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PubMed2002

[Mechanisms of glatiramer acetate action in demyelinating diseases: antigen-specific, organ-specific or process-specific treatment].

Use of the "disease modifying" medicines is a significant success in multiple sclerosis (MS) treatment. These ways of MS treatment were scientificantly based and proved in large well-designed randomized studies, while direct mechanisms of their action is still under investigation. This review is discussing the mechanisms of action of glutiramer acetate (GA)--one of these medicines, modifying MS course. Its positive clinical effects in relapsing-remitting MS were shown in large clinical studies, confirmed by MRI and supported by extension trials. Immunomodulative effects of GA in MS and its experimental model (EAE) may be associated with induction of GA-specific cells clone, which have several positive for MS features, for example producing anti-inflammatory Th2-cytokines. Other characteristics of these cell clones should be studied further.

Adjuvants, Immunologic↗
PubMed1981

Clonal variation and functional correlation of organ-specific metastasis and an organ-specific metastasis-associated antigen.

Monoclonal antibodies were used to probe the cell surface of organ-selected metastatic variant cells. Previously we defined a liver metastasis-associated antigen (LMAA) by means of the reaction of a monoclonal antibody with a liver metastasis selected tumour variant cell line, MDCC-AL2. The monoclonal anti-LMAA antibodies specifically inhibit liver metastasis of AL2. There is a correlated, clonal variation in LMAA expression and liver metastasis in both the AL2 cell line and an overy-selected metastatic variant MDCC-AL3. The variation in liver metaatatic ability is thought to represent clonal progression of the tumour cell lines. The LMAA probably represents only one of the ways in which a tumour cell may give rise to a live metastasis. Two hypotheses are discussed utilizing the LMAA in a functional role in the specific trapping of metastatic tumour cells in the liver or the successful colonization of the liver by metastatic tumour cells.

Animals↗
PubMed1984

Longevity-dependent organ-specific accumulation of DNA damage in two closely related murine species.

To measure directly the accumulation of DNA damage with age, and to understand better the effect of modulators of DNA damage in vivo, the DNA of brain, liver, and kidney of two mice from different families, Mus musculus and Peromyscus leucopus, have been examined for age-dependent accumulation of single-strand breaks plus alkali-labile bonds, by the alkaline sucrose sedimentation method. These two species of small rodents are closely related taxonomically, yet differ significantly in maximum achievable lifespan. Using the reciprocal of the number average molecular weight for estimation of DNA size, these analyses indicate that: (a) DNA damage does not measurably accumulate in brain tissue; (b) the accumulation of DNA damage was more pronounced in hepatic DNA than other tissue DNA; and (c) the rate of accumulation of DNA damage in liver and kidney cells with age was greater in the shorter-lived species (M. musculus) and was inversely proportional to maximum achievable lifespan. There are suggestions that a similar threshold might exist for tolerance of DNA damage in the two species in specific organs, and that these species differ in the rate at which this threshold is reached as a function of maximum achievable lifespan.

Animals↗
PubMed2004

Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies.

BACKGROUND: Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs. METHODS: Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed. RESULTS: Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-gamma and TNF-alpha; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells. CONCLUSION: Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.

Autoantibodies↗
PubMed1980

Organ specificity of lymphocyte migration: mediation by highly selective lymphocyte interaction with organ-specific determinants on high endothelial venules.

Evidence is presented that the organ specificity of lymphocyte migration is determined by selective interaction of lymphocytes with specialized endothelial cells. Mouse Peyer's patch and lymph node lymphocytes bind preferentially to high endothelial venules (HEV) in frozen sections of Peyer's patches and peripheral nodes, respectively, and this in vitro binding preference accurately predicts their differential segregation in vivo 30 min after i.v. injection. Both in vivo and in vitro, about 1.4 times as many as many Peyer's patch as lymph node lymphocytes bind HEV in Peyer's patches, and, conversely, twice as many lymph node cells interact with HEV in nonmesenteric lymph nodes. Even greater specificity is shown by certain homogeneous lymphocyte populations, i.e. thymic lymphomas. Some lymphomas bind with remarkable selectivity to HEV in Peyer's patches, and others interact almost exclusively with those in lymph nodes indicating that the mechanisms mediating selective recognition of HEV are capable of nearly absolute discrimination. Mesenteric node HEV are unique in that they allow both Peyer's patch- and lymph node-specific cells to bind. It is proposed that lymphocyte surface receptors specific for organ-restricted endothelial cell determinants mediate the antigen-independent organ specificity of lymphocyte migration. According to this model, there are at least 2 sets of complementary lymphocyte and endothelial cell receptors, one mediating lymphocyte-HEV adherence in Peyer's patches, the other in lymph nodes.

Animals↗
PubMed2005

Screening phage display libraries for organ-specific vascular immunotargeting in vivo.

The molecular diversity of the luminal endothelial cell surface arising in vivo from local variations in genetic expression and tissue microenvironment may create opportunities for achieving targeted molecular imaging and therapies. Here, we describe a strategy to identify probes and their cognate antigens for targeting vascular endothelia of specific organs in vivo. We differentially screen phage libraries to select organ-targeting antibodies by using luminal endothelial cell plasma membranes isolated directly from tissue and highly enriched in natively expressed proteins exposed to the bloodstream. To obviate liver uptake of intravenously injected phage, we convert the phage-displayed antibodies into scFv-Fc fusion proteins, which then are able to rapidly target select organ(s) in vivo as visualized directly by gamma-scintigraphic whole-body imaging. Mass spectrometry helps identify the antigen targets. This comprehensive strategy provides new promise for harnessing the power of phage display for mapping vascular endothelia natively in tissue and for achieving vascular targeting of specific tissues in vivo.

Amino Acid Sequence↗
PubMed1997

Tissue suspension agglutination: a simple method to screen species-specific and organ-specific reactions.

Agglutination tests with preparations of parenchymatous organs were developed. The tissue suspensions were dried at room temperature after they had been spread as a very thin layer on a glass plate, or otherwise, they were lyophilized. The dried preparations were pulverized and then prepared as stable suspensions in saline. The agglutination test was conducted on a slide by mixing one drop of the tested serum at a convenient dilution with one drop of tissue powder suspension. Agglutination in the form of readily discernible clumps could be assessed after 1-10 min. By means of this procedure, species-specific reactions were studied using suspensions of kidneys of various species. Organ-specific reactions were noted with suspensions of brain and thyroid. Agglutination of thyroid powder was observed with rabbit anti-rabbit thyroid sera as well as with many, albeit not all, sera of patients with Hashimoto's disease.

Agglutination Tests↗
PubMed2001

Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: implications for local gene therapy.

BACKGROUND: Many gene therapy strategies would benefit from efficient, regional organ delivery of therapeutic genes. METHODS: Regional perfusions of lung, liver, or bladder were performed to determine if rapid and efficient gene transfer can be accomplished in vivo, and to determine if in vivo gene transfer can be limited to the organ of interest. In addition, herpes simplex virus tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factoralpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fisher rats. RESULTS: A 20-minute perfusion using HSV carrying beta-galactosidase (HSVlac) produced significant expression of this marker gene isolated to the target organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis factor alpha also resulted in high-level local organ production of this cytokine (2851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung). For the current vector construct, expression of the gene of interest peaked between 2 and 4 days and was undetectable by 2 weeks after perfusion. In animals undergoing perfusion as treatment for pulmonary sarcoma, there was no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor counts than controls (111 +/- 24 nodules per lung, P <.02). CONCLUSIONS: Regional organ perfusion using herpes viral vectors is an effective and well-tolerated in vivo method of transiently delivering potentially toxic gene products to target organs in directing gene therapy. Regional lung perfusion with HSV amplicons reduces tumor burden in a rat model of pulmonary metastases, though HSVtnf cannot be demonstrated to augment the cytopathic effect of the HSV amplicon alone in the current model.

Animals↗
PubMed2000

Organ specificity of the structural organization and fine distribution of lymphatic capillary networks: histochemical study.

Histochemical studies of the microcirculatory system were reviewed with regard to the organ specificity of the structural organization and fine distribution of the lymphatic capillary network. The lymphatics and blood vessels are characterized by an enzyme-histochemical method using 5'-nucleotidase (5'-Nase), alkaline phosphatase (ALPase) and/or diaminopeptidase (DAPase) staining in addition to an immunohistochemical method. The 5'-Nase-positive lymphatic vessels can be distinguished histochemically from arterial and venous vessels based on ALPase and DAPase activity, respectively. The specificity and localization of the enzyme reactions were confirmed by comparative histochemical studies of the same specimen with light microscopy and scanning or transmission electron microscopy. These histochemical methods are discussed in relation to their ability to demonstrate the organ specificity of vascular networks under normal and pathological conditions.

Animals↗
PubMed1991

Tissue-specific and organ-specific expression of soybean auxin-responsive transcripts GH3 and SAURs.

We used in situ hybridization to localize two classes of auxin-regulated transcripts, GH3 and SAURs, within organs and tissues of soybean seedlings and flowers. GH3 transcripts occurred in the inner cortex and protoxylem ridges of roots and were expressed transiently during flower and pod development. SAUR transcripts were expressed in the epidermis, cortex, and starch sheath of epicotyls and immature hypocotyls. SAUR transcripts became more abundant on the bottom side of hypocotyls that were undergoing gravitropic curvature. SAURs were also expressed in developing xylem elements of the hypocotyl hook. When soybean organ sections were treated with 50 micromolar 2,4-dichlorophenoxyacetic acid (2,4-D), GH3 transcripts became more abundant in the vascular regions of all organs analyzed. High levels of GH3 transcripts were also found in developing palisade mesophyll cells of leaves, cotyledons, and flowers treated with 2,4-D. SAUR transcripts became more abundant in the epidermis, cortex, starch sheath, and pith of epicotyls and hypocotyls after 2,4-D treatment. Our results showed that a variety of tissues and cell types express auxin-responsive transcripts and that different tissues respond rapidly to exogenous auxin by expressing different hormone-responsive genes.

Gene Expression Regulation↗
PubMed1996

Durability of donor-specific and organ-specific heart transplant tolerance induced by intrathymic pretreatment with allogeneic spleen cells.

Permanent acceptance of an experimental cardiac allograft can be achieved in the rat by pretreating the recipient with antilymphocyte serum and intrathymic donor lymphocytes. We investigated the durability and specificity of the tolerance produced by this pretreatment in a rat model of heterotopic heart transplantation with Lewis-Brown Norway donors and Lewis recipients. Pretreated Lewis rats received 1 ml antilymphocyte serum intraperitoneally and 5 x 10(7) Lewis-Brown Norway splenocytes intrathymically, followed 21 days later by Lewis-Brown Norway cardiac transplantation. The first Lewis-Brown Norway cardiac allograft survived long term (mean 140 days) in pretreated recipients who were given no subsequent immunosuppression. After 60 days with a beating Lewis-Brown Norway allograft, tolerant Lewis recipients underwent a second cardiac allograft with either a Lewis-Brown Norway heart or a third-party Wistar-Furth heart. The second Lewis-Brown Norway cardiac allograft was not rejected (mean survival 76 days), but that from the third-party Wistar-Furth donor was rejected in a normal fashion (mean survival 10.4 days). The presence of second grafts did not affect survival of first grafts. Tolerant Lewis recipients of two Lewis-Brown Norway heart grafts underwent subsequent transplantation with Lewis-Brown Norway skin. Skin allograft survival in this group (mean 8.4 days) was not different from that in Lewis recipients without pretreatment. Rejection of skin grafts had no effect on the heart grafts. These data suggest that tolerance to cardiac allografts produced by intrathymic pretreatment is durable and extends to a second heart graft from a genetically identical donor. Tolerant rats reject third-party hearts and primary donor skin grafts normally, and tolerance to previously placed heart grafts is not abrogated by this rejection. Non-major histocompatibility complex skin antigens not present on cardiac cells may account for the tissue specificity of the tolerance produced by intrathymic treatment in this model.

Animals↗
PubMed1987

Reaction pattern of mitochondrial antibodies of primary biliary cirrhosis (PBC) is species specific but not organ specific.

The cross reactivity of a well-characterized PBC serum was studied with mitochondria from a number of sources. These studies were to establish the nonorgan, species specificity of the reaction of PBC sera. As well as confirming some previously reported data, we have strong evidence suggesting that, in spite of species differences in Mr of the major antigenic bands, all mitochondria contain a set of common cross-reactive epitopes. The multiplicity of antigenic bands seen for mitochondria from some sources are shown to arise, in part, as proteolytically derived artefacts of bands of higher Mr, retaining some antigenic reactivity.

Animals↗