Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the involvement of nitric oxide (NO) in intestinal graft-vs.-host reaction (GvHR) in mice. Treatment of mice with L-NG-monomethyl arginine (L-NMMA), a specific inhibitor of NO synthesis, abolished the mucosal pathology of intestinal GvHR and reduced the associated lymphocytic infiltration of the epithelium. L-NMMA had no effect on splenomegaly in GvHR, nor did it interfere with the growth of an undifferentiated crypt stem cell line, or the production of tumor necrosis factor-alpha by activated macrophages in vitro. In contrast, L-NMMA inhibited the enhanced activity of natural killer (NK) cells which occurs in GvHR. We conclude that a NO-dependent mechanism is essential for intestinal immunopathology in GvHR and that this may reflect a role for NO in NK cell function.
 ...
PMID:Nitric oxide mediates intestinal pathology in graft-vs.-host disease. 163 8

As a means of investigating further the pathogenesis of intestinal immunopathology, we have attempted to produce a destructive enteropathy by inducing an acute graft-versus-host reaction (GVHR) in mature, immunocompetent mice. Adult (C57b1/10 X DBA/2)F1 (BDF1) mice given C57B1/10(B10) spleen cells develop a severe GVHR which is associated with marked weight loss and high mortality. In the intestine an initial phase of enteropathy characterized by intense crypt hyperplasia is replaced by more severe intestinal damage which includes villus atrophy and loss of intra-epithelial lymphocytes. These pathological alterations are paralleled by the generation of anti-host cytotoxic T lymphocytes (CTL), marked immunosuppression and the loss of natural killer (NK) cells. In contrast to these findings, adult BDF1 mice given DBA/2 donor cells do not develop an acute systemic GVHR and have no CTL or intestinal pathology, despite prolonged splenomegaly and enhanced NK cell activity. Thus, destructive enteropathy can be induced during a GVHR in intact hosts and our results confirm that this enteropathy has a biphasic pattern, with villus atrophy representing the progression of initial crypt hyperplasia in severe forms of disease associated with weight loss and specific CTL.
 ...
PMID:Experimental studies of immunologically mediated enteropathy. V. Destructive enteropathy during an acute graft-versus-host reaction in adult BDF1 mice. 213 68

Monoclonal antibodies (MoAb) to L3T4 have been used successfully to suppress autoimmunity in murine models for several human autoimmune diseases. To clarify the immunologic and clinical consequences of treatment with anti-L3T4, we examined the effects of chronic administration of anti-L3T4 on the composition of lymphoid organs, the function of lymphocytes, and the histopathology of autoimmune disease in lupus-prone NZB/NZW F1 (B/W) mice. Weekly treatment with anti-L3T4 (2 mg/mouse) from age 5 to 8 months depleted L3T4+ cells from the spleen and lymph nodes, and prevented the development of splenomegaly and lymphadenopathy. The MoAb bound to target cells in the thymus and modulated their expression of the L3T4 antigen but, in contrast to its effect in extrathymic sites, anti-L3T4 did not deplete the target population from the thymus. In fact, after 3 months of therapy, mice that had been treated with anti-L3T4 had much larger thymuses than control mice that had been treated with saline, suggesting that treatment with anti-L3T4 prevented the thymic atrophy that occurs spontaneously in murine lupus. Despite depleting L3T4+ cells from the spleen, treatment with anti-L3T4 did not diminish the response of splenic lymphocytes to T and B cell mitogens, and it augmented splenic natural killer (NK) cell activity. Finally, treatment with anti-L3T4 decreased the diverse histopathologic manifestations of murine lupus. It dramatically reduced glomerular immunoglobulin and complement deposition and diminished lymphocytic infiltration and vasculitis in the kidneys. Treatment also reduced extrarenal immunopathology, including focal hepatitis and salivary gland infiltration. These observations have implications regarding the use of CD4 MoAb in people with autoimmune diseases.
 ...
PMID:Treatment of murine lupus with monoclonal antibody to L3T4. I. Effects on the distribution and function of lymphocyte subsets and on the histopathology of autoimmune disease. 326 85

Interleukin (IL) 2-deficient mice develop a fatal immunopathology characterized by lymphoadenopathy, splenomegaly, T cell infiltration of the bone marrow, loss of B cells, anemia, and inflammation of the gut. The thymus dependence of these disease symptoms was tested by introducing the IL-2 mutation into athymic mice. With the exception of an increase in CD8+ intrahepatic alpha/beta T cells, IL-2 deficiency had no detectable effect on leukocyte composition or health of athymic mice, indicating a key role for thymus-derived T cells in the initiation of disease and demonstrating that B cell development and survival are independent of IL-2. In adoptive transfer studies, lymph node and spleen cells from euthymic IL-2-deficient mice induced disease in athymic mice with an intact IL-2 gene, suggesting that thymus-independent IL-2-expressing cells are unable to control the development of immune pathology. Both IL-2+ and IL-2-/- bone marrow cells repopulated the thymus and the peripheral T cell compartment of the recombination activator gene 2-deficient recipients, and chimeras that had received IL-2-deficient bone marrow developed immune pathology. Disease development was, however, fully or at least partially prevented when 30% of the bone marrow inoculum was derived from mice able to express IL-2. These results demonstrate that the IL-2 deficiency syndrome depends on the intrathymic differentiation of T cells carrying the IL-2 mutation, and that the abnormal activation of IL-2-deficient lymphocytes can be controlled by thymus-derived but not thymus-independent lymphocytes.
 ...
PMID:Immunopathology of interleukin (IL) 2-deficient mice: thymus dependence and suppression by thymus-dependent cells with an intact IL-2 gene. 750 21

Despite a normal development of all major lymphoid subsets, with time, interleukin-2 (IL-2)-deficient mice develop a fatal immunopathology. The disease phenotype is characterized by lymphoadenopathy, splenomegaly, T cell infiltration of various organs, overproduction of a number of cytokines and autoantibody formation. Phenotypically, CD4+ and CD8+ T cells exhibit features characteristic of antigenically experienced cells. The accumulation of cells with a memory phenotype together with the previous suggestion of an involvement of IL-2 in the termination phase of immune responses prompted us to study the fate of superantigen-reactive T cells in IL-2-deficient mice in comparison to their IL-2-producing littermates. We show that expansion in vivo of CD4+ and, to a lesser extent, CD8+ T cells reactive to the superantigens staphylococcal enterotoxin A and B (SEA and SEB) proceeds normally in the absence of IL-2, but that fewer CD4+ cells are subsequently deleted. The residual superantigen-reactive cells fail to become anergic as measured by proliferation in vitro in response to the same superantigen. T cell blasts generated in vitro from lymph node cells of IL-2-deficient mice by superantigen stimulation in the absence of exogenous IL-2 also fail to become anergic. In contrast to cells from IL-2-producing littermates, they do not exhibit Fas-induced apoptosis when cultured on anti-Fas antibody-coated plates, although Fas expression by IL-2-deficient cells is normal or even elevated compared to the IL-2-producing control cells. The data suggest that activation of T cells in the absence of IL-2 fails to generate a signal which is necessary to activate the apoptotic pathway and thus leads to an accumulation of antigen-experienced cells and the chronic inflammatory responses observed in IL-2-deficient mice.
 ...
PMID:Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. 758 28

Interleukin-1 (IL-1) is an important mediator of inflammation and has been implicated in several forms of immunopathology. Here we have investigated whether IL-1 plays a role in the enteropathy which occurs during a graft-versus-host reaction (GVHR) in mice. Non-irradiated (CBA x BALB/c) F1 mice with GVHR had increased production of IL-1 and treatment with rabbit anti-IL-1 alpha antibodies abolished the crypt hyperplasia and significantly reduced the parallel increase in crypt length which occurs in the jejunum. Antibody treatment had no effect on the accompanying increase in intraepithelial lymphocyte (IEL) counts or on the splenomegaly. Recombinant IL-1 itself produced villus atrophy, crypt hyperplasia and increased IEL counts in normal mice and stimulated the proliferation of an intestinal epithelial cell line in vitro. We propose that IL-1 plays an effector role in immunologically mediated enteropathy, either via direct effects on epithelial cells or secondary to an action on other, stromal cells in the mucosa.
 ...
PMID:A role for interleukin-1 alpha in immunologically mediated intestinal pathology. 824 50

To investigate the role of cell-mediated immunity in the control of Mycobacterium avium infection, we studied the effects of targeted gene disruptions in components of the T lymphocyte-dependent, macrophage-mediated response on resistance of mice to this pathogen. Normal mice developed a chronic, asymptomatic infection, with rapid induction of mRNAs for IFN-gamma, IL-12, and TNF-alpha in spleen, liver, and lung. Bacterial loads in gene knockout, scid, and wild-type mice were indistinguishable for the first 4 wk of infection. However, by 8 wk postinfection, scid mice as well as animals with a targeted disruption of the IFN-gamma gene showed enhanced bacterial growth compared with wild-type controls. In contrast, knockout mice lacking the genes for the TNF-alpha p55/p75 receptors or inducible nitric oxide synthase not only developed comparable bacterial loads to wild-type animals, they also failed to display the splenomegaly and profound suppression of mitogen-induced lymphocyte proliferative responses evident in infected wild-type controls. Thus, M. avium is clearly distinct from other intracellular pathogens (e.g., Leishmania monocytogenes, Toxoplasma gondii, and Mycobacterium tuberculosis) whose initial replication in the host is tightly controlled by Th1-dependent effector mechanisms. Instead, the major effect of host cell-mediated immunity is to limit bacterial growth during the chronic phase of infection. Surprisingly, inducible nitric oxide appears to be more important for the immunopathology than for the host resistance induced by this bacterial pathogen.
 ...
PMID:Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection. 914 97

When mice were infected i.v. with either Listeria monocytogenes or Brucella abortus, bioactive IL-12 was briefly detected in serum and supernatants of spleen homogenates immediately ex vivo. Although the time scale was more prolonged for the more slowly growing B. abortus, in both instances IL-12 production ceased while bacteria still persisted in high numbers. Production of IL-12, detected in serum and spleen, was neither increased nor prolonged by injecting Abs to IL-10 or IL-4. In contrast with live organisms, heat-killed bacteria did not induce detectable IL-12 in vivo and were less efficient when added in vitro to resident peritoneal cells or spleen cells. Mice lacking the receptors for TNF (TNFR-/- mice) were severely deficient in IL-12 production, suggesting a controlling role for TNF, which we have previously shown to be triggered by live, rather than dead, bacteria. Infection in the TNFR-/- mice was exacerbated, although in the Brucella-infected mice splenomegaly, the main indicator of immunopathology, was reduced. Production of NO by macrophages was deficient, but the TNFR-/- mice were not deficient in IFN-gamma production. In addition to being poor inducers of IL-12, killed bacteria actively suppressed IL-12 production in response to live bacteria, by mechanism(s) unknown. The implications of these findings are discussed in light of the fact that only live bacteria satisfactorily induce cell-mediated immunity to infection.
 ...
PMID:Control of IL-12 and IFN-gamma production in response to live or dead bacteria by TNF and other factors. 968 10

We report the development of an in vivo system to induce the generation, and study the potential role, of autoantibodies to the lymphokine interleukin-2 (IL-2). To elicit IL-2 autoantibodies, mice were immunized with purified fusion proteins containing the N-terminal region of different IL-2 allotypes, where major changes have been observed. This part of the IL-2 molecule includes a conserved sequence with an essential residue for interacting with the beta-chain of the heterotrimeric IL-2 receptor. Mice bearing an RF IL-2 allotype, immunized with several N-terminal IL-2 fusion proteins, produced IgG antibodies against Mus musculus, C57BL/6, Mus spretus and the self molecule RF IL-2, but there were large differences among then in reactivity. These N-terminal IL-2 immunogens break the maintenance of self tolerance possibly by the introduction of new T cell epitopes on self IL-2. The immunized mice developed a complex set of immunopathologies such as splenomegaly, haemolytic anaemia and lymphoadenopathy with a long latency period after the last immunization. These pathologies resembled those described for IL-2-deficient mice (IL-2(-/-)) and mice injected with anti-IL-2 receptor alpha-antibody. Human IL-2 autoantibodies have been detected in several immune-affected situations and therefore this model would be of interest to study the potential evolution of these autoantibodies in relation to immunopathology. The production of these autoantibodies against conserved epitopes of mouse IL-2 may facilitate studies on the structural homologies between different IL-2 allotypes and from various species, and could be applied to other cytokines.
 ...
PMID:Induction of autoantibodies to different interleukin-2 allotypes. 1022 31

Murine acquired immunodeficiency syndrome (MAIDS) is a complex immunopathology caused by a defective murine leukemia virus (LP-BM5) that mainly targets B-lymphocytes. Lymphadenophathy, splenomegaly, hypergammaglobulinemia and progressive immunodeficiency are prominent features of MAIDS. Previously, we showed that the ubiquitin proteolytic system was upregulated in infected lymph nodes [Crinelli, R., Fraternale, A., Casabianca, A. & Magnani, M. (1997) Eur. J. Biochem. 247, 91-97]. In this report, we demonstrate that increased 26S proteasome activity is responsible for accelerated turnover of the IkappaBalpha inhibitor in lymph node extracts derived from animals with MAIDS. The molecular mechanisms mediating IkappaBalpha proteolysis involved constitutive phosphorylation of IkappaBalpha at Ser32 and Ser36 and subsequent ubiquitination, suggesting persistent activation of an NF-kappaB inducing pathway. Interestingly, enhanced IkappaBalpha degradation did not result in enhanced NF-kappaB DNA binding activity, but rather in a different subunit composition. The modulation of NF-kappaB/IkappaB system may affect multiple immunoregulatory pathways and may in part explain the mechanisms leading to the profound immune dysregulation involved in MAIDS pathogenesis.
 ...
PMID:Activation of the ubiquitin proteolytic system in murine acquired immunodeficiency syndrome affects IkappaBalpha turnover. 1042 5


1 2 3 Next >>