61 While the latter, negative results do not allow for unequivocal identification of the responsible compartment (for which there is a choice of at least two likely candidates, ie, MAPK inhibitor peripheral nerves65 and FDCs), titration experiments indicate that adoptive bone marrow transfer robustly reconstitutes the capability of the spleen to accumulate (and perhaps replicate) prions of the Rocky Mountain Laboratory (RML) strain after intraperitoneal inoculation.61 This latter result was unexpected, and may suggest that hematopoietic cells (perhaps lymphocytes) may replicate prions, or may be otherwise involved in the transport of the agent from the site Inhibitors,research,lifescience,medical of inoculation to the

spleen. Brown and colleagues have recently reported that, using a different prion strain called ME7, no accumulation of prions was detected in spleens of 13 PrPC knockout mice reconstituted with PrPC-positive hematopoietic

cells and killed at unspecified “intervals Inhibitors,research,lifescience,medical through the incubation period.”66 Our laboratory has therefore repeated the experiments Inhibitors,research,lifescience,medical published previously and confirmed their unambiguous reproducibility in a large-scale study involving assessment of prion titers and PrPSc accumulation at 30, 60, 90, 120, and 270 days after inoculation in mice (P. Käser et al, unpublished results). Assuming that the experimental design of the Zurich and the Edinburgh studies is indeed comparable, the discrepancy between the Blättler results and those reported

by Brown point to the possibility that different prion strains exhibit different tropisms for specific components of the immune system. There maybe precedents for this: BSE Inhibitors,research,lifescience,medical prions are hardly detectable in lymphoid organs (with the possible exception of gut-associated lymphoid tissue for a transient period of time), while nvCJD prions extensively colonize human lymphoid organs. The identification of the molecular Inhibitors,research,lifescience,medical determinants of such differences in organ tropism may shed light on a basic mechanism of prion pathogenesis, and is also of prime public health interest for the reasons detailed above. Anatomy of prion neuroinvasion Suplatast tosilate What are the cellular requirements for the lympho-invasion of prions? This question was addressed by screening mouse strains with spontaneous and engineered deficiencies in various compartments of the immune system. From these studies, one clear-cut result emerged: any genetic defect that impairs the terminal differentiation of B lymphocytes completely blocks the colonization of lymphoid organs by prions, as well as the development of disease in the CNS upon peripheral inoculation.67 This phenomenon is obviously due to a block of neuroinvasion, since B-cell-deficient mice display the same susceptibility to disease as wild-type mice when inoculated intracerebrally.