Intensive investigation in management of Hodgkin's disease.
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Ninety-eight patients with clinically localised Hodgkin's disease underwent laparotomy and splenectomy to determine the extent of microscopic spread. In 68 patients the procedure was carried out for untreated disease apparently confined above the diaphragm. Abdominal disease cannot be confidently excluded on the basis of non-invasive investigation at presentation. Clinical assessment of splenic disease was unreliable unless gross splenomegaly was present. Pedal lymphography was accurate in assessing para-aortic and iliac disease but of no value in assessing other intra-abdominal lymph node involvement, including that of the mesenteric lymph node. Trephine bone marrow biopsy findings were normal in all patients before surgery, and only one patient was found to have diseased bone marrow by Stryker-saw biopsy at operation. Liver disease was identified at operation in nine patients, some of whom were asymptomatic with clinically undetectable splenic and nodal disease. Detailed clinical staging failed to detect disease in one-third of patients who underwent laparotomy. These studies show that if radiotherapy is to remain the treatment of choice for disease truly localised to lymph nodes a detailed staging procedure, including laparotomy and splenectomy, remains essential. The value of this potentially curative treatment is considerably diminished in the patient who has been inadequately staged. (+info)
A tailless fas-FADD death-effector domain chimera is sufficient to execute Fas function in T cells but not B cells of MRL-lpr/lpr mice.
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The Fas receptor delivers signals crucial for lymphocyte apoptosis through its cytoplasmic death domain. Several Fas cytoplasmic-associated proteins have been reported and studied in cell lines. So far, only Fas-associated death domain protein (FADD), another death domain-containing molecule has been shown to be essential for Fas signals in vivo. FADD is thought to function by recruiting caspase-8 through its death-effector domain. To test whether FADD is sufficient to deliver Fas signals, we generated transgenic mice expressing a chimera comprised of the Fas extracellular domain and FADD death-effector domain. Expression of this protein in lymphocytes of Fas-deficient MRL-lpr/lpr mice completely diminishes their T cell but not their B cell abnormalities. These results suggest that FADD alone is sufficient for initiation of Fas signaling in primary T cells, but other pathways may operate in B cells. (+info)
Combined liver-spleen-kidney scintigraphy and subsequent subtraction of the kidney scintiphotograph in the evaluation of displaced kidney.
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The displacement of kidney was studied by using the combined liver-spleen-kidney scintigraphy and the subsequent subtraction of the kidney scintiphotograph to leave the liver-spleen scintiphotograph alone. A suprarenal mass was shown as cold spot between the liver and right kidney on the combined study. When the liver scintiphotograph and kidney scintiphotograph were over-lapped and the differential diagnosis was difficult, the subsequent subtraction of the kidney scintiphotograph was useful in the diagnosis of the enlarged liver. (+info)
Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens.
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The contribution of interleukin (IL)-10 and interferon (IFN)-gamma to the regulation of type 1 and type 2 cytokine responses was investigated in Brazilians with different clinical forms of schistosomiasis mansoni. Cells from members of a family with acute intestinal schistosomiasis responded to schistosomal soluble egg antigen (SEA) or soluble adult worm antigen preparation (SWAP) with greater amounts of IFN-gamma than did cells from several patients with chronic intestinal schistosomiasis; IL-10 levels were similar. Neutralization of IL-10 had no effect on the SEA-specific IFN-gamma response in patients with acute infection, whereas SWAP-induced IFN-gamma was increased in both groups. Anti-IL-10 also up-regulated SEA-specific IFN-gamma protein and mRNA responses in most splenocyte cultures from hepatosplenic schistosomiasis patients but had no effect on antigen-specific IL-4 or IL-5 production. Neutralization of IFN-gamma resulted in a comparable increase in SWAP-specific IL-10 and IL-5, while IL-4 was not affected. These studies demonstrate that early disease in schistosomiasis is associated with a significant IFN-gamma response and that IL-10 contributes to the suppression of that response during both early and chronic infection. (+info)
Genetics of graft-versus-host disease, I. A locus on chromosome 1 influences development of acute graft-versus-host disease in a major histocompatibility complex mismatched murine model.
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Graft-versus-host disease (GVHD) is the major complication occurring after bone marrow transplantation. The severity of GVHD varies widely, with this variation generally being attributed to variation in the degree of disparity between host and donor for minor histocompatibility antigens. However, it is also possible that other forms of polymorphism, such as polymorphisms in immune effector molecules, might play a significant role in determining GVHD severity. In order to investigate this hypothesis, we are studying the genetic factors that influence GVHD development in a murine model. We here report the first results of this analysis, which demonstrate that a locus on Chromosome 1 of the mouse, and possibly also a locus on Chromosome 4, exert considerable influence over the development of one aspect of acute GVHD - splenomegaly - in a parent-->F1 murine model. These results demonstrate that non-MHC genes can exert quite significant effects on the development of GVHD-associated pathology and that gene mapping can be used as a tool to identify these loci. Further analysis of such loci will allow identification of the mechanism whereby they influence GVHD and may lead in the future to improved selection of donors for human bone marrow transplantation. (+info)
Oxidative modification of lipids and proteins in aniline-induced splenic toxicity.
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Our earlier studies with aniline suggested the involvement of oxidative stress as an early toxic event in the spleen. In order to understand the status and consequences of the damaging oxidative reactions, especially during the progression of characteristic splenic lesions, time-dependent subchronic studies were conducted in rats. Male Sprague-Dawley rats were treated with 65 mg/kg/day aniline in the drinking water, while control rats received drinking water only. The animals were euthanized after 1, 2, or 3 months of aniline exposure. Total iron content was remarkably greater in the aniline-treated rats than in age-matched controls. There were time-dependent increases in splenic lipid peroxidation of aniline-treated rats. Malondialdehyde-protein adducts were quantitated by a competitive ELISA and showed greater concentrations in the spleens of aniline-treated rats, further substantiating our lipid peroxidation results. Protein oxidation in the spleens of aniline-treated rats was also greater, with a maximum increase of approximately 76% at 3 months. Western blot analysis for oxidized proteins showed two distinct protein bands at approximately 114 kD and approximately 69 kD in both post-nuclear and mitochondrial fractions of the spleens. Furthermore, densitometric analysis of the blot showed increased band intensities of the oxidized proteins in both these spleen fractions from aniline-treated rats, suggesting the susceptibility of these proteins to aniline-induced oxidative stress. The most prominent morphological changes in the spleens of aniline-treated rats included thickening of the capsule, and capsular cells with nuclear prominence and hyperchromia indicative of capsular hyperplasia. These capsular changes and fibrosis of capsule, splenic trabeculae, and red pulp were noted at all three time points after aniline exposure. Our studies thus suggest that aniline-induced oxidative stress in the spleen is an ongoing event that leads to oxidative modifications of biomolecules. Such oxidative modifications, directly or indirectly, could contribute to the splenic toxicity leading to deleterious consequences, including capsular hyperplasia and fibrosis, as observed in this study, and possibly tumorigenesis in chronic aniline exposure conditions. (+info)
A central role for alpha beta T cells in the pathogenesis of murine lupus.
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We have previously shown that female transgenic mice expressing IFN-gamma in the epidermis, under the control of the involucrin promoter, develop inflammatory skin disease and a form of murine lupus. To investigate the pathogenesis of this syndrome, we generated female IFN-gamma transgenic mice congenitally deficient in either alpha beta or gamma delta T cells. TCR delta-/- transgenics continued to produce antinuclear autoantibodies and to develop severe kidney lesions. In contrast, TCR beta-/- IFN-gamma transgenic mice failed to produce antinucleosome, anti-dsDNA, or antihistone autoantibodies, and kidney disease was abolished. Both alpha beta- and gamma delta-deficient transgenics continued to develop IFN-gamma-associated skin disease, lymphadenopathy, and splenomegaly. The data show that the autoantibody-mediated pathology of murine lupus in IFN-gamma transgenic mice is completely alpha beta T cell dependent and that gamma delta T cells cannot drive autoantibody production. These results imply that production of antinuclear autoantibodies in IFN-gamma transgenic animals is Ag driven, and we identified clusters of apoptotic cells in the epidermis of the mice as a possible source of self Ags. Our findings emphasize the relevance of this murine lupus model to the human disease. (+info)
Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6.
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Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]) is a herpesvirus linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma, and a proportion of Castleman's disease. KSHV encodes viral interleukin-6 (vIL-6), which is structurally homologous to human and murine IL-6. The biological activities of vIL-6 are largely unknown. To gain insight into the biology of vIL-6, we expressed vIL-6 in murine fibroblasts NIH3T3 cells and inoculated stable vIL-6-producing clones into athymic mice. vIL-6 was detected selectively in the blood of mice injected with vIL-6-expressing clones. Compared with controls, vIL-6-positive mice displayed increased hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. vIL-6-expressing NIH3T3 cells gave rise to tumors more rapidly than did control cells, and vIL-6-positive tumors were more vascularized than controls. Vascular endothelial growth factor (VEGF) was detected at higher levels in the culture supernatant of vIL-6-expressing cells compared with controls, and immunohistochemical staining detected VEGF in spleen, lymph nodes, and tumor tissues from mice bearing vIL-6-producing tumors but not control tumors. Thus, vIL-6 is a multifunctional cytokine that promotes hematopoiesis, plasmacytosis, and angiogenesis. Through these functions, vIL-6 may play an important role in the pathogenesis of certain KSHV-associated disorders. (+info)