Osteopetrosis is a disease of bone resorption that may be inherited with m a n y separate genes in various m a m m a l i a n species (1, 2). There are four distinct mutations in the mouse that can individually result in this disorder: osteopetrotic (op) (3), microopthalmic (mi) (4), gray-lethal (gl) (5), and osteosclerotic (oc) (6). A major advance in our understanding of osteopetrosis was provided by the experiments of Walker (7-9), demonstrating the ability of normal hemopoietic cells to cure this disorder in mi/mi and gl/gl mice. Additionally, it was shown that spleen cells from these mutants transfer the disease into irradiated normal littermate recipients (8, 9). The response of other murine osteopetrotic m u t a n t s in transplantation assays remains unknown. At the cellular level, osteopetrosis is a disease of a functionally a n d / o r quantitatively a b n o r m a l osteoclast (1, 10), The osteoclast is a multinuclear cell that is most p r o b a b l y formed through a fusion of cells of the m o n o c y t e -m a c r o p h a g e lineage (11). Therefore, the osteoclast belongs to the progeny of the hemopoietic stem cell (HSC) 1 (12, 13), and this explains the positive response of mi/mi and gl/gl mice to transplants of hemopoietic cells. This cure of osteopetrosis by hemopoietic grafts is a more general p h e n o m e n o n and was recently observed also in juvenile osteopetrosis in man (14, 15) and in two rat mutants: ia/ia (16) and op/op (17). Studies (18) in op rat additionally linked osteopetrosis with abnormalities in the T lymphocyte system. O n the other hand, the osteopetrosis in tl/tl rat failed to respond to the bone marrow transplant (19), suggesting that the p r i m a r y lesion in this m u t a n t resides beside the hemopoietic tissue, presumably in the hemopoietic microenvironment (HM). The H M is m a d e by stromal tissue of bones and spleen, histogenetically different from the hemopoietic system and largely derived from cells with fibroblast-like morphology (20). The classic example of the disorder of H M is a n e m i a in S1/S1 d mice, which is * Supported in part by a grant from the Polish Academy of Sciences to W. Wiktor-Jedrzeiczak , and by the Naval Medical Research and Development Command. The opinions and assertions contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the U. S. Navy Department or the naval service at large. The experiments reported herein were conducted according to the principles set forth in the current edition of the "Guide for the Care and Use
The murine immune response to a haptenated lipopolysaccharide (LPS) lacking repeating oligosaccharide determinants was studied. The LPS was extracted from a rough strain of bacteria (Salmonella minnesota R595) and chemically haptenated with either trinitrophenol or fluorescein isothiocyanate. These preparations of hapten-R595 LPS were shown to be immunogenic. Furthermore, the immune response to the hapten was demonstrated to occur independent of T cells and was not merely the result of enhanced polyclonal B-cell activation. The capacity of such hapten-LPS conjugates without repeating polymeric structures to stimulate T-independent antibody responses provides information on the molecular requirements for the activation of murine B lymphocytes.
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A multiple dose IL-1 therapy was evaluated for its capability to stimulate hematopoiesis in normal primates and to restore hematopoiesis after autologous bone marrow transplantation. The administration of IL-1 to normal animals over a dose range of 0.5 to 10 micrograms/kg/d led to a 7-12 fold increase in peripheral blood neutrophil and monocyte counts after 24 hours. This increase in the mature peripheral blood myeloid cells was followed by changes in the myeloid composition of the bone marrow, where the percentage of myeloid elements increased along with a transient increase in myeloid progenitor cell activity. IL-1 treatment also led to an initial decrease in platelet counts of 10-30% during the first 3 days of treatment. However, a striking finding was a significant and long lasting stimulation of increased platelet production with platelet counts increasing to 77% of baseline 3 days after cessation of treatment and remaining elevated for the next 10 days. The therapeutic potential of the IL-1 regimen to restore hematopoiesis was further evaluated in an established autologous bone marrow transplantation model. In monkeys receiving IL-1 doses, 1.0 and 5.0 ug/kg/d, neutrophil counts recovered to greater than 0.5 x 10e9/1 on day 16, one day earlier than control, but the recovery to baseline neutrophil counts occurred 5 days sooner than control. IL-1 therapy had its greatest effect on the restoration of platelet counts after transplantation, reaching greater than 100 x 10e9/1 by day 21, two weeks earlier than control. This work demonstrates that IL-1 therapy stimulates myelopoiesis but its most promising clinical application is the stimulation of platelet production.
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