GRANULOCYTE/MACROPHAGE COLONY-STIMULATING FACTOR-STIMULATED HEPATIC DENDRITIC CELL PROGENITORS PROLONG PANCREATIC ISLET ALLOGRAFT SURVIVAL

Hepatic allografts are accepted without immunosuppressive therapy when transplanted between many MHC-incompatible mouse strains and certain rat strains (1, 2). Moreover, transplants of the liver protect other organ grafts of the same donor or donor strain from rejection (3–7). It has been postulated that this inherent tolerogenicity of the liver—a comparatively leukocyte-rich organ compared with the kidney or heart—is a consequence of donor-recipient leukocyte interaction leading to long-lasting, mutual, immunologic unresponsiveness (8, 9). A corollary of this hypothesis is that failure to establish and maintain donor cell chimerism results in imbalanced donor-recipient cell interaction, which may lead to graft rejection. Possible effector mechanisms of this two-way paradigm have been suggested (10). However, a cellular and molecular basis for interactions that may predispose to the development of mutual, donor-recipient immunologic nonreactivity has not been elucidated. In the multilineage cell chimerism that has been described in recipient tissues following transplantation of the liver or other organs, donor-derived dendritic cells (DC*) known to migrate to secondary lymphoid tissue (11) have been featured prominently (1, 9, 12). Although the DC resident in normal lymphoid tissue are potent antigen-presenting cells (13), freshly-isolated DC from commonly transplanted non-lymphoid tissues, such as the liver, kidney, or heart, are functionally “immature” (13, 14). Their maturation is thought to reflect the up-regulation by cytokines of both MHC gene product and costimulatory molecule expression (15). It has been suggested (8, 16) that these costimulatory molecule-deficient DC may constitute potentially tolerogenic precursors of the chimeric leukocytes seen in organ graft recipients. The magnitude, tissue-specific site dependency, replicative capacity, or maturational stage of chimeric DC that might be necessary to mediate postulated tolerizing effects has not been established. Recently, we have succeeded in propagating DC progenitors from normal mouse liver in response to granulocyte/macrophage colony stimulating factor (GM-CSF) (17). Following local or systemic injection, these cells migrate to T-dependent areas of allogeneic host lymphoid tissue, and express cell surface donor MHC class II. They persist indefinitely, although in diminished numbers (18). Furthermore, in spontaneously tolerant liver transplant recipients (but not in animals rejecting donor strain hearts), donor-derived DC can be propagated from host bone marrow and spleen using GM-CSF (19). These observations have raised questions about the functional significance of GM-CSF-stimulated, donor-derived DC progenitors in allograft recipients, and their possible relation to liver tolerogenicity. The potential of exploiting these putative tolerogenic cells for the therapy of graft rejection has also been suggested (16, 17). In this study, we have examined whether systemic injection of GM-CSF-stimulated, liver-derived DC progenitors can affect the survival of subsequent (pancreatic islet) allografts from the same donor strain. The results show that the liver-derived cells, but not “mature” GM-CSF-stimulated spleen-derived DC, significantly prolong islet transplant survival. They suggest a possible role of donor-derived, GM-CSF-responsive DC progenitors in allograft acceptance that may be related to the inherent tolerogenicity of the liver.