We observed that administration of a monoclonal antibody (MAb H81.9) directed at major histocompatibility complex (MHC) class II antigens prevents long-term hemopoietic reconstitution in irradiated dogs transplanted with autologous bone marrow, although it does not interfere with initial granulocyte recovery. These results suggested that the MAb interfered with the function of hemopoietic stem cells but not committed progenitors. The proposed studies are aimed at establishing the basis on which to define the mechanisms involved. Studies with H81.9-labeled, positively selected marrow cells will determine whether these cells are capable of hemopoietic reconstitution, which would suggest that the relevant antigen and epitope are expressed on pluripotent hemopoietic stem cells. A negative result would suggest that nonhemopoietic cells, presumably in the microenvironment, are recognized by this MAb, and are involved in preventing hemopoietic reconstitution. We will determine whether F(ab')2 fragments can also mediate this effect which would be compatible with the notion that the mechanism is not cytolytic but involves blocking of surface structures or signal transduction. We will then attempt to characterize cells in the microenvironment that are recognized by MAb H81.9 as compared to an ineffective anti-class II MAb, B1F6, of the same isotype. Cells recognized by H81.9 might prove helpful in abrogating the block in hemopoietic reconstitution if infused after MAb administration. Similarly, under the assumption that a factor is lacking or blocked in its function, administration of exogenous hemopoietic growth factors or cytokines concurrently with or following MAb infusion may bypass the block. Finally, we plan to determine specifically which canine MHC class II gene product is recognized by MAb H81.9. The results are expected to provide insight into the role of MHC class II molecules in in vivo regulation of hemopoiesis, and to shed light on mechanisms underlying certain marrow failure states. We anticipate that extrapolation of data from these studies will allow for novel approaches to clinical problems of marrow aplasia and to hemopoietic reconstitution after marrow transplantation.
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