Introduction

Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are autoimmune diseases in which persistent inflammation, if untreated, will result in damage of the cartilage and bone of joints. Despite the use of combinations of antirheumatic drugs, corticosteroids and the newer so called biologicals (blocking the TNFα, Interleukin-1 or Interleukin-6 pathways) a proportion of individuals with arthritis remain resistant also to these therapies and suffer from a very severe, debilitating and sometimes potentially fatal disease. For children with refractory disease autologous stem cell transplantation (ASCT) is successfully performed since 1997 . Although ASCT holds considerable morbidity and even mortality, overall favourable responses were seen with a drug free remission rate of 50–55 %. In the more recent years late relapses were noted with lower percentages for drug free long term outcome .

Since a few years mesenchymal stromal cells (MSC) are a fast growing field of interest for science. MSC are adult (non-embryonic) stromal cells that are present in bone marrow, fat and in lower numbers in many other tissues. MSC are now widely studied for their regenerative capacities as well their immunosuppressive qualities . MSC have strong immunosuppressive qualities in vitro. The immunosuppression seems to work both by paracrine action and cell–cell contact. MSC inhibit NK-cells, B-cells, dendritic cells, Th1-cells and activate regulatory T-cells . Another great advantage is that MSC are valuable donor cells since they are hardly recognized by any immune systemic because they normally do not express MHC class II and only little MHC class I.

In the human joint the presence of floating single MSC in human synovial fluid (SF) is a normal phenomenon and it has been shown that they are even capable of adhesion-independent survival and expansion . The number of mesenchymal progenitor cells in SF is much lower in RA than in osteoarthritis (OA) without significant differences between early and established RA higher . Synovial fluid in RA might be impaired in recruiting MSC to the joint . Furthermore the proliferation potential of MSC in RA patients could be suppressed by the severity of the synovitis in RA or exhausted suggested by the observed telomere length decrease irrespective of previous treatments . The in vitro anti-proliferative effect of MSC on PBMCs however was preserved independent of the clinical activity of the autoimmune disease .

In preclinical studies we showed the beneficial effect of syngeneic bone-marrow derived MSC in a non-collagen induced rheumatoid arthritis model, proteoglycan induced arthritis (PGIA), which is a chronic, progressive, and self maintaining disease, where repeated inflammatory episodes eventually result in the complete deterioration of the articular cartilage . The syngeneic murine MSC administered in established arthritis were able to decrease the arthritis score and the histological analysis confirmed this clinical observation . Our findings are in agreement with a study by Augello et al., who showed in a collagen induced arthritis (CIA) model that a single intraperitoneal (ip) injection of high dose (5 million) allogeneic murine MSC in established arthritis at time of boost injection (day 21) prevented exacerbation of the clinical severity and the occurrence of bone and cartilage erosions in the joints . Also Mao et al. and Gonzalez et al. showed that injection of 1–5 million xenogenic MSC intravenously or ip could prevent the occurrence or deterioration of CIA. The effect depended on timing, dose and route of administration of MSC . Immortalized MSC from the C3-celline have been shown to worsen CIA , whereas the same group showed beneficial effects on CIA when using freshly isolated MSC .

Administration of additional MSC might therefore have great potential in the treatment of inflammatory arthritis in patients. They are easily harvested and expandible outside the body and are not only immunosuppressive but also hardly recognized by the immune systemic itself . Therefore the hazardous immune ablation as needed in ASCT can be omitted. In 2004 Dr. Le Blanc published a patient with a severe graft-versus-host disease (GVHD) after an HLA identical Stromal Cell Transplantation who received MSC from his mother with a striking clinical response . This resulted in a new therapeutic approach of steroid resistant GVHD since 2006 that is being evaluated by the European Group for Blood and Marrow Transplantation. The median dose of bone-marrow derived MSC was 1.4×10 E ⁶ (min–max range 0.4-9 × 10 E ⁶ ) cells per kg bodyweight. Twenty-seven patients received one dose, 22 received two doses, and 6 three to five doses of cells obtained from HLA-identical sibling donors ( n = 5), haploidentical donors ( n = 18), and third-party HLA-mismatched donors ( n = 69). Thirty patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of MSC. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (37% vs 72%; p = 0.002) and higher overall survival 2 years after haemopoietic-stromal-cell transplantation (53% vs 16%; p = 0.018) . Since 2009 we conduct an open-label, non-randomized prospective phase II study for prednisone resistant GVHD using MSC, extracted from the bone marrow of healthy volunteers, expanded with human plasma and platelet lysate (hPPL). The current experience within the European Blood and Marrow Transplantation Group (EBMT) of more than 700 patients with aGVHD after allogeneic SCT also show that allogeneic MSC infusion is safe.

Recently, a patient group with another autoimmune disease with much lower short term mortality, systemic lupus erythematosus (SLE), was studied for the beneficial effect of MSC . Eighty-seven patients with persistently active SLE who were refractory to standard treatment or had life-threatening visceral involvement were enrolled . Allogeneic bone marrow or umbilical cord-derived MSCs were harvested and infused intravenously (1 × 10 ⁶ cells/kg of body weight). During the 4-year follow-up and with a mean follow-up period of 27 months, the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87). Disease activity declined as revealed by significant changes in the SLEDAI score, levels of serum autoantibodies, albumin, and complements. A total of five patients (6%) died after MSCT from non-treatment-related events in the 4-year follow-up, and no transplantation-related adverse event was observed. Allogeneic MSCT resulted in the induction of clinical remission and improvement in organ dysfunction in drug-resistant SLE patients.

Nowadays clinical trials have been completed or are recruiting patients for MSC injection against many diseases amongst which cardiac failure, osteoarthritis and many autoimmune diseases including lupus nephritis, systemic sclerosis, multiple sclerosis, Crohn’s disease and diabetes mellitus, and even two recent ones for rheumatoid arthritis.