? We have shown that CD 1 reactive NK T cells induce lupus-like disease when injected into irradiated nu/nu BALB/c mice and that administration of anti-CD 1 mAb ameliorates lupus in NZB/NZW mice. The goal of the proposed studies is to test the hypothesis that the interaction between NK T cells and plasmacytoid and myeloid dendritic cells (pDCs and mDCs) via CD 1 is a critical step in the pathogenesis of lupus. In murine as well as human lupus this interaction is theorized to lead to the activation ofpDCs and mDCs, causing them to secrete elevated levels of interferon-alpha and IL-12, respectively, which enhance both innate and cognate immune responses and promote autoimmunity in susceptible hosts. We will use three different murine models of lupus to study the in vitro effects of anti-CD 1 mAb on NK T cell activation and pDC and mDC activation in the presence or absence of otgalacto sylceramide, a glyocolipid presented by CD ld molecules on antigen presenting cells that activates NK T cells. In addition, we will evaluate the in vivo effects of anti-CD 1 mAb on the maturation and activation status of pDCs and mDCs in healthy and lupus-prone mice. Finally, we will determine whether DCs are required for the development of lupus by transplanting lethally irradiated mice lacking functional DCs with syngeneic (DC-/-) or normal histocompatible (DC+/+) bone marrow alone or in combination with disease inducing CD 1 reactive NK T cells. The results of these studies should provide important insights into the role of CD 1 molecules and DCs in the pathogenesis of lupus. ? ?
