The association between hematopoietic stem cells and their microenvironment is central to the development and maintenance of a functional hematopoietic system. The TIE2/TEK receptor tyrosine kinase and its ligands, Angiopoietin-1 and-2, have been shown to be involved in the formation of the embryonic vasculature. Although the defect of vasculo-angiogenesis was confirmed in both knockout mice of TIE2 and Angiopoietin-1, the precise function of these molecules is not well understood. Here, we evaluated the expression and function of TIE2 in the para-aortic splanchnopleural mesoderm (P-Sp) during embryogenesis, and especially in the omphalomesenteric artery and vitelline artery. In the vitelline artery at 9.5 days postcoitum (dpc), TIE2+ hematopoietic cells aggregated and adhered to TIE2+ endothelial cells. Soluble TIE2-Fc chimeric protein inhibited the development of hematopoiesis and angiogenesis in the P-Sp explant culture, and TIE2-deficient mice showed severely impaired definitive hematopoiesis. An in vitro study revealed that Angiopoietin-1 and -2 promoted the adhesion to fibronectin (FN) through integrins and cell-cell adhesion in TIE2-transfected cells. Finally, we showed that Angiopoietin-1 enhanced the adhesion of TIE2+ primary cells sorted from 9.5 dpc P-Sp to FN. These data demonstrate the TIE2-Angiopoietin signals play a critical role in the development of definitive hematopoiesis, as well as that of angio-vasculogenesis.

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Human T-cell lymphotropic virus type I (HTLV-I) is associated with various clinical disorders including adult T cell leukemia, myelopathy, arthropathy. Hypercalcemia resulting from osteoclast activation and a variety of hematopoietic abnormalities have been also observed in HTLV-I infected patients, however, precise mechanism about initial trigger(s) prior to presenting symptoms is still unknown. In this study, to assess effects of HTLV-I on hematopoiesis, we analyzed characteristics of early hematopoietic precursors and cell surface molecules of lymphocyte in HTLV-I env-pX transgenic rats. Progenitor cells for osteoclasts were significantly increased even in the marrow of asymptomatic env-pX rats. Progenitors for B cells were also highly enriched, while colony forming cells (CFC) elicited by GM-CSF (CFU-GM) and M-CSF (CFU-M) were comparable to normal littermates. Following arthritis in env-pX transgenic rats, osteoclastogenesis was further augmented and the CFCs were increased. Bone marrow cells carrying adjuvant-induced arthritis retained a constant number of progenitors for osteoclast and B lymphocytes, whereas the number of CFU-GM and CFU-M increased. In env-pX rats without arthritis the expression of CD80/86 and ICAM-I were upregulated on the surface of peripheral lymphocytes, compared with those of normal rats and rats with adjuvant-induced arthritis. These results indicate that the env-pX transgene affect early stages of osteoclast and B-cell lineages and lymphocytes prior to developing diseases, in contrast, an increase of the CFCs was caused indirectly by arthritis. This study provides a novel standpoint for the mechanisms of pathogenesis by HTLV-I.

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A human MCAF/MCP-1 transgenic mouse (Tgm) which constitutively produces high amounts of human MCAF/MCP-1 (7-13ng/ml in the serum) under human β-actin promoter was established. Expression of the transgene was detected in the brain, liver, kidney, testis, thymus, and spleen. Although an accumulation of macrophages was observed in the lymphoid organs, no tissue destruction was observed. We found a reduced in vivo phagocytosis by peritoneal macrophages against latex beads and a delayed absorption of granulomas in the liver generated by zymosan injection. However, peritoneal exudate cells from Tgm showed almost the same activities as those from non-Tgm littermate when NO production upon stimulation with LPS and phagocytosis of latex beads analyzed in vitro. The differences seen between in vivo and in vitro functions may be due to down-regulation and/or desensitization of the MCAF/MCP-1 receptors in the consistent presence of high concentration MCAF/MCP-1 in vivo. It seemed that cancellation of deactivation was induced after releasing mononuclear cells from high MCAF/MCP-1 environment ex vivo. On the other hand Tgm peritoneal macrophages showed higher activities in autophosphorylation of Src-family protein-tyrosine kinases (Src-PTKs), Fgr and Hck, than those of normal littermates. This up-regulation of Fgr and Hck may compensate down-regulation of CCR signaling pathway resulted from sustained exposure to a high level of MCAF/MCP-1. This Tgm may represent and could be utilized as a model of primary and secondary high MCAF/MCP-1-emia.

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Macrophage scavenger receptors (MSRs) are trimeric membrane-bound glycoproteins consisting of six domains. They participate in endocytosis of negatively charged macromolecules including modified LDL, and are implicated in the pathological deposition of cholesterol in arterial walls during atherogenesis. Besides modified LDL, MSRs have an extraordinary wide range of ligand binding capability including bacterial pathogens, indicating a role for MSRs in host defense against various pathogens. Targeted disruption of the MSR gene resulted in a reduction in the size of atherosclerotic lesions in both apoE-deficient, and LDL receptor-deficient mice, indicating an accelerating role for MSR in atherogenesis. Foam cell formation in remained atherosclerotic lesion in MSR-deficient mice indicates the participation of the other scavenger receptors, such as CD36, macrosialin/CD68, or MARCO (macrophage receptor with collagenous structure). Susceptibility to infection of Listeria monocytogenes and delayed formation of Corynebacterium parvum-induced hepatic granuloma in MSR-deficient mice indicate the participation of MSRs in host defense mechanism.

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A 81-year-old Japanese female was referred to our hospital with fever up, lumbago and marked splenomegaly (10cm below the left costal margin) without lymphadenopathy. Laboratory findings showed leukocytosis (60.5×10⁹/l), mild thrombocytopenia (89×10⁹/l) and M-proteinemia (total protein 8.1g/dl, IgG 5.469g/dl, IgG-λ positive). 92% of leukocytes were villous lymphocytes and the tartrate-resistant acid phosphate reaction was negative. The immunophenotypes of these cells were CD3^-, CD5^-, CD10^-, CD11c⁺, CD19⁺, CD20⁺, CD22⁺, CD25^-, FMC7⁺, MikB1⁺, sIgM⁺. The DNA analysis of the immunoglobulin gene of the peripheral blood showed rearrangement of JH gene. The first lumbar vertebra was fractured. We diagnosed splenic lymphoma with villous lymohocytes, started radiation to bone involvement and chemotherapy with VMCP regimen, but splenomegaly increased to the pelvis and leukocytosis persisted. Furthermore, serum electropheresis showed biclonal gammopathy (IgG-λ, IgM-λ), and the immunophenotypes of villous lymphocytes revealed IgG-κ and IgM-κ potitive.
After two years she complained abdominal pain. Splenomegaly decreased rapidly and peripheral villous lymphocytes increased extremely to 150×10⁹/l without blastic transformation. Abdominal computed tomography showed decreased splenomegaly with a few nodules of low density and slight ascites. Splenic infarction or rupture were not showed. Metabolic acidosis, hypoglycemia and paralytic ileus occured. She died next day.
Autopsy showed systemic intravascular and severe extravascular infiltrations of the villous lymphocytes. The parenchyma of spleen was involved with severe lymphoid infiltration (μ⁺, γ⁺, α^-, κ⁺, λ^-) and white pulp was dissappeard. Bone marrow also showed the plasmacytoid cells (γ⁺ [>>μ⁺], λ⁺, κ^-). Severe acute ischemic enterocolitis without thrombosis was seen in small intestine and colon. We suspect that rapidly increased villous lymphocytes came to peripheral circulatory insufficiency, but we couldn't know the relationship between decreased splenomegaly and rapidly increased villous lymphocytes.

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