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Biomedical subjects

W Strober

Publications and source records attributed to W Strober.

At least 163 records · Page 9Linked to original sources
PubMed1987

Induction of CD4 suppressor T cells with anti-Leu-8 antibody.

To characterize the conditions under which CD4 T cells suppress polyclonal immunoglobulin synthesis, we investigated the capacity of CD4 T cells that coexpress the surface antigen recognized by the monoclonal antibody anti-Leu-8 to mediate suppression. In an in vitro system devoid of CD8 T cells, CD4, Leu-8+ T cells suppressed pokeweed mitogen-induced immunoglobulin synthesis. Similarly, suppressor function was induced in unfractionated CD4 T cell populations after incubation with anti-Leu-8 antibody under cross-linking conditions. This induction of suppressor function by anti-Leu-8 antibody was not due to expansion of the CD4, Leu-8+ T cell population because CD4 T cells did not proliferate in response to anti-Leu-8 antibody. However, CD4, Leu-8+ T cell-mediated suppression was radiosensitive. Finally, CD4, Leu-8+ T cells do not inhibit immunoglobulin synthesis when T cell lymphokines were used in place of helper CD4 T cells (CD4, Leu-8- T cells), suggesting that CD4 T cell-mediated suppression occurs at the T cell level. We conclude that CD4 T cells can be induced to suppress immunoglobulin synthesis by modulation of the membrane antigen recognized by anti-Leu-8 antibody.

Antibodies, Monoclonal↗
PubMed1987

Crohn's disease. New concepts of pathogenesis and current approaches to treatment.

One theory of the pathogenesis of Crohn's disease is that rather than being caused by a unique environmental agent, it is the result of an abnormal immune response in the gastrointestinal tract. Recent studies indicate that Crohn's disease in its early stages is frequently associated with the presence of circulating antigen-non-specific suppressor T cells. Such T cells are also found in experimental inflammation caused by Chlamydia organisms in the gastrointestinal tract of nonhuman primates. Taken together, these data suggest that the suppressor T cells are markers of an underlying and persistent, antigen-specific immune response to an as yet unidentified antigen or set of antigens. We postulate that this underlying antigen-specific response is the result of a primary immunoregulatory abnormality involving an imbalance between the effects of antigen-specific helper and suppressor T cells which recognize a common antigen or antigens present in the mucosal environment.

Animals↗
PubMed1987

Metabolism of immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels.

The metabolism of human IgE was studied in normals, severe atopics, and patients with the hyperimmunoglobulin E-recurrent infection (HIE; Job's) syndrome to determine whether IgE metabolism is altered in patients with marked elevation of serum IgE. Purified polyclonal 125I-IgE was administered intravenously and serial plasma and urine samples were obtained. After analysis, the metabolic data support previously published evidence that IgE (at concentrations found in normal individuals) is catabolized at a higher fractional rate than other immunoglobulins and is catabolized by both an intravascular and an extravascular pathway. In addition, the data show that the fractional catabolic rate for IgE is significantly less for the atopic patients (mean +/- SEM = 0.20 +/- 0.01) and for the HIE patients (0.15 +/- 0.02) than for the normal volunteers (0.52 +/- 0.06; P less than 0.01) and is inversely related (r = -0.851; P less than 0.001) to the serum IgE concentration. These findings have specific importance in showing that decreased fractional catabolic rate contributes substantially to elevation of IgE in atopic and HIE patients. In addition, the findings have general significance in that they lead to a unifying hypothesis of immunoglobulin catabolism.

Body Fluid Compartments↗
PubMed1986

T cell-induced expression of membrane IgG by 70Z/3 B cells.

To study T cell regulation of B cell isotype differentiation, we determined the capacity of clonal T cell populations (hybridomas derived by fusing BW5147 with Con A-activated Peyer's patch (PP) and spleen T cells) to induce "downstream" isotype expression by the pre-B cell lymphoma 70Z/3. In initial studies, we found that 70Z/3 B cells cultured in the presence of LPS (1 microgram/ml) expressed membrane IgM (mIgM) but not membrane IgG (mIgG). In contrast, 70Z/3 B cells cultured with HAJ-3 T cells, a PP-derived T cell hybridoma (as well as other similarly derived PP and spleen hybridomas), or with HAJ-3 T cells plus LPS do express mIgG. Such expression occurred in spite of mitomycin C-induced blockage of cell proliferation, and is observed in 70Z/3 B cell subclones cultured with HAJ-3 T cells. For these reasons, it is not due to selective expansion of a small pre-switched mIgG-bearing 70Z/3 B cell subpopulation. In other studies it was shown that 70Z/3 B cells expressing mIgG after induction by HAJ-3 T cells continue to express mIgM and do not secrete IgG. Finally, exposure of 70Z/3 B cells to the macrophage factor IL 1 and the T cell factors IL 2, BSF-pl, and BCGF-II present in EL-4 cell supernatants did not result in mIgG expression. On the basis of these studies, we conclude that a clonal B cell population expressing mIgM can be induced by T cells to co-express mIgG. Because the B cells do not express mIgG unless exposed to T cells, this represents a T cell-induced isotype switch.

Animals↗
PubMed1986

An autoreactive T cell clone that can be activated to provide both helper and suppressor function.

To understand further the biologic significance of the autologous mixed lymphocyte reaction, we determined the functional properties of autoreactive T cell lines and clones. Initially, we found that cells in an uncloned autoreactive Leu-3+ T cell line helped immunoglobulin production when added to cultures containing fresh T and non-T cells in the absence of pokeweed mitogen (PWM) but suppressed immunoglobulin production in the same cultures in the presence of PWM. To explain this phenomenon, we studied the immunoregulatory potential of an autoreactive T cell clone termed MTC-4. This clone bore the phenotype Leu-3+, 2-, 8-, 11-, DR+ and underwent proliferation when co-cultured with autologous, but not allogeneic non-T cells. Of interest, the immunoregulatory potential of the MTC-4 cells varied according to how the cells were activated. When MTC-4 cells were cultured with autologous non-T cells in the absence of antigen or mitogen (unactivated non-T cells), polyclonal immunoglobulin production (detected by reverse PFC assay) was observed. This helper activity was MHC-restricted in that it was elicited only by autologous non-T cells or MHC-matched allogeneic non-T cells; however, once activated by autologous non-T cells, it could also help allogeneic non-T cells. In contrast, when MTC-4 cells were cultured with autologous non-T cells in the presence of PWM (activated non-T cells), immunoglobulin production was greatly suppressed. This suppression was also observed when MTC-4 cells were added to cultures containing exogenous T cell help (such as that provided by autologous fresh T cells) and was not due to a direct effect of PWM on the T cell clone, because preincubation of MTC-4 cells with PWM before culture with non-T cells did not result in suppression. On the basis of these data, we conclude that autoreactive T cells can have dual immunoregulatory function that is manifest, at least in part, at the single cell level. Moreover, these regulatory functions are differentially elicited depending on the state of activation of the stimulating autologous non-T cells: when stimulated by MHC antigens present on unactivated B cells, they provide helper activity; and when stimulated by MHC antigens present on activated B cells, they act as suppressor cells. Autoreactive T cells with dual regulatory potential appear to make up a substantial proportion of all autoreactive T cells and are cells that are uniquely adapted to maintain immunologic homeostasis.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Selective immunoglobulin A deficiency associated with primary biliary cirrhosis in a family with liver disease.

A family is described in which multiple members are afflicted with liver disease and primary biliary cirrhosis (PBC). In the third generation, one member died of PBC, and a second individual has both symptomatic PBC and selective immunoglobulin A (IgA) deficiency, an association not previously reported. By culturing this patient's lymphocytes in vitro it was shown that the IgA deficiency was due to a failure of B cells to secrete IgA. Two other siblings of this patient have multiple serum biochemical and serologic abnormalities that are sometimes associated with PBC, but they do not have histopathologically overt PBC or IgA deficiency. All three surviving family members have a diminished autologous mixed lymphocyte reaction, an immunologic abnormality that has previously been found in patients with PBC, selective IgA deficiency, and several autoimmune diseases. As there is an association between selective IgA deficiency and certain autoimmune diseases, it is possible that this immunodeficiency contributed to the development of PBC in the patient in whom the two diseases coexisted. Furthermore, the occurrence of PBC in a patient with selective IgA deficiency indicates that the pathogenesis of PBC does not require IgA-dependent immune mechanisms.

Aged↗
PubMed1986

Phenotypic analysis of lamina propria lymphocytes. Predominance of helper-inducer and cytolytic T-cell phenotypes and deficiency of suppressor-inducer phenotypes in Crohn's disease and control patients.

To better define the nature of intestinal T cells, the phenotypes of isolated lamina propria lymphocytes (LPL) were determined in both Crohn's disease patients and control patients using combinations of monoclonal antibodies that have been found to correlate with particular immunoregulatory functions. Isolated LPL and autologous peripheral blood lymphocytes (PBL) were stained with multiple combinations of monoclonal antibodies and studied by dual immunofluorescence flow cytometry. In LPL, compared with PBL, there was a significant increase in the proportion of T cells having the Leu-3+, Leu-8- and Leu-3+, 2H4- phenotypes (associated with helper-inducer function) and a corresponding decrease in the proportion of T cells having the Leu-3+, Leu-8+ and Leu-3+, 2H4+ phenotypes (associated with suppressor-inducer function). It was also found that in LPL, compared with PBL, the percentage of cells with the Leu-2+, Leu-15+ phenotype (associated with suppressor-effector function) was significantly lower. However, the percentage of T cells with the Leu-2+, 9.3+ phenotype (associated with cytolytic function) was similar in PBL and LPL in control patients. There were no major differences comparing Crohn's disease patients with control patients, except that the proportion of Leu-2+, 9.3+ lymphocytes was higher in PBL in Crohn's disease patients. These results show that the lymphocyte subpopulations in the lamina propria differ from those in peripheral blood in having predominantly the phenotypes of helper-inducer and cytolytic T cells, whereas the phenotypes of suppressor-inducer cells and activated suppressor cells are less frequently observed.

Adult↗
PubMed1985

Circulating activated B cells in primary biliary cirrhosis.

Since patients with primary biliary cirrhosis (PBC) have evidence of abnormal function of the humoral immune system, we determined if B cells from patients with this disease show evidence of activation and can be stimulated by polyclonal activators. Using a reverse hemolytic plaque assay, it was found that patients with PBC had a significant increase in the number of circulating immunoglobulin-secreting cells, compared to normal controls and patients with chronic type B hepatitis virus (HBV) infection. However, the total number of activated cells was less than 1% of the total circulating B-cell population. Furthermore, we were unable to detect an increase in the expression of transferrin receptors, a membrane receptor associated with B-cell activation, in the majority of B cells in patients with PBC. In other studies, immunoglobulin production by lymphocytes from patients with PBC, when stimulated with the polyclonal activators pokeweed mitogen and Epstein-Barr virus (EBV), was reduced. This hyporesponsiveness was not due to a decrease in the number of B cells, as determined by staining with the monoclonal antibody anti-Leu 12. Furthermore, the decreased response to B cells to polyclonal activation in PBC patients was not due increased suppressor T-cell function, since EBV-simulated cultures of lymphocytes from patients with PBC demonstrated diminished suppression of immunoglobulin-secreting cells after 14 days of culture compared to controls. These findings suggest that the humoral abnormalities in PBC are due to the activation of a small subpopulation of B cells rather than to generalized B-cell hyperactivity.

Antibody-Producing Cells↗
PubMed1985

Animal models of inflammatory bowel disease--an overview.

It is obvious from the above discussion that, whereas no really clear-cut animal model of IBD has been established, a number of specific insights into the nature of the human illness can be derived from the study of naturally occurring and induced gastrointestinal inflammations occurring in animals. One of the most important emerges from the finding that both immune complex deposition in the gastrointestinal tract as well as stimulation of the mucosal T-cell system results in an ulcerative colitis-like gastrointestinal inflammation. The simplest explanation of the fact that vastly different methods of inducing immune-mediated injury in the gastrointestinal tract can lead to a similar kind of gastrointestinal inflammation is that the inflammatory response in the gastrointestinal tract is rather restricted in its overall pathologic appearance and that the histologic lesions characteristic of ulcerative colitis and Crohn's disease can arise from primary disturbance of the B-cell system, the T-cell system, or both. Another explanation of this fact, however, is that no matter what the initial immunological disorder may be, the mechanism underlying the gastrointestinal inflammation ultimately comes to involve a response to materials in the mucosal environment so that pathologic events are inevitably channeled into an inflammatory pathway that is either ulcerative colitis-like or Crohn's disease-like in its final configuration. This second explanation is buttressed by other findings derived from the study of animal models which, in general, suggest that no matter what the initial result, an immunologic interaction against a constituent of the bowel flora determines the ultimate course of the gastrointestinal inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Immunoregulatory function of lamina propria T cells in Crohn's disease.

The pathogenesis of Crohn's disease may involve altered function of immunoregulatory T cells in the intestine. To investigate this hypothesis, lamina propria lymphocytes were isolated from intestinal specimens resected from patients with active Crohn's disease and control subjects (colon carcinoma and diverticular disease) using an enzymatic technique. The T-cell phenotypes and function of these lymphocytes were compared with that of peripheral blood lymphocytes. The proportion of Leu-2-positive (suppressor/cytotoxic) cells was similar in peripheral blood and isolated lamina propria lymphocytes, both in Crohn's disease and control patients. Although the proportion of Leu-3-positive (helper/inducer) lymphocytes was lower in lamina propria lymphocytes than peripheral blood lymphocytes, there was no difference comparing Crohn's disease and control patients. Helper T-cell function, as determined by measuring the ability of T cells to increase immunoglobulin synthesis by pokeweed mitogen-stimulated normal peripheral blood B cells, was similar in peripheral blood lymphocytes and lamina propria lymphocytes, and comparing Crohn's disease with control patients. Suppressor T-cell function, as determined by measuring the ability of T cells to inhibit immunoglobulin production by cultures containing pokeweed mitogen-stimulated normal peripheral blood T and B cells, was also similar comparing peripheral blood lymphocytes and lamina propria lymphocytes, and comparing Crohn's disease with control patients: neither peripheral blood lymphocytes nor lamina propria lymphocytes significantly suppressed immunoglobulin synthesis. OKT8 (suppressor/cytotoxic)-enriched lamina propria lymphocytes mediated only marginal suppression, whereas concanavalin A-activated intestinal T cells did mediate significant suppression, in both Crohn's disease and control patients. Thus, patients with active Crohn's disease have no alteration of immunoregulatory T-cell function for polyclonal mitogen-induced immunoglobulin synthesis at the gut mucosal level, despite the presence of an inflammatory process in the intestine.

Adolescent↗