Adult Stem Cell Treatment of Scleroderma

Alan Tyndall; Daniel E. Furst


Curr Opin Rheumatol. 2007;19(6):604-610. 

In This Article

Mesenchymal Stem Cells

MSCs are multipotent cells capable of differentiating in vitro and in vivo to different MSC lineages, including adipose tissue, bone, cartilage and myelosupportive stroma.[23,24,25,26] MSCs are found in bone marrow, skeletal muscle, adipose tissue, synovial membranes and other connective tissues of human adults.[27,28,29,30] Although controversy exists as to how best to identify MSCs, they seem best defined by using a combination of phenotypic markers and functional properties. Controversy still exists over the in-vivo phenotype of MSCs: however, ex-vivo expanded MSCs do not express the hematopoietic markers CD14, CD34, CD45 and major histocompatibility (MHC) class II.[26,31] In addition to their multipotentiality, they can be identified as cells that stain positive for CD73, CD90 and CD105, and by flow cytometry.[25,26,31,32,33]

In vitro, MSCs have vast proliferative potential, can clonally regenerate, and can give rise to differentiated progeny. They also exhibit antiproliferative and antiinflammatory properties in vitro and in vivo, making them candidates for treatment of acute inflammatory autoimmune disease.[34••] Regardless of whether or not MSCs are true stem cells, the clinical benefit from MSCs may not require sustained engraftment of large numbers of cells. It is possible that the therapeutic benefit is due to MSCs homing to inflamed tissue and the release of local cytokines and growth factors resulting in a local antiproliferative and immunomodulatory effects.

MSCs were originally thought to be immunoprivileged, in that they did not induce lymphocyte proliferation when cocultured with allogeneic lymphocytes and were not targets for CD8+ cytotoxic lymphocytes or KIR-ligand mismatched natural killer (NK) cells.[35,36,37,38] Recent data, however, suggest that in a nonimmunosuppressed host, allogeneic MSCs will be eliminated[39] and that allogeneic MSCs under some circumstances may be targeted by NK cells.[40]

In-vitro results indicate that MSCs possess immunosuppressive properties. Rodent, baboon and human MSCs suppress T and B-cell lymphocyte proliferation in mixed lymphocyte cultures or when induced by mitogens and antibodies, in a dose-dependent fashion.[35,37,38,41,42,43,44,45] The suppression is MHC independent and in human cell cultures, the magnitude of suppression is not significantly reduced when the MSCs are separated from the lymphocytes in transwells, indicating that cell-cell contact is not required.[35,38,46] The mechanisms underlying the immunosuppressive effect remain to be clarified. Various factors produced by MSCs, including hepatocyte growth factor, transforming growth factor-β1,[38] prostaglandin E2,[47] indoleamine 2,3-deoxygenase[48] and inducible nitric oxide synthetase[49] have been implicated as responsible for reduced lymphocyte proliferation. Clearly, a major antiproliferative mechanism in lymphocytes is arrest of the cell cycle in G0/G1.[45]

An immunosuppressive effect of MSC in vivo was first suggested in a baboon model, in which infusion of ex-vivo expanded donor or third-party MSCs delayed the time to rejection of histoincompatible skin grafts.[43] MSCs also downregulate bleomycin-induced lung inflammation and fibrosis in murine models, if given early (but not late) after the induction.[50] A similar effect was seen in a murine hepatic fibrosis model (carbon tetrachloride induced) using a MSC line bearing the fetal liver kinase-1 marker.[51] Tissue protective effects of MSCs were also seen in a rat kidney model of ischaemia/reperfusion injury in which syngeneic MSCs but not fibroblasts were used.[52]

Autologous bone marrow-derived MSCs have been shown to be highly antiproliferative to activated T cells from normal individuals and autoimmune (rheumatoid arthritis, SSc, Sjoegrens, systemic lupus erythematosus) patients,[53••] and in SSc patients these MSCs were normal with respect to proliferation, clonogenicity and differentiation.[54]

In the two experimental autoimmune encephalomyelitis murine models both clinical and histological improvement occurred. The responses were dependant on the timing of MSC treatment - the earlier the better - and the effects were reversed with interleukin-2 treatment, indicating that anergy rather than apoptosis had occurred.[55,56] In a murine model of arthritis, however, collagen-induced arthritis was not improved by the addition of MSCs and the in-vitro immunosuppressive effects were reversed by the addition of tumor necrosis factor-α. MSCs were not found in the joints.[57] A second murine arthritis model, however, showed a positive outcome.[58]

Ex-vivo-expanded allogeneic MSCs have been infused in several phase I studies.[59,60,61,62,63] No adverse events during or after MSC infusion have been observed and no ectopic tissue formation has been noted. After infusion, MSCs remain in the circulation for no more than an hour.[62] Although durable stromal cell chimerism has been difficult to establish, low levels of engrafted MSCs have been detected in several tissues.[60,63,64]

Infusion of haploidentical MSCs to a patient with steroid-resistant severe acute GvHD of the gut and liver promptly improved liver values and intestinal function.[65] Upon discontinuation of cyclosporine, acute GvHD recurred but was still responsive to a second MSC infusion. Lymphocytes from the patient, when investigated on multiple occasions after MSC infusion, continued to proliferate against lymphocytes derived from the haploidentical MSC donor in coculture experiments. This suggests an immunosuppressive effect of MSCs in vivo, rather than a development of tolerance.

The EBMT is currently planning protocols for prevention and treatment of acute GvHD using MSCs, through the Developmental Sub-Committee (W. Fibbe, K. Le Blanc, personal communication).


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