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

Abstract

A major goal of immunotherapy remains the control of pathogenic T cell responses that drive autoimmunity and allograft rejection. Adherent progenitor cells, including mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs), represent attractive immunomodulatory cell therapy candidates currently active in clinical trials. MAPCs can be distinguished from MSCs on the basis of cellular phenotype, size, transcriptional profile, and expansion capacity. However, despite their ongoing evaluation in autoimmune and allogeneic solid organ transplantation settings, data supporting the immune regulatory potential of clinical-grade MAPCs are limited. In this study, we used allogeneic islet transplantation as a model indication to assess the ability of clinical-grade MAPCs to control T cell responses that drive immunopathology in human autoimmune disease and allograft rejection. MAPCs suppressed T cell proliferation and Th1 and Th17 cytokine production while increasing secretion of IL-10 and were able to suppress effector functions of bona fide autoreactive T cells from individuals with type 1 diabetes mellitus, including killing of human islets. Furthermore, MAPCs favored the proliferation of regulatory T cells during homeostatic expansion driven by γ-chain cytokines and exerted a durable, yet reversible, control of T cell function. MAPC suppression required licensing and proceeded via IDO-mediated tryptophan catabolism. Therefore, the common immune modulatory characteristics of clinical-grade MAPCs shown in this study suggest that they can be regarded as an alternative source of adult progenitor cells with similar clinical usefulness to MSCs. Taken collectively, these findings may guide the successful deployment of both MSCs and MAPCs for the amelioration of human autoimmunity and allograft rejection.

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

“…The MultiStem product is an expanded population of MAPC originating from adherent adult stem cells harvested from the BM of an unrelated volunteer, healthy donor [13,15,17,21]. For this study, stem cells isolated from a single qualified donor were expanded ex vivo in cell factories to create a cryopreserved master cell bank under current good manufacturing practice.…”

“…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].…”

“…MAPC differ from MSC as they are isolated and grown in hypoxic conditions with media, supplemented with growth factors, and grown at some confluent culture densities. 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].…”

Soliciting Strategies for Developing Cell-Based Reference Materials to Advance Mesenchymal Stromal Cell Research and Clinical Translation

“…Maintaining a hypoxic environment during culture, supplementing with growth factors including basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor, and maintaining cells at subconfluent levels are important parameters that are associated with these improvements [11,12]. These conditions are known to influence retention of telomerase activity and maintenance of signaling pathways that are associated with pluripotency in other environments [13].…”

Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia

“…Compared with MSCs, they have significantly greater proliferation potential and differentiation potential (e.g., functional endothelium in vitro as well as in vivo) [11]. Like MSCs, MAPC cells have potent immunomodulatory effects in T cells [12][13][14], are nonimmunogenic for T-cell proliferation and cytokine production and even suppress T-cell activation and proliferation induced by alloantigens and mitogens in vitro. Human MAPC cells also have inhibitory effects in natural killer cells [15].…”