Exogenous stem or progenitor cells:Autologous and allogeneic MSCs

Mesenchymal stem cells and immune modulators

Mesenchymal stem cells (MSCs) are nonhematopoietic stem cells of mesodermal origin, with the capacity to differentiate into both mesenchymal and nonmesenchymal lineages. MSCs are found primarily in the bone marrow of adults and give rise to blood, skeletal muscle, vascular, and connective tissues throughout the body. Postnatally, bone marrow MSC can be isolated from adipose tissue, liver, synovial membrane, teeth, and tendons. In particular, MSCs are easily isolated from a small aspirate of bone marrow and can be expanded with high efficiency. MSCs have great potential in clinical therapy because they express intermediate to low levels of HLA Class I, low levels of HLA Class II, and low levels of costimulatory molecules to avoid self-recognition by the immune system.69 In immunocompetent patients, MSCs have also been demonstrated to suppress allogeneic T-cell proliferation and evade alloreactive recognition.70 The immunomodulatory properties of MSCs are thought to involve the secretion of soluble mediators and cell-cell contact inhibition; however, the exact mechanisms of action are unclear.71 In an acute lung injury model in mice using bleomycin, systemic administration of MSCs has been demonstrated to decrease the accumulation of collagen, fibrosis and levels of matrix metalloproteinases.68 The proposed mechanism of action for these findings was the secretion of interleukin-1 receptor antagonist by the MSCs.72 In endotoxin-induced lung injury models, intratracheal administration of MSCs has been demonstrated to decrease mortality, tissue inflammation, and concentrations of inflammatory mediators (in particular TNFα and MIP 1β) within bronchoalveolar lavage fluid.73 Recent studies suggest that the release of angiopoietin-1 by MSCs is potentially another important mechanism in stabilizing the endothelial fluid leak and maintaining alveolar-capillary barrier function in an endotoxin injury model.74,75

Clinical trials of MSCs

Autologous and allogeneic MSCs are currently being tested in clinical trials for a variety of diseases including Crohn’s disease, multiple sclerosis, diabetes mellitus and end-stage liver disease, and to prevent transplant rejection and restore left ventricular function in patients with congestive heart failure.76 An open-label Phase II trial utilizing Prochymal^®, an allogenic MSC infusion in patients with severe Crohn’s disease, who were unresponsive to corticosteroids, infliximab (anti-TNF antibody), and other immunosuppressive therapies, has recently been completed. The study reported significant improvements in symptoms as assessed by the Crohn’s disease activity index (CDAI). This has led to the approval by the Food and Drug Administration for a Phase III double-blind, placebo-controlled trial of this therapy for the treatment of Crohn’s disease.77

In 2008, Osiris therapeutics initiated a multi-center, double-blind, placebo-controlled Phase II clinical trial of Prochymal in patients with moderate to severe COPD. At the six-month interim report, the trial contained 62 patients (58% men). The age range of the subjects was from 47 to 80 years, and 23 of the patients had moderate and 39 had severe disease. The important findings of the interim report were that Prochymal was safe and significantly reduced systemic inflammation in these patients compared with those receiving placebo, as determined by circulating levels of C-reactive protein.78 However Prochymal did not significantly alter lung function in these patients.78 Final completion of this two-year trial will provide new insights in the potential utility of MSCs in treating patients with COPD.

Conclusion

Despite significant progress in our understanding of lung stem cells and their functional capacities over the past decade, much remains unknown about the processes involved in lung repair. Accumulating data from both animal models and clinical trials suggest that adult-derived stem cells may provide potential therapeutic strategies for lung repair in COPD. Pivotal clinical trials are currently underway, which in a few years will provide major insights on the utility of using stem and progenitor cells as therapeutic agents in COPD.