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We report a case of upper gastrointestinal bleeding caused by a gastrointestinal stromal tumor in a 50-year old man. The patient was having melena for two months, and on admission he was hemodynamically stable. Upper G.I endoscopy showed diffuse gastritis and an extrinsic compressing mass in the upper part of the stomach. CT scan of the abdomen showed exophytic mass in the fundus of the stomach, with central necrosis. The patient was submitted to operative management. There were no features of dissemination but there was invasion of the hilum of the spleen. Wide local resection and splenectomy performed. Post operative course was complicated by a bleeding from the anastomotic site that required re-exploration and suturing of the bleeding vessel. Histologic examination revealed that it was composed of spindle-shaped cells with elongated nuclei. Post operatively the patient received adjuvant treatment with Imatinib [Gleevec]. The patient has an uneventful follow-up period so far.

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BACKGROUND: The EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study assessing the efficacy and tolerability of interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), and IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this analysis was to assess whether reductions in T2 burden of disease (BOD) were greater for patients receiving IFN beta-1a, 44 mcg sc tiw, than for those treated with IFN beta-1a, 30 mcg im qw, and to assess the impact of neutralizing antibodies (NAbs). METHODS: A post-hoc analysis was performed on magnetic resonance imaging (MRI) data collected prospectively from the EVIDENCE study. The analysis included all patients with evaluable T2 MRI scans at the start of dosing and at week 48, and those who received at least one drug dose (n = 553). Lesions were identified by a radiologist blinded to treatment codes and the total volume of T2 lesions (BOD) was reported in mm3. RESULTS: Both median percentage decreases and absolute reduction in BOD were greater in the IFN beta-1a, 44 mcg sc tiw, treatment group. The adjusted mean treatment difference in percentage change in BOD from baseline to week 48 showed a significant treatment benefit for patients treated with IFN beta-1a, 44 mcg sc tiw, over those treated with IFN beta-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002). The presence of NAbs reduced the effect of IFN beta-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN beta-1a, 30 mcg im qw. CONCLUSION: Patients with RRMS treated with IFN beta-1a, 44 mcg sc tiw, had greater reduction in T2 BOD after 48 weeks than those treated with IFN beta-1a, 30 mcg im qw, which is consistent with other clinical and MRI outcome measures in the EVIDENCE study. In patients testing positive for NAbs (NAb+) to IFN beta-1a 44 mcg sc tiw, changes in BOD were smaller than in NAb negative (NAb-) patients, but similar to those receiving IFN beta-1a, 30 mcg im qw.

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OBJECTIVES: To develop a measure of treatment satisfaction assessing attributes specific to injected interferon-beta-1a (IFN-beta-1a) for multiple sclerosis (MS), and to test pain and instrument sensitivity to change among patients changing injection devices. MATERIALS AND METHODS: The MS Treatment Concerns Questionnaire (MSTCQ) was developed and tested with pain assessments before and 3 months after patients changed devices from Rebiject to Rebiject II. RESULTS: The MSTCQ was organized with two domains: Injection System Satisfaction and Side Effects (three subscales: Injection Site Reactions, Global Satisfaction, and Flu-Like Symptoms). Significant improvements (P = 0.002 to P < 0.001) occurred with the new injection device in all MSTCQ subscales (except Flu-Like Symptoms), and all pain measures (P < 0.0001). Clinically meaningful improvement was demonstrated in all scales, except Flu-Like Symptoms, by effect sizes (0.23-0.59). CONCLUSIONS: These statistically significant and clinically meaningful improvements in MSTCQ and pain measures show the value of technologically advanced devices in domains of concern to patients.

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The mechanism of action underlying the beneficial effect of IFNbeta in Multiple Sclerosis is poorly understood. Experimental Autoimmune Encephalomyelitis (EAE) is the experimental model for Multiple Sclerosis; therefore, we investigated the effects of recombinant mouse IFNbeta on the severity of EAE induced in SJL mice and on cytokine production by Th1 and Th2 lymphocytes. The results indicated that rmIFN beta reduced the disease activity with an I.P. dosage of 10,000 U/day every other day, and successfully treated EAE mice revealed reduced amounts of IFN gamma; no changes in the levels of IL4 were observed, although thera was a significant increase in IL10 and TGFbeta production. Beneficial effects on EAE are associated with inhibition of inflammatory cytokines and stimulation of anti-inflammatory cytokines.

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Some autoimmune diseases are thought to arise after an infection. Infectious agents can initiate a chronic inflammatory response associated with autoimmune reactions. Chagas disease, caused by the intracellular parasite Trypanosoma cruzi, is an excellent model for autoimmune disease induced by an infection. The chronic disease is characterized by rich inflammatory infiltrate in myocardial and nervous tissues, with virtually no demonstrable parasites. We were able to demonstrate the presence of antibody to myelin basic protein (MBP) in the serum from T. cruzi chronically infected mice. Lymphocytes from mice immunized with T. cruzi-derived soluble extract antigen (TCSE) proliferate in response to MBP in vitro. Lymphocytes from animals immunized with MBP also were activated by TCSE in vitro. By studying the overlapping peptides from the MBP molecule, we were able to identify two regions responsible for the cross-reactivity.

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Murine chronic relapsing experimental autoimmune encephalomyelitis (CR-EAE) is a model of inflammatory demyelinating disease of the central nervous system (CNS) with similarity to multiple sclerosis (MS) in humans. Mice with confirmed neurologic deficits from CR-EAE were treated by oral administration of whole bovine myelin to investigate the effect of long-term oral delivery of myelin antigens on clinical disease and on the inflammatory response in the CNS. EAE-positive mice were fed doses of 1 mg, 10 mg, or 20 mg of bovine myelin every other day for 6 months. We found that prolonged oral delivery of neuroantigen suppressed inflammatory and demyelination foci in the CNS of myelin-treated mice with no exacerbation of clinical disease status compared with the control group. Analysis of histologic sections of brain and spinal cords with hematoxylin-eosin (H&E) and Luxol fast blue (LFB) staining showed a decrease in the inflammatory cell infiltration and active centers of demyelination, respectively. Furthermore, after 6 months of treatment, there was no increased sensitization to myelin antigens seen, as measured by antimyelin basic protein (MBP) or anti-proteolipid apoprotein (PLP) antibodies. These results demonstrate that prolonged oral administration of myelin antigens in diseased animals has an ameliorating effect on the pathologic process and supports its potential long-term use in humans with MS.

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Antigen-driven tolerance is an effective method of suppressing cell-mediated immune responses. We have previously demonstrated that exposure of gut-associated lymphoid tissue to myelin basic protein (MBP) via oral administration suppresses experimental autoimmune encephalomyelitis (EAE). To further study presentation of antigen to the immune system by mucosal surfaces as a method of antigen-driven tolerance, the effect of inhalation of MBP was investigated. MBP was given as an aerosol to Lewis rats on Days -10, -7, -5, and -3 prior to immunization with MBP in Freund's adjuvant and on Days 0, 2, and 4 following immunization. Aerosolization of MBP completely abrogated clinical EAE in 100% of treated rats. Central nervous system inflammation and delayed-type hypersensitivity and antibody responses to MBP were also significantly reduced in aerosol-treated animals. Aerosolization of histone, a basic protein of similar weight and charge as MBP, had no effect. Disease was also suppressed with one aerosol treatment on Day -3 or by administering MBP nasally. Aerosolization was more effective than oral administration of MBP over a wide dose range (0.005-5 mg). Splenic T cells isolated from animals postaerosolization adoptively transferred protection to naive animals immunized with MBP. Aerosolization of MBP to animals with relapsing EAE after recovery from the first attack decreased the severity of a subsequent attack. Aerosol and oral MBP were equally effective at suppressing the in vitro immune response as measured by proliferation and interferon-gamma production. We then tested aerosolization of a different autoantigen in a different disease model and found that aerosolization of type II collagen was effective in suppressing collagen-induced arthritis. Thus, aerosolization of an autoantigen is a potent method to downregulate an experimental T cell-mediated autoimmune disease and suggests that exposure of antigen to lung mucosal surfaces preferentially generates immunologic tolerance.

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The microheterogeneity of myelin basic protein, expressed as the ratio between the least cationic (C-8) charge isomer and the most cationic (C-1), was examined in experimental allergic encephalomyelitis (EAE) cases. These included acute EAE of 2 months' duration induced with bovine proteolipid protein in complete Freund's adjuvant (CFA), chronic EAE induced with mouse spinal cord homogenate in varying doses from 0.5 to 2.0 mg in CFA, and chronic relapsing EAE of 12 months' duration induced with synthetic peptide 139-151 of the proteolipid protein sequence. The C-8/C-1 ratio was within the normal range for all groups of animals. However, the C-8/C-1 ratio was six- to sevenfold increased in a spontaneously demyelinating transgenic model, ND4, which contains 70 copies of the cDNA for DM20 (Mastronardi et al.: 1996). Since an increase in the C-8/C-1 ratio was also observed in victims of multiple sclerosis but not other neurological diseases, the ND4 model may address primary changes prior to demyelination, while the EAE model addresses the autoimmune aspects of the disease.

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Oral administration of myelin antigens reduces the incidence and severity of EAE in rat and mouse models and decreases the frequency of MBP-reactive cells and the frequency of attacks in some patients with multiple sclerosis. Low-dose oral tolerance has been shown to be mediated by Th2-type regulatory cells that secrete TGFbeta and IL-4/IL-10. Adjuvants and cytokines may modulate oral tolerance. The addition of betaIFN to the experimental therapy regimen, either orally or by intraperitoneal injection, has been shown to enhance the suppressive effects of oral myelin antigens when either are fed the suboptimal dosing regimen to suppress EAE. The current studies were conducted to elucidate the mechanism of the observed in vivo synergy of betaIFN and antigen feeding. Analysis of the in vitro proliferative response and cytokine production by lymphocytes from fed animals in response to specific antigen in culture shows that the synergistic effect may be related to both independent suppression of the immune response by oral betaIFN and enhanced production of TGFbeta and IL-4/IL-10. There was an unexpected increase in the production of gammaIFN by lymphocytes in vitro after three doses of oral betaIFN in vivo. These observations have important implications for the use of cytokines to modulate oral tolerance.

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We investigated the immune response to proteolipid protein (PLP), the most abundant central nervous system myelin protein in humans. A total of 8207 short-term T cell lines were generated from 49 individuals, 39 patients with multiple sclerosis and 10 control subjects. As we have reported previously, the frequency of PLP-reactive T cells did not differ between the two groups. To determine immunodominant PLP epitopes, proliferative responses of 971 PLP-specific lines were tested with 27 overlapping 20-amino acid peptides encompassing the human PLP sequence and the binding affinities of the PLP peptides to DRB5*0101 and DRB1*1501, DR2 MHC class II isotypes associated with multiple sclerosis, were determined. The T cell response after primary PLP stimulation was focused on two immunodominant epitopes comprising residues p30-49 and p180-199. These two fragments were recognized after processing of native protein by APCs and were situated in hydrophilic regions of PLP exhibiting only moderate affinity to DR2 molecules. In contrast, when T cells from DR2+ subjects were stimulated initially by individual synthetic peptides with either high or low affinity to DRB5*0101 and DRB1*1501 isotypes, additional cryptic epitopes were recognized. MHC restriction of lines specific for the cryptic PLP epitopes were related to binding affinity to DR2 isotypes. Our results indicate that protein Ags are recognized in vivo as immunodominant epitopes after Ag processing by APCs and as cryptic epitopes after processing, presumably by extracellular proteolytic enzymes.

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Oral administration of myelin basic protein (MBP) is an effective means of suppressing experimental autoimmune encephalomyelitis (EAE). In the Lewis rat model, we have previously shown that this effect is mediated by active suppression as T lymphocytes from animals orally tolerized to MBP suppress in vitro immune responses and in vivo adoptively transfer disease protection to naive recipients. This effect is mediated by the cytokine TGF-beta which is secreted by T cells from orally tolerized animals after being triggered by the oral tolerogen. In the present study we investigated Peyer's patches in SJL mice following orally administered MBP. Peyer's patches are one of the major lymphoid structures of gut-associated lymphoid tissue, and a site thought to play an important role in the induction of oral tolerance. Twenty-four hours after one feeding of 1 mg of MBP, there were no proliferative responses to MBP in Peyer's patches. However, when Peyer's patches from MBP-fed animals were stimulated with IL-2 in the presence of MBP, reduced proliferation to IL-2 was observed, and this inhibition was reversed with anti-TGF-beta antibody. Suppression of IL-2-induced proliferation by MBP was not observed in unfed animals or if Peyer's patches from MBP-fed animals were stimulated with a control antigen (ovalbumin). Stimulation of Peyer's patches T cells from MBP-fed animals with MBP resulted in secretion of TGF-beta in a dose-related fashion with less TGF-beta secretion at higher doses. Furthermore, cells from Peyer's patches of animals fed MBP adoptively transferred protection to actively induced EAE. Thus, MBP-specific TGF-beta-secreting regulatory cells recovered from Peyer's patches after a single oral administration of MBP are not evident as measured by proliferation, but are capable of suppressing in vitro and in vivo cell-mediated immune responses. Peyer's patches appear to be an important site for the induction of cells which mediate the active suppression component of oral tolerance.

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Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.

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Experimental allergic encephalomyelitis (EAE) is an autoimmune disease that can be induced in laboratory animals by immunization with the major myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP). We analyzed the role of the T cell receptor (TCR) repertoire in susceptibility to EAE induced by these two autoantigens. Autoreactive T cells induced after immunization with MBP use a limited set of TCR. In contrast, we demonstrate that T cell clones that recognize the encephalitogenic PLP epitope (PLP 139-151) use diverse TCR genes. When the TCR repertoire is limited by introduction of a novel rearranged TCR V beta 8.2 chain in transgenic SJL mice, EAE could be induced in the transgenic mice by immunization with the encephalitogenic epitopes of PLP, but not with the encephalitogenic epitope of MBP. Thus, skewing the TCR repertoire affects the susceptibility to EAE by immunization with MBP but not with PLP. These data demonstrate the biological consequences of the usage of a more diverse T cell repertoire in the development of an autoimmune disease.

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OT is a relevant biological pathway for generating peripheral tolerance against both self and external antigens with minimal side effects (fig. 3). This route might, therefore, contain promising potential for the treatment of autoimmune and allergic diseases in the human (fig. 3). Thus, oral administration of autoantigens suppresses experimental autoimmune diseases (EAE, EAU, AA, collagen-induced arthritis, NOD diabetes) in a disease- and antigen-specific manner, and oral administration of alloantigens has led to increase of allograft survival. OT might be important in treatment of immune complex diseases and food allergies. OT is mediated by T lymphocytes using at least two nonmutually exclusive mechanisms: suppression and anergy. Suppression can be adoptively transferred by CD8+ T lymphocytes which act by releasing TGF-beta and IL-4 following antigen-specific triggering. Antigen-driven tissue-directed suppression occurs following oral administration of an antigen from the target organ, even if it is not the disease-inducing antigen (bystander suppression). Thus, synthetic peptides can induce OT, and tolerogenic epitopes of antigen may be different from the autoreactive epitope. Due to the promising results in animal models, OT is being tested in clinical trials in multiple sclerosis, rheumatoid arthritis and uveitis [193, 194].

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Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.

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Immunization with the multideterminant autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a model for multiple sclerosis (MS). MBP peptides Ac1-11 and p35-47 induce potent EAE in mice of the H-2u haplotype. T cells specific for Ac1-11 predominantly utilize one T-cell receptor (TCR) V beta gene segment, V beta 8.2. All T-cell clones and hybridomas analyzed, regardless of TCR V beta usage, utilize D beta 2 and J beta 2 elements. The NZW mouse strain (H-2z), which contributes to the spontaneous 'lupus-like' illness in (NZB x NZW)F1 mice, has a genomic deletion encompassing D beta 2 and J beta 2 gene segments. The NZW strain expresses class II (I-A and I-E) genes which share identical sequences with H-2u class II. We investigated whether these strains are susceptible to EAE induced with intact MBP and known encephalitogenic MBP peptides. In vitro analysis demonstrated that NZW antigen-presenting cells (APC) can present MBP and MBP peptide Ac1-11 to an encephalitogenic T-cell clone derived from an H-2u mouse, confirming the functional identity of NZW class-II (I-A) molecules with their respective H-2u class-II gene products. In vivo results demonstrated that NZW and (NZB x NZW)F1 mice are susceptible to EAE induced with intact MBP and Ac1-11. MBP p35-47 caused EAE in (NZB x NZW)F1 mice, which express alleles for both the normal (NZB) TCR beta-gene locus, and the abnormal (NZW) TCR beta-gene locus containing the J beta 2 deletion.(ABSTRACT TRUNCATED AT 250 WORDS)

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We have been studying the suppression of experimental autoimmune encephalomyelitis in the Lewis rat after oral administration of myelin basic protein (MBP). Suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress immune responses in vitro. This suppression is mediated by secretion of TGF-beta following triggering by the fed antigen. In the present study, we tested the ability of overlapping 20 amino acid peptides from MBP to trigger suppression mediated by spleen cells from Lewis rats orally tolerized to MBP. Using a transwell system, we found that spleen cells from MBP orally tolerized animals stimulated by residues 21-40, 51-70 and 101-120 of MBP suppress proliferative responses of an ovalbumin specific cell line. This suppression correlated with secretion of TGF-beta by cells stimulated with the peptide. In addition, T cells from animals fed the tolerogenic peptide 21-40 alone secreted TGF-beta whereas no TGF-beta release or in vitro suppression was observed in animals fed the MBP encephalitogenic determinant 71-90. The 71-90 peptide triggered proliferation of MBP primed cells from animals immunized with MBP/CFA whereas the suppressor epitopes identified above did not. Furthermore, oral administration of peptide 21-40 suppressed disease induced by peptide 71-90. DTH responses to 71-90 were not affected by oral administration of peptide 21-40 whereas DTH responses to whole MBP were suppressed. These results demonstrate that distinct suppressor determinants exist on MBP which are separate from encephalitogenic determinants, and that epitope-driven bystander suppression plays an important role in down-regulation of tissue specific autoimmune processes following oral tolerization. These findings have important implications for the design of tissue specific targeted immunotherapy by oral tolerization in humans.

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