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T Marth

Publications and source records attributed to T Marth.

32 records · Page 2Linked to original sources
PubMed1998

Oral tolerance.

Oral tolerance is the immunologic mechanism by which the mucosal immune system maintains unresponsiveness to the myriad of antigens in the mucosal environment which might otherwise induce untoward immune responses. Recent studies have shown that it is mediated by several distinct, yet interacting mechanisms including the generation of suppressive T cells producing antigen nonspecific cytokines and the induction of clonal deletion and/or anergy. In this review of oral tolerance, we discuss these mechanisms in detail and show how oral tolerance or lack thereof may explain the occurrence of mucosal inflammation. In addition, we discuss how induction of oral tolerance can be used to treat autoimmune states.

Humans↗
PubMed1997

Regulation of interleukin-12 by complement receptor 3 signaling.

Complement receptor type 3 (CR3, CD11b/CD18) serves as a receptor for a number of endogenous ligands and infectious organisms, and is involved in adhesion and host defense functions. Here, we report that signaling via CR3 plays an important role in regulating production of interleukin-12 (IL-12), a key mediator of cell-mediated immunity (CMI). We demonstrate with a variety of stimuli a dose-dependent, specific downregulation of IL-12 secretion by human monocytes in vitro after exposure to antibodies to CR3 (anti-CD11b and anti-CD18), as well as to the natural CR3 ligands, iC3b, and Histoplasma capsulatum. CR3 antibodies also suppressed interferon-gamma (IFN-gamma) production in cultures of human peripheral blood mononuclear cells (PBMC). We determined that one mechanism by which CR3 antibodies may suppress IL-12 production is by the inhibition of IFN-gamma-induced tyrosine phosphorylation. Finally, in a murine model of IL-12-dependent septic shock, we provide evidence that administration of CR3 antibodies leads to suppression of IL-12 and IFN-gamma in vivo. Our studies thus define a novel role for CR3 in regulating CMI functions via IL-12.

Animals↗
PubMed1997

Regulation of transforming growth factor-beta production by interleukin-12.

The induction of peripheral tolerance following oral antigen administration in several autoimmune disease and conventional animal models correlates with the production of transforming growth factor-beta (TGF-beta) and T helper type 2 (Th2) cytokines. The factors regulating TGF-beta production and its relation to the Th2 response, however, have not been defined. We demonstrate that the systemic administration of antibodies to interleukin (IL)-12 to ovalbumin (OVA)-T cell receptor (TCR) transgenic mice fed high doses of OVA, followed by systemic OVA challenge, substantially enhances TGF-beta, but not IL-4 production by peripheral T cells. Furthermore, we demonstrate in an in vitro T cell differentiation model that naive (CD4+/Mel-14hi) OVA-TCR-T cells stimulated with OVA-pulsed dendritic cells (DC) produce four- to fivefold higher amounts of TGF-beta when cultured with anti-IL-12 or anti-interferon-gamma (IFN-gamma). In this in vitro system, IL-4 was not required for TGF-beta production by T cells; however, it appeared to enhance levels of TGF-beta by promoting the growth of TGF-beta-producing cells. Our findings demonstrate that IL-12 and IFN-gamma are important negative regulators of TGF-beta production both in vivo and in vitro, and that their modulation may be of benefit for the treatment of autoimmune disorders.

Adjuvants, Immunologic↗
PubMed1997

Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation.

The above new findings concerning the immunological mechanisms governing mucosa, immune responses and oral tolerance in TCR-transgenic mice, as well as those operative in mice with experimental colitis, greatly expand our understanding of the processes that normally control mucosal inflammation and possibly other types of inflammation as well (Fig. 1). They indicate that, in the nondiseased mouse, ingested proteins evoke a Th1-cell (IFN-gamma) response in the mucosal follicles that is quickly counter-regulated by induction of T-cell anergy/deletion, if this Th1-cell response is inhibited (experimentally by anti-IL-12), TGF beta-producing cells appear, and these are capable of active immune suppression. This reciprocal relationship between IFN-gamma production and TGF-beta production is further supported in mouse models of mucosal inflammation. Thus, in the TNBS-colitis model, there is direct stimulation of the immune cells in the lamina propria as a result of diffuse haptenization of mucosal proteins, which leads to a massive Th1-cell response capable of overwhelming any suppressive counter-regulatory mechanisms normally generated in the PPs. This highly polarized Th1-cell response is controlled only by direct abrogation of IL-12 production with exogenous administration of anti-IL-12, or with indirect inhibition of this response via induction of oral tolerance and accompanying production of TGF-beta (Refs 6-8). The data obtained from this model are consistent with those obtained with another model of intestinal inflammation--inflammation in severe combined immunodeficiency (SCID) mice following lymphoid repletion with CD45Rbhi (naive) T cells. In this model, inflammation is again mediated by Th1 cells and is prevented by co-repletion with CD45Rbhi (memory) T cells, which appear to work by secreting TGF-beta (Refs 9, 10). Thus, a common feature of the various experimental models of intestinal inflammation studied to date is the Yin-Yang relationship of IFN-gamma and TGF-beta, with the former being proinflammatory and the latter anti-inflammatory. Is the IFN-gamma TGF-beta dichotomy that is evident both in the normal state and in models of inflammation simply a reflection of an underlying Th1 Th2 dichotomy? The answer to this important question is not yet known. Thus, while it is clear from the in vitro studies already discussed that IL-12 and/or IFN-gamma inhibit TGF-beta production, the role of IL-4 in this process is more elusive. These in vitro studies indicate that IL-4 is not required for TGF-beta production, a finding that is consistent with studies in which the transfer of CD45Rbhi, T cells from IL-4-/- mice protected SCID mice from colitis induced by CD45Rbhi T cells. However, the addition of IL-4 to in vitro cultures containing anti-IL-12 augmented TGF-beta production, most probably by IL-4 acting as a growth factor for TGF-beta-producing cells rather than as an inducing factor (T. Marth et al., unpublished). Obviously, more work will be necessary to resolve this issue. Finally, it should be noted that the above considerations apply to human inflammatory diseases of the gastrointestinal tract, such as Crohn's disease. Recently, it has been shown that T cells extracted from Crohn's disease tissues manifest skewed Th1-cell responses. The hypothesis can therefore be put forward that this disease results from a dysregulated Th1-cell response to ubiquitous mucosal antigens that is not appropriately controlled by normal counter-regulatory mechanisms. Interventions that artificially bring the excessive Th1-cell response back into balance, such as administration of IL-12 antagonists, should therefore find a central place in the treatment of the disease.

Animals↗
PubMed1997

Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease.

BACKGROUND & AIMS: Whipple's disease (WD) is a systemic infection in which the causative bacteria typically accumulate within macrophages. The aim of this study was to test whether this macrophage dysfunction is the cause or result of previously shown T-cell defects. METHODS: In vitro production of interleukin (IL)-12, IL-10, tumor necrosis factor alpha, interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) from purified monocytes and peripheral blood mononuclear cells, cytokine expression on duodenal biopsy specimens, and serum cytokine and immunoglobulin (Ig) levels were tested in 9 patients with WD. RESULTS: Reduced monocyte IL-12 production and decreased IFN-gamma secretion by peripheral blood mononuclear cells in vitro were found, as well as reduced immunohistological staining for IL-12 and IFN-gamma, but no decrease in other cytokines in patients with WD. A similar but less severe defect in 2 relatives with WD argued for a genetic basis of this abnormality. Serum IgG2, an IFN-gamma-dependent Ig subclass, and serum TGF-beta levels were reduced in patients with WD. CONCLUSIONS: The described monocyte defects in WD may result in a secondary reduction of IFN-gamma production and IgG2 serum levels. This provides a rationale for additive immunotherapy in patients with antibiotic-refractory WD.

Antibody Formation↗
PubMed1996

High dose oral tolerance in ovalbumin TCR-transgenic mice: systemic neutralization of IL-12 augments TGF-beta secretion and T cell apoptosis.

The immune response to oral Ag administration, including the development of oral tolerance, was explored with the use of OVA TCR-transgenic mice. Feeding high doses of OVA enhanced IFN-gamma production in the Peyer's patches, but induced tolerance in the peripheral lymphoid tissues marked by suppressed proliferative and cytokine responses. Systemic administration of Abs to IL-12 (anti-IL-12) simultaneous with Ag feeding modestly enhanced the degree of tolerance in the peripheral lymphoid tissues, as shown by increased suppression of proliferative responses after in vitro restimulation, and secondary responses in the popliteal lymph nodes following in vivo challenge and in vitro restimulation. Systemic anti-IL-12 treatment was associated with augmented TGF-beta production and T cell apoptosis in both Peyer's patches and peripheral lymphoid tissues. Cell mixing studies and proliferation assays in the presence of anti-TGF-beta provided evidence that the increased suppression of responses induced by anti-IL-12 was due primarily to the secretion of TGF-beta. These findings suggest that IL-12 negatively regulates two of the main mechanisms of oral tolerance, TGF-beta production and clonal deletion via apoptosis. in addition, they suggest that the combination of oral Ag feeding and systemic anti-IL-12 administration may be of benefit in the treatment of autoimmune diseases.

Administration, Oral↗
PubMed1996

[Gastric hamartoma and thyroid gland carcinoma with follicular and neuroendocrine differentiation in Cowden syndrome].

A 40-year old male patient presented with a history of subtotal strumectomy, excision of multiple cutaneous lesions at the upper trunk and gastrointestinal polyposis of unknown origin. The patient was admitted for weight loss and intermittent diarrhea. Physical examination revealed craniomegaly, papillomatosis of the oral mucosa and epigastric tenderness. Endoscopically, multiple polyps were seen in the stomach, the duodenum, the terminal ileum, the distal colon and the rectum. Histologically, these lesions were classified as hamartomatous and hyperplastic polyps. In the punctate of the relapsed nodular goitre, neoplastic follicular cells were found. These findings led to the diagnosis of Cowden's disease. A complete thyroidectomy was performed. The histology verified a follicular thyroid carcinoma and showed a combined expression of thyroglobulin and of the neuroendocrine marker synaptophysin (appr. 50% of all tumor cells). Chromogranin A (a neuroendocrine tumor marker) was also elevated in the serum of the patient. Postoperatively, a radioiodine therapy was performed and the clinical condition of the patient has improved ever since. The presented case of Cowden's disease is the first male patient with thyroid carcinoma. Early consideration of Cowden's disease is substantial as multiple malignant neoplasms may occur in this disorder in increased incidence.

Adenocarcinoma, Follicular↗
PubMed1996

Whipple's disease.

Whipple's disease (WD) is a rare systemic disease caused by infection with the recently identified actinomycetes, Tropheryma whippelii. The disorder affects mostly middle-aged men, and the major clinical features are weight loss, arthropathy, and diarrhea; other symptoms, caused by systemic infection, are not infrequent. The diagnosis is usually established by duodenal biopsy, which shows the pathognomonic periodic acid Schiff-positive infiltrates in the lamina propria. In addition, RT-polymerase chain reaction of tissue specimens can be used to verify the presence of T whippelii. In most cases, patients can be successfully treated by prolonged administration of antimicrobials, such as trimethoprim-sulfamethoxazole. The unusual chronic-relapsing course of the disease, the predisposition of middle-aged, HLA-B27-positive men for WD, and other characteristics of the disease imply that host factors are involved in the etiopathogenesis of WD. Indeed, it has been shown that patients with WD have suppressed delayed-type hypersensitivity responses in vivo and decreased in vitro T-cell responses, eg, to phytohemagglutinin and concanavalin A. In addition, serum-suppressor factors and shifts in T-cell subpopulations have been found. Perhaps most importantly, WD macrophages have a decreased ability to degrade intracellular microorganisms and patients have reduced numbers of circulating cells expressing CD11b, a cell adhesion and complement receptor molecule on macrophages involved in the activation of intracellular killing of pathogens. Most of those immunologic alterations also occur in patients with longstanding clinical remission, suggesting that this subtle host-defense defect plays an important role in disease pathogenesis.

Anti-Bacterial Agents↗
PubMed1994

Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease.

Several small studies have indicated an impaired cell mediated immune response as a possible cause for the delayed elimination of the bacteria in Whipple's disease. A specific defect, however, has not been defined. We examined the expression of cell surface molecules and mitogenic responses of peripheral blood mononuclear cells in 27 patients with Whipple's disease at different disease stages by indirect immunofluorescence and by measurement of [3H]thymidine incorporation, respectively. E-rosette formation and cutaneous reaction to seven recall antigens were determined. Matched healthy donors served as controls. We found a significantly reduced number of cells expressing the complement receptor 3 alpha-chain (= CD11b) in all patients. In florid disease, the number of activated cells (in particular CD58 positive cells) was increased and CD4/CD8 ratios were diminished. Proliferation to phytohemagglutinin and to sheep red blood cells was reduced at all stages of the disease. Serum of control persons reversed this decreased responsiveness especially in patients with active disease. Skin reaction was hypoergic in all patients. Determination of CD58 positive cells increased in patients with active disease may be useful to define the activity of the disease and the duration necessary for treatment. Transient inhibiting serum activities may impair the CD2/CD58 interaction. The reduction of cells expressing CD11b, the decreased proliferation, and the cutaneous hypoergy indicate a persisting defect of cell mediated immunity in vivo and in vitro. These defects may contribute to the impaired ability of patients with Whipple's disease to eliminate bacteria.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1994

An evaluation of antimicrobial treatment for Whipple's Disease. Tetracycline versus trimethoprim-sulfamethoxazole.

Whipple's disease is a multisystemic disorder in which almost all organ systems can be invaded by rod-shaped bacteria. Without extended antimicrobial therapy, its course is lethal. Empirically, treatment consists of tetracyclines given for one to two years. Trimethoprim-sulfamethoxazole, a compound that crosses the blood-brain barrier, has been suggested as an alternative when patients were observed with progressive cerebral involvement. There has never been a formal evaluation of the selection of antibiotics for the treatment of Whipple's disease. In the present nonrandomized, partially retrospective study, we compared the result of two treatment regimens in 30 patients, all examined personally. Twenty-two patients were treated with tetracycline and eight patients with trimethoprim-sulfamethoxazole. In five patients, therapy with tetracycline was changed to another antimicrobial agent because of treatment failure or drug intolerance. The main treatment measure was disappearance of the clinical symptoms such as weight loss, arthritis, malabsorption, fever, edema, central nervous system manifestations, lymphadenopathy, and congestive heart failure. Drug intolerance requiring a change of medication was also considered a treatment failure. We found that trimethoprim-sulfamethoxazole induced complete clinical remission in 12 of 13 treatment cycles, tetracycline in 13 of 22 treatment cycles (P < 0.05; mean difference 33%; 95% confidence interval 8% to 58%). Trimethoprim-sulfamethoxazole was also more efficacious than tetracycline in the treatment of cerebral Whipple's disease. However, trimethoprim-sulfamethoxazole did not prevent cerebral manifestations in all cases. The only deaths due to Whipple's disease occurred in patients with cerebral involvement. It is concluded that treatment with trimethoprim-sulfamethoxazole was significantly superior to that with tetracycline in inducing clinical remission of Whipple's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Administration Schedule↗