Atsuko Masunaga

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

Many mechanisms involving TNF-α, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-α to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14+ monocytes cultured in the presence of TNF-α and GM-CSF converted to CD14+ CD1alow adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-α, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (Mφ). The mature DC (CD83+ CD70+ HLA-DR high CD14low) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-γ and TNF-α, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-α added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the Mφ (CD14highCD70+CD83−HLA-DR−) produced large amounts of MMP-9 and TNF-α without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated Mφ. Therefore, additional stimulation of monocytes with TNF-α may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated Mφ-mediated innate immunity.

Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin

We report a 13-year-old boy who developed dyspnea at rest 1 year after the occurrence of cGVHD following an allogeneic bone marrow transplant (BMT). Pulmonary function data, imaging studies, lung biopsy, and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). Although reports suggest that oral methylprednisolone or methylprednisolone pulse therapies improve BOOP after BMT, we treated our patient with a combination of oral prednisolone (1 mg/kg) and low dose erythromycin (10 mg/kg) to avoid the side-effects of high-dose steroids. With this therapy, our patient showed clinical and radiological improvements within 1 week. The steroids were tapered off 12 months later and erythromycin was given for 14 months. We conclude that therapy consisting of a combination of oral prednisolone and low-dose erythromycin for BOOP after BMT may minimize the dose and duration of steroid use. Bone Marrow Transplantation (2000) 26, 907–910.

Follicular dendritic cell tumor with histiocytic characteristics and fibroblastic antigen

A report is presented of a follicular dendritlc cell (FDC) tumor arising In the lymph nodes and Inguen of a 55‐year‐old Japanese female, who had suffered from schizophrenla for 25 years. The left submandibular lymph nodes had completely lost their normal architecture, except for the capsule, due to tumor cell infiltration. Occaslonal nodular structures resembling epltheliold granulomas, attributable, at least In part, to follicular Involvement of tumor cells, were observed. These nodules were composed of epithellold‐ or fibroblast‐like tumor cells forming interwoven fascicles, to which small lymphocytes were attached. Tumor cells were also scattered in the internodular areas. For more atyplcal tumor cells, arranged in a sheet‐like structure, were present In the inguinal specimen, the tumor cells of which expressed Ki‐M4p, CD21, CD35 and other antigens known to be expressed on FDC. Furthermore, they also expressed the monocytdmacrophage antlgens, α1‐antltrypsin, α‐antlchymotrypsin, lysozyme, CD14, CD33, CD68 and Mac387 and fibroblastic antigen. Ultrastructural studies demonstrated lysosomal granules as well as a few desmosomes, Indicating the tumor cells possessed fibrohistiocytic and FDC characteristics.

Expression of multidrug resistance-associated protein (MRP) in thyroid cancers

It was found that the mechanism of anti-cancer drug resistance in anaplastic carcinoma of the thyroid was not explicable only in terms of expression of mdr1 and its gene product, P-glycoprotein. The multidrug resistance-associated protein (MRP), another member of the mdr gene family, may be involved in anti-cancer drug resistance of this carcinoma. The MRP expression was examined immunohistochemically in 8 cell lines and 73 thyroid cancer tissues; its frequency in anaplastic carcinoma (52%) was significantly higher than that in other thyroid cancer types.

Progress reports on immune gene therapy for stage IV renal cell cancer using lethally irradiated granulocyte-macrophage colony-stimulating factor-transduced autologous renal cancer cells

Abstract There is no effective treatment for patients with stage IV renal cell cancer (RCC), although the introduction of new therapy is imminent. Cancer gene therapy is currently considered to be one of the most promising therapeutic modalities in the field of cancer treatment. Based on the results of animal studies, vaccination using autologous granulocyte-macrophage colony-stimulating factor-transduced renal cancer cells appears promising. Before initiating a clinical study using an ex vivo gene-transduced autologous cell vaccine-based immunogene therapy for RCC in Japan, in 1992 we initially planned a Japanese version of a clinical protocol in collaboration with a US group. In 1993, the original protocol was refined. We performed five preclinical qualification studies using RCC nephrectomy specimens from patients in 1997, and the results showed that preparation of RCC cells for autologous vaccines at the Clinical Cell Technology Facility, Research Hospital of the Institute of Medical Science, University of Tokyo, was feasible. Subsequently in August 1998, the Ministry of Health and Welfare and the Ministry of Education, Science, Culture, and Sport approved our clinical protocol. We have recruited two patients with stage IV RCC to our study so far. Here we report the background to the initiation of cancer gene therapy in Japan.

Autopsy cases of fulminant bacterial infection in adults: clinical onset depends on the virulence of bacteria and patient immune status

To assist physicians in recognizing the potentially fatal onset of symptoms in cases of fulminant bacterial infection, we analyzed 11 autopsy cases of such infection (four caused by Streptococcus pneumoniae, four by S. pyogenes, one by S. dysgalactiae subsp. equisimilis, one by Staphylococcus aureus, and one by Vibrio vulnificus). Clinicohistopathologic features were evaluated. All patients experienced sudden onset of hypotension and multiple organ failure, leading to unexpected death. Blood culture confirmed bacteremia. The main chief complaints were gastrointestinal symptoms (45%) and limb pain (36%). All had an underlying chronic illness (82%), e.g., a hematologic disorder (36.3%) or liver cirrhosis (27.2%). Necrotizing fasciitis occurred in only 55% of cases, with none involving pneumococcal infection. Laboratory tests typically showed C-reactive protein elevation but without leukocytosis, indicating a high-level inflammatory state. In ten cases, death was attributed to circulatory collapse due to sepsis; severe pulmonary congestion and hemorrhage were present in these cases. The onset of fulminant bacterial infection depends on both virulence of the bacterium and status of the host defense system.

Autopsy cases of fulminant-type bacterial infection with necrotizing fasciitis Group A beta hemolytic Streptococcus pyogenes versus Vibrio vulnificus infection

Two autopsy cases of fulminant‐type infection associated with necrotizing fasciitis were analyzed clinicopathologically. Both cases involved 57‐year‐old alcohol abusers. The former was a woman with group A (beta) hemolytic Streptococcus pyogenes infection, and the latter was a man with Vibrio vulnificus infection. The sudden onset of shock with high fever resulted in sepsis, decreased clotting, and hepatorenal symptoms, followed by death within a few days. Post‐mortem examination showed widespread congestion and bleeding, and alcoholic liver cirrhosis was observed. Necrotizing fasciitis was identified in both cases. Bacteria from the pharynx or intestinal tract invaded the blood, and marked bacterial proliferation produced sepsis, resulting in necrotizing fasciitis. Despite the presence of sepsis, bilateral pulmonary congestion and bleeding were observed without pneumonia. Due to the rapid progression of sepsis, there was no time for granulocyte migration from the bone marrow. It seems that almost all mature granulocytes which had already existed in the bone marrow accumulated at the focus of necrotizing fasciitis because the bone marrow had few mature granulocytes and lacked hypercellularity. The cause of death in each case was circulatory collapse due to septic shock. It was difficult to distinguish the type of infection on histopathology. Cultures were necessary to determine the bacterial agents involved.

Reduced expression of apoptosis-related antigens in thymuses from patients with myasthenia gravis

Expression of the apoptosis-related antigens, Fas and BM-1, in thymuses from patients with myasthenia gravis (MG) was examined using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Fas antigen was markedly decreased in lymphoid follicles in thymuses from patients with MG, but was expressed diffusely in the remaining thymus tissues and in neonatal thymuses. BM-1 antigen was not expressed in the lymphoid follicles or other parts of the thymus. Fas mRNA was also decreased to various degrees in the thymuses from MG patients. Therefore, Fas antigen may play an important role in autoimmune diseases including MG.

Primary uterine T-cell lymphoma

A uterine CD8-positive, HTLV-1-negative T-cell lymphoma associated with atypical endometrial hyperplasia was found in a 63-year-old Japanese woman. Primary T-cell lymphoma of the uterus has not been previously reported.

Clinicopathological findings in fulminant-type pneumococcal infection: report of three autopsy cases.

Reported herein are three autopsy cases of fulminant‐type pneumococcal sepsis with disseminated intravascular coagulation (DIC) resulting in death within a few days of onset of symptoms. Two of the three patients had previously had a splenectomy because of a hematological disorder. None of the patients had received pneumococcal vaccination. On post‐mortem every organ had congestion as well as bleeding. Interestingly, severe inflammation of the alveoli was absent despite the sepsis. The cause of death was rapidly progressive pneumococcal sepsis leading to DIC and circulatory failure, which appeared to cause pulmonary congestion and hemorrhage without pneumonia. It is important to understand the pathogenesis of fulminant‐type pneumococcal infection because it is life‐threatening for compromised hosts.