To address the issue of comparing and contrasting suppressive cell populations with cell therapy potential, a series of investigative workshops have been planned within the context of The ONE Study. The first of these workshops has already taken place this year with an emphasis exclusively on producing and comparing suppressive populations of cells derived from monocytes, namely tolerogenic dendritic cells (tol DCs), myeloid-derived suppressor cells (MDSCs), IL-10-induced DCs (DC-10 cells) and regulatory macrophages (M regs)[11, 12]. A central premise of this workshop is that each cell type is produced side-by-side in a single laboratory from the same leucapheresis products, thus eliminating differences attributable to cell sources and inter-laboratory conditions. This type of collaborative effort is only possible through a large-scale integrating grant such as The ONE Study. While the final results of this first workshop are still pending, the assembled group of workshop participants decided it would be informative to perform a separate review of each of the monocyte-derived regulatory cell populations under investigation.
In the current issue of Transplantation Research, workshop participants present literature and their perspectives on the specific cell population that they produced for comparison. It is important to keep in mind that the workshop investigators are studying the different monocyte-derived regulatory cells more from a cell production standpoint, versus taking a view towards normal physiological development. Indeed, the in vivo temporal and complex signals directing a blood monocyte or tissue macrophage to become activated, to take on professional antigen-presenting functions, to migrate to lymphoid structures, or to become suppressive, are not fully understood. However, the workshop participants primarily aim to distinguish or show similarities between suppressive monocyte-derived cell populations that can be generated under defined in vitro conditions. This is an important undertaking since cell therapy applications demand an ex vivo cultivation phase to manufacture a homogenous and reproducible cell product.
For comparison, six cell populations were derived from blood monocytes by investigators of the workshop group: (1) tol DCs, (2) DC-10 cells, (3) rapamycin-conditioned DCs (rapa DCs), (4) MDSCs, (5) M regs and (6) monocytes conditioned with mesenchymal stem cells (MSCs). The variety of stimuli that are considered for cell production is especially evident with tol DCs. The workshop group concentrated on tol DCs generated under conditions including stimulation with low concentrations of GM-CSF, and with combinations of GM-CSF, IL-4 and IL-10 (DC-10 cells) or rapamycin (rapa DCs). Besides comparing the characteristics (gene expression, phenotype, function, etc.) of these closely related cells to each other, they are comparable to cells such as MDSCs, which can be generated under similar conditions, but in the presence of prostaglandin E2 or other stimuli. Interestingly, to further show the potential overlapping properties of monocyte-derived suppressive cells, recent evidence suggests that MSCs mediate their immunosuppressive effect through induction of an auxiliary macrophage via IL-10 or prostaglandin E2; whether these conditioned macrophages are unique or similar to other suppressive macrophages is a question to be addressed through the workshop. Finally, our own group in Regensburg has been actively studying the suppressive properties of monocyte-derived cells generated through M-CSF-induced maturation in combination with late ex vivo interferon gamma stimulation (M regs). While M regs have a distinct phenotype compared to other known suppressive macrophages, and have already been used in a limited number of transplant recipients, it remains unclear how these cells compare phenotypically and functionally to ex vivo generated tol DCs or MDSCs; The ONE Study workshop also seeks to answer this question.
In preparing to assess the results of the first ONE Study workshop on monocyte-derived suppressor cells, the involved investigators deemed it useful to review the present literature on tolerogenic DCs and macrophage/myeloid derived suppressor cell populations. The authors of the reviews consider the similarities and differences of these closely related cell populations, and suggest how they may best be applied as a cell therapy meant to reduce organ transplant rejection. Indeed, cell therapy is entering a critical early phase of testing in transplantation, mandating that we take the necessary steps to determine which cell populations are most adaptable and effective for this purpose. The reviews in this issue of Transplantation Research offer a view into the future of cell therapy involving suppressive cells derived from readily available circulating monocytes.