
Mesenchymal stem cells at the intersection of cell and gene therapy.
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Scallon B et al.
Binding and functional comparisons of two types of tumor necrosis factor antagonists.
J Pharmacol Exp Ther 2002;301:418– 426

Schaible HG et al.
The role of proinflammary cytokines in the generation and maintenance of joint pain.
Ann NY Acad Sci 2010;1193:60–69

Shultz LD, et al.
Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice.
J Immunol 1995;154:180–191

Wajant H et al.
Tumor necrosis factor signaling.
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Wallis RS.
Tumor necrosis factor antagonists: Structure, function, and tuberculosis risks.
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From Stem Cells Translational Medicine.

Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.