Human Multipotent Adult Progenitor Cells Are Nonimmunogenic and Exert Potent Immunomodulatory Effects on Alloreactive T-Cell Responses

Abstract

Multipotent adult progenitor cells (MAPCs) are bone marrow-derived nonhematopoietic stem cells with a broad differentiation potential and extensive expansion capacity. A comparative study between human mesenchymal stem cells (hMSCs) and human MAPCs (hMAPCs) has shown that hMAPCs have clearly distinct phenotypical and functional characteristics from hMSCs. In particular, hMAPCs express lower levels of MHC class I than hMSCs and cannot only differentiate into typical mesenchymal cell types but can also differentiate in vitro and in vivo into functional endothelial cells. The use of hMSCs as cellular immunomodulatory stem cell products gained much interest since their immunomodulatory capacities in vitro became evident over the last decade. Currently, the clinical grade stem cell product of hMAPCs is already used in clinical trials to prevent graft-versus-host disease (GVHD), as well as for the treatment of acute myocardial infarct, ischemic stroke, and Crohn's disease. Therefore, we studied the immune phenotype, immunogenicity, and immunosuppressive effect of hMAPCs in vitro. We demonstrated that hMAPCs are nonimmunogenic for T-cell proliferation and cytokine production. In addition, hMAPCs exert strong immunosuppressive effects on T-cell alloreactivity and on T-cell proliferation induced by mitogens and recall antigens. This immunomodulatory effect was not MHC restricted, which makes off-the-shelf use promising. The immunosuppressive effect of hMAPCs is partially mediated via soluble factors and dependent on indoleamine 2,3-dioxygenase (IDO) activity. At last, we isolated hMAPCs, the clinical grade stem cell product of hMAPCs, named MultiStem, and hMSCs from one single donor and observed that both the immunogenicity and the immunosuppressive capacities of all three stem cell products are comparable in vitro. In conclusion, hMAPCs have potent immunomodulatory properties in vitro and can serve as a valuable cell source for the clinical use of immunomodulatory cellular stem cell product.

Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity

“…This is in agreement with a recent report illustrating that human MAPCs are nonimmunogenic and suppress T cell proliferation in an IDOdependent and PGE 2 -independent manner (40). In addition, our Transwell system reveals that maximal suppression is achievable solely by secreted factors, provided that MAPCs are in close proximity to activated PBMCs.…”

Single and Multiple Dose MultiStem (Multipotent Adult Progenitor Cell) Therapy Prophylaxis of Acute Graft-versus-Host Disease in Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Phase 1 Trial

“…These conditions allow for maintaining activity of the telomerase enzyme, which, as a consequence, contributes to an increase in expansion capacity before senescence [13]. MAPC also possess active immunomodulatory and antiinflammatory properties [14][15][16], and comparison studies with MSC in side-by-side cultures have been favorable [13]. The MultiStem (Athersys, Inc., Cleveland, OH) product is a clinical-grade expanded MAPC population that appears nonimmunogenic, can suppress activated T cell proliferation, and has anti-inflammatory and angiogenic properties in both in vitro and in vivo rodent models [15,17].…”

Secretion of immunoregulatory cytokines by mesenchymal stem cells

“…IDO is one of the key immunoregulators secreted by MSCs, tumors and during pregnancy. IDO is expressed by a wide range of MSCs, like decidual MSCs [167] , amnionic fluid MSC [168] , multipotent adult progenitor cells (MAPCs) [169] , umbilical cord MSCs [170] , AT-MSCs [171] etc. IDO expression is species specific.…”