The DARC side of GWAS.

received isolated fractions of T cells demonstrating that allogeneic CD4 ϩ T cells, and not CD8 ϩ T cells, were the predominant effectors. In addition, using transplantation protocols that included donor T cells isolated from Fas ligand– deficient mice and in separate experiments bone marrow from Fas-deficient donors, the authors clearly showed that Fas-Fas ligand interactions were necessary to mediate the hematopoietic loss, and that the targets for GVHD were not the re-populating hematopoietic progenitors. This last observation is very intriguing as it suggests that host cells with functions in hematopoietic support could be targets of the GVHD. To investigate this notion, hematopoietic progenitors were isolated from animals with ongoing GVHD and control chimeras and retrans-ferred into myeloablated hosts. These experiments, done in a competitive reconstitu-tion setting compared with untreated progenitors , showed that hematopoietic progenitors isolated from GVHD mice could reconstitute lethally irradiated recipients in a multilineage fashion to the same extent as progenitors isolated from control groups. As expected for host mice deficient in hematopoietic support, syngeneic hematopoietic progenitors failed to engraft efficiently in mice undergoing GVHD. Advances in the field of bone marrow hema-topoiesis have described multiple nonhemato-poietic cells with the potential of contributing to the homing, maintenance, and renewal of early hematopoietic progenitors. These cells collectively define " hematopoietic niches " and include cells of the osteoblastic lineage, vascular endo-thelium, and cells of the sympathetic nervous system. 3-7 The relative importance of each of these components has been a point of debate, and new concepts are emerging on their specific roles supporting hematopoiesis at different levels and in different physiologic conditions. To identify which of these compartment(s) could be affected by the GVHD process, the authors made a comparative histologic analysis of the bone marrow in animals with GVHD and control counterparts. These studies showed a dramatic decrease in osteoblastic cells, identified by their endosteal location and morphology. These cells were almost absent as early as 7 days after transplanta-tion. Their osteoblastic identity was established by strict complementary approaches including evaluation of expression of osteoblast lineage-specific genes, and measurement of rate of bone formation by dynamic histomorphometry. These 2 parameters were completely obliterated as product of the GVHD, documenting a dramatic compromise of the osteoblast compartment. Vascular parameters measured as micro-vascular permeability were also affected. However, there was not a parallel loss of endo-thelial cells. GVHD in the experimental model caused major disruptions in the bone …