LIVE CELL IMAGING REVEALS THE HETEROGENEITY OF OLFACTORY ENSHEATHING CELLS: IMPLICATIONS FOR NEURAL THERAPIES

The therapeutic transplantation of olfactory ensheathing cells (OECs)is being trialled in humans for spinal injury regeneration and other neural disorders. However in humans and in animal models of these therapies, the results have been limited or inconsistent. One reason for the variation in results is that it is often assumed that OECs are a uniform population of cells that have the same characteristics, and are therefore uniformly suitable for neural regenerative therapies. We have now used time-lapse imaging of OEC interactions to examine in detail the behavioural characteristics of anatomical and developmental subpopulations of OECs. We have found that OECs are a heterogeneous population of cells with fundamental differences in their behaviour and migration. Not only were peripheral OECs significantly different from OECs derived from the olfactory bulb, but OECs from different anatomical regions of the olfactory bulb displayed vastly different characteristics. These behaviours were consistent with their proposed roles in vivo with OECs from the olfactory bulb display a mix of adhesion, repulsion or indifference following cell-cell contact. Consistent with our previous findings, lamellipodial waves along the shaft of the OEC processes are always associated with initiating cell-cell contact and mediating the resultant behaviours of both peripheral and central OECs. These results have important implications for the use of OECs in neural regeneration therapies as it is clear that OECs are not a uniform population of cells. Instead, these cells display distinct behavioural differences depending on their topographical location and age. These differences in cell origin and behaviour are likely to contribute to the variations in OEC transplantation outcomes

Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8(+) T cells that induce GVHD without antileukemic effects

IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8(+) Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host dendritic cells (DCs) together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (eg, RORγt, T-bet) and cytokines (eg, IL-17A, IL-22, interferon-γ, granulocyte macrophage colony-stimulating factor, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD; however, Tc17 cells are noncytolytic and fail to mediate graft-versus-leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyperinflammatory, poorly cytolytic effector population, which we term "inflammatory iTc17" (iTc17). Because iTc17 cells mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL.Kate H. Gartlan, Kate A. Markey, Antiopi Varelias, Mark D. Bunting, Motoko Koyama, Rachel D. Kuns, Neil C. Raffelt, Stuart D. Olver, Katie E. Lineburg, Melody Cheong, Bianca E. Teal, Mary Lor, Iain Comerford, Michele W. L. Teng, Mark J. Smyth, James McCluskey, Jamie Rossjohn, Brigitta Stockinger, Glen M. Boyle, Steven W. Lane, Andrew D. Clouston, Shaun R. McColl, Kelli P. A. MacDonald, and Geoffrey R. Hil

CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease

Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17-dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80(+)CSF-1R(+)CD206(+)iNOS(-). Cutaneous cGVHD developed in a CSF-1/CSF-1R-dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r(-/-) mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80(+) macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and king cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti-CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD