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Biomedical subjects

B L Kelsall

Publications and source records attributed to B L Kelsall.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses.

Recent studies have demonstrated that the treatment of mice with anti-gp39 antibodies impairs T-cell functions in the murine collagen type II-induced arthritis model, in acute semi-allogenic graft-versus-host disease, and in the allo-specific CTL-reaction, that is, reactions that are believed to be mediated by Th1-type T cells. On the other hand, the administration of anti-gp39 antibody did not influence Th2 T-cells responses, suggesting that CD40-CD40L interactions are more crucial for Th1 than Th2 T-cell development. Recent studies also demonstrate that dendritic cells (DC) are capable of driving a Th1 T-cell response that is mediated by IL-12. In addition, stimulation of CD40 on human monocytes results in IL-12 production, suggesting that activated T cells expressing CD40L may directly induce the production of IL-12 by antigen-presenting cells, thus allowing for the generation of a Th1 T-cell response in the absence of intracellular pathogens. We investigated whether the CD40-CD40L interaction was important in the production of IL-12 by DCs in an in vitro system that allowed precise control of cytokine concentrations. Initially we showed that FACS-purified mouse spleen DCs produce high amounts of IL-12 p40 in response to CD40 crosslinking by CD40L-expressing fibroblasts. We then demonstrate that DCs also produce IL-12 p40 in a more physiologic system using purified DCs pulsed with ovalbumin (OVA) and then cultured with LECAM-1hi T cells from ovalbumin T-cell receptor transgenic mice. Finally, we show that IL-10 has a potent capacity to shut down CD40-induced IL-12 p40 secretion; and, in addition, IL-4 partially inhibits CD40-induced IL-12 p40 secretion and enhances IL-10-mediated inhibition in an additive fashion. We also investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (TNBS)-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response completely prevented IFN-gamma production by CD4 T cells from the intestinal lamina propria and also the clinical and histological evidence of disease. In further studies we showed that the prevention of disease activity was due to an inhibition of IL-12 secretion. Thus, the injection of recombinant IL12 p75 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. In conclusion, these findings suggest that DCs produce IL-12 in response to CD40 signaling, that a mechanism by which IL-4 may induce Th2 development is by acting with IL-10 to inhibit IL-12 production by DCs, and that the CD40L-CD40 interaction is crucial for the IL-12-dependent priming of Th1 T cells in vivo.

Animals↗
PubMed1996

Differential roles for IL-12 in the maintenance of immune responses in infectious versus autoimmune disease.

IL-12 has been shown to be important in the generation of a functional Th1 response in animal models of both infectious and autoimmune disease. Furthermore, the role of IL-12 in the maintenance of the immune responses in these diseases is now emerging. Herein, we discuss the idea that memory responses for certain infections may be IL-12 independent, whereas memory responses for specific autoimmune diseases still require IL-12 to maintain a pathogenic response.

Adjuvants, Immunologic↗
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

Experimental granulomatous colitis in mice is abrogated by induction of TGF-beta-mediated oral tolerance.

In previous studies we showed that a chronic colitis associated with a Th1 T cell response can be induced by the rectal administration of the haptenizing reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). We report here that oral administration of haptenized colonic proteins (HCP) before rectal administration of TNBS effectively suppresses the ability of the latter to induce colitis. This suppression (oral tolerance) appears to be due to the generation of mucosal T cells producing TGF-beta and Th2-type cytokines after oral HCP administration. Peyer's patch and lamina propria CD4+ T cells from HCP-fed animals stimulated with anti-CD3/anti-CD28 had a 5-10-fold increase in their production of TGF-beta and secreted increased amounts of IL-4 and IL-10 but lower levels of IFN-gamma in comparison to T cells from ovalbumin-fed control animals. In addition, the colons of HCP-fed mice showed strikingly increased TGF-beta but decreased IL-12 expression by immunohistochemical studies and isolated mononuclear cells from HCP-fed animals secreted less IL-12 heterodimer. Finally, and most importantly, the suppressive effect of orally administered HCP was abrogated by the concomitant systemic administration of anti-TGF-beta or rIL-12 suggesting a reciprocal relationship between IL-12 and TGF-beta on tolerance induction in TNBS-induced colitis. In parallel studies we demonstrated that TNBS-induced colitis can be transferred to naive recipient animals with purified CD4+ T cells from the colon of TNBS-treated animals and that such animals develop lethal pancolitis when exposed to very low doses of TNBS. Feeding of HCP suppressed this sensitivity to TNBS, indicating that oral feeding can suppress the response of pre-committed T cells in vivo. These studies suggest for the first time that TGF-beta production can abrogate experimental granulomatous colitis even after such colitis is established, and thus, that regulation of TGF-beta levels may have relevance to the treatment of human inflammatory bowel disease.

Animals↗
PubMed1996

Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch.

Despite the fact that the Peyer's patch (PP) is the primary site for antigen uptake in the intestine, the cellular basis of antigen handling after transport into the PP is poorly understood. We performed immunohistology of murine PPs using the dendritic cell (DC)-reactive monoclonal antibodies N418, NLDC-145, M342, and 2A1, as well as antibodies to other T cell, B cell, and macrophage markers. N418+, 2A1+, NLDC-145-, M342- cells form a dense layer of cells in the subepithelial dome (SED), just beneath the follicle epithelium, and are scattered throughout the follicle, sparing the germinal center. In contrast, N418+, 2A1+, NLDC-145+, and M342+ DCs are present in the interfollicular T cell regions (IFR). CD3+ and CD4+, but no CD8+ T cells were present in the SED and the follicle, including the germinal center, while CD3+, CD4+, and CD8+ T cells were present in the IFR. B cells and macrophages were poorly represented in the SED as no B220+ cells, only few Mac-1lo cells, and no F4/80+ cells were present at this site. In contrast, Mac-1hi cells were found in the IFR and lamina propria of intestinal villi, while F4/80+ cells were found only in the latter. In further phenotypic studies, we analyzed surface molecules of PP and spleen DCs by flow cytometry and found that these cells had similar fluorescence profiles when stained with N418, NLDC-145, and 33D1 DC-reactive antibodies, and antibodies to the costimulatory molecules B7-1 (1G10) and B7-2 (GL1). In contrast, PP DCs expressed 5-10-fold higher levels of major histocompatibility complex class II antigens (IEk) than spleen DCs. Finally, in functional studies, we demonstrated that both PP and spleen DCs process soluble protein antigens during overnight culture and induce similar levels of proliferation in CD3+ T cells, and CD4+/Mel 14hi T cells from T cell receptor transgenic mice. The in vivo relevance of such presentation was shown by the fact that PP DCs isolated from Balb/c mice after being fed ovalbumin stimulated proliferation in ovalbumin T cell receptor T cells. Taken together, our data suggest that DCs in the SED of the PP are uniquely positioned for the processing of antigens passed into the PP from the overlying M cell, and that PP DCs are effective at processing and presenting oral antigens to naive T cells.

Animals↗
PubMed1995

Antibodies to interleukin 12 abrogate established experimental colitis in mice.

In this study, we describe a novel murine model of chronic intestinal inflammation induced by the hapten reagent 2,4,6-trinitrobenzene sulfonic acid (TNBS). Rectal application of low doses of TNBS in BALB/c and SJL/J mice resulted in a chronic transmural colitis with severe diarrhea, weight loss, and rectal prolapse, an illness that mimics some characteristics of Crohn's disease in humans. The colon of TNBS-treated mice on day 7 was marked by infiltration of CD4+ T cells; furthermore, in situ polymerase chain reaction studies revealed high levels of interferon (IFN)-gamma mRNA in diseased colons. Isolated lamina propria (LP) CD4+ T cells from TNBS-treated mice stimulated with anti-CD3 and anti-CD28 antibodies exhibited a Th1 pattern of cytokine secretion: a 20-50-fold increase in IL-2 and IFN-gamma levels and a 5-fold decrease in IL-4 levels as compared with those of stimulated LP CD4+ T cells from control BALB/c mice. Administration of monoclonal anti-IL-12 antibodies to the TNBS-treated mice both early (at 5 d) and late (at 20 d) after induction of colitis led to a striking improvement in both the clinical and histopathological aspects of the disease and frequently abrogated the established colitis completely. Furthermore, LP CD4+ T cells isolated from anti-IL-12-treated mice failed to secrete IFN-gamma upon in vitro stimulation. In summary, the data demonstrate the pivotal role of IL-12 and IFN-gamma in a TNBS-induced murine model of chronic intestinal inflammation. Furthermore, they suggest the potential utility of anti-IL-12 antibodies in patients with Crohn's disease.

Animals↗
PubMed1995

Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.

The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.

Animals↗
PubMed1995

Immunization of rats with the 260-kilodalton Entamoeba histolytica galactose-inhibitable lectin elicits an intestinal secretory immunoglobulin A response that has in vitro adherence-inhibitory activity.

The 260-kDa galactose-inhibitable lectin of Entamoeba histolytica mediates binding of amebic trophozoites to purified colonic mucins and intestinal epithelial cells. Parenteral immunization of Lewis rats with immuno-affinity-purified lectin with Freund's adjuvant and then intra-Peyer's patch inoculation of lectin with cholera toxin B subunit as adjuvant elicited a significant anti-lectin secretory immunoglobulin A response in the bowel lumen. Purified intestinal secretory immunoglobulin A from three or four immunized animals studied possessed inhibitory activity (P < 0.02) in an in vitro assay of trophozoite galactose-specific adherence to Chinese hamster ovary cells.

Animals↗
PubMed1994

Secretory immunoglobulin A antibodies to the galactose-inhibitable adherence protein in the saliva of patients with amebic liver disease.

Monoclonal antibodies directed against the 260-kD galactose-inhibitable adherence protein (GIAP) of Entamoeba histolytica inhibit binding of amebic trophozoites to purified colonic mucins, suggesting that anti-GIAP secretory immunoglobulin A (sIgA) may have a role in host defense in invasive amebiasis. We determined by enzyme-linked immunosorbent assay (ELISA) whether a salivary anti-GIAP sIgA response was present in patients from the Republic of South Africa with invasive E. histolytica infection. In 13 patients with amebic liver abscess (ALA), salivary anti-GIAP sIgA was significantly higher (mean +/- SD optical density [OD] = 0.448 +/- 0.258) than that determined for seven South African adult patients hospitalized with nonamebic illness (0.084 +/- 0.072; P = 0.002), seven healthy South African Adults (0.194 +/- 0.119: P = 0.025), and seven healthy adults from Charlottesville, Virginia (0.036 +/- 0.023; P = 0.004). Of the patients with ALA, nine had acute disease, and four had been cured of amebiasis 2-8 months previously. There was no significant difference between these two groups in the anti-GIAP sIgA levels. All ALA patients had a high titer serum anti-amebic antibody response, and there was no direct correlation between the level of anti-GIAP salivary IgA and anti-GIAP serum antibodies (R = 0.187). These findings demonstrate that the E. histolytica GIAP is a mucosal antigen in naturally occurring invasive E. histolytica infection.

Adult↗
PubMed1994

Role of mucosal secretory immunity in the development of an amebiasis vaccine.

Invasive colonic infection by the enteric protozoan Entamoeba histolytica elicits a mucosal anti-amebic IgA antibody response. The E. histolytica galactose-inhibitable adherence protein (GIAP) mediates parasite binding to colonic mucins and epithelial cells. Anti-GIAP secretory IgA antibodies are found during invasive amebiasis and can be elicited by immunization of rats with the native protein. Entamoeba histolytica contains potent IgA degradative activities due to its cysteine-specific proteases. Research is needed to further understand the role of secretory antibodies in natural or vaccine-induced immunity to E. histolytica.

Animals↗
PubMed1993

Antigenicity, immunogenicity and vaccine efficacy of the galactose-specific adherence protein of Entamoeba histolytica.

Entamoeba histolytica is an enteric protozoan that causes amoebic colitis and liver abscess. Human immunity to E. histolytica is apparently mediated by a serum antibody response and amoebicidal cellular mechanisms. The galactose-specific adherence protein of E. histolytica is a 260 kDa glycoprotein which mediates amoebic in vitro adherence to human colonic mucins, epithelium, and inflammatory cells. Amoebic lysis of cells is dependent upon binding by this adherence protein. Serum IgG and salivary IgA antibodies from greater than 90% of subjects with invasive amoebiasis recognize the adherence protein's 170 kDa heavy subunit. Incubation of peripheral blood mononuclear cells from antibody-positive subjects with the purified galactose-specific adherence protein induces in vitro T lymphocyte proliferation, IL-2 and gamma interferon production, and direct lymphocyte amoebicidal activity. The rationale for an adherence protein vaccine includes sIgA blockage of amoebic binding to colonic mucins, humoral IgG prevention of parasitic adherence in tissues, and development of amoebicidal cell-mediated immunity. Immunization of gerbils with purified adherence protein in Freund's adjuvant provides protection against intrahepatic challenge with the trophozoites. In summary, the galactose specific adherence protein of E. histolytica contains highly conserved B- and T-cell epitopes, and has a high degree of vaccine efficacy in the gerbil model of amoebic liver abscess.

Animals↗
PubMed1993

Degradation of human IgA by Entamoeba histolytica.

To determine whether the virulent enteric pathogen Entamoeba histolytica degrades human IgA molecules, serum and secretory IgA was exposed to viable axenic trophozoites (strain HM1:IMSS), a parasite sonicate, and medium conditioned by incubation with live trophozoites. IgA was completely degraded under all conditions, proteinase activity was maximal at a neutral pH, and there was a four- to eightfold enrichment of amebic IgA proteolytic activity in a soluble fraction of amebic sonicate. Degradation of serum IgA by amebic sonicate was completely inhibited by the cysteine proteinase inhibitors trans-epoxysuccinyl-L-leucyl-amino(4-guanidino)butane (E-64, 100 microM) and benzyloxycarbonyl-phenyl-alanyl-alanyl-fluoromethyl (Z-Phe-Ala-CH2F, 12.5 microM). Secretion of degradative activity, the optimal pH, and the inhibition by E-64 and Z-Phe-Ala-CH2F indicates that cysteine proteinase activity is predominantly responsible for the degradation of human IgA by E. histolytica.

Animals↗
PubMed1992

Evaluation of diarrhea in the returning traveler.

Diarrhea in the returned traveler raises the possibility of a wide range of infectious, post-infectious, and idiopathic (e.g., inflammatory bowel disease) disorders that require a thoughtful evaluation. Specific clues in the history and clinical presentation are helpful in distinguishing inflammatory from noninflammatory processes and in suggesting persistent parasitic or other syndromes. The authors describe a practical approach to the diagnosis and management of diarrhea in the returned traveler.

Acute Disease↗
PubMed1992

Evaluation of skin problems.

Travelers frequently return to North America with noninfectious skin problems. However, the physician who evaluates a returning traveler or immigrant with cutaneous abnormalities must also consider the possibility of infection. Attention should be paid to the nature of the skin lesions, the presence or absence of systemic manifestations, and the details of the travel history, e.g., geographic sites visited, duration of travel, activities, and prophylactic medications. This article highlights the conditions most likely to be encountered among typical immunocompetent North American travelers.

Humans↗