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PubMed1999

Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease.

BACKGROUND: Interleukin-6 (IL-6) has multiple immunological effects on a wide variety of cells and tissues. The expression of IL-6 and IL-6 receptor (IL-6R) may be important to the pathogenesis of inflammatory bowel disease (IBD). METHODS: In the present study, we examined whether mucosal IL-6 and soluble IL-6R were associated with the pathophysiology of IBD using the colonic mucosal specimens obtained from patients with IBD. Enzyme-linked immunosorbent assay was used to measure the levels of IL-6 and sIL-6R in organ cultures of mucosal tissues and in cell cultures of fractionated mucosal cells as well as in the serum. Expression of IL-6 and IL-6R was analysed by reverse transcription-polymerase chain reaction analysis using freshly isolated lamina propria mononuclear cells (LPMC). RESULTS: The levels of IL-6 and sIL-6R in organ cultures were substantially elevated in patients with IBD, especially in those with histologically active inflammation. In contrast, considerably higher levels of sIL-6R were detected in patients with other types of colonic inflammation who were included as inflammatory controls, but elevation of IL-6 was less prominent in such patients. The positivity for expression of IL-6 and IL-6R mRNA in LPMC was in parallel with the results obtained in organ cultures. In cell cultures, mucosal macrophages were the main cell type producing both IL-6 and sIL-6R on a per cell basis and other cell fractions including colonic epithelial cells and lymphocytes produced substantially lower amounts of these molecules. The levels of IL-6 and sIL-6R in organ cultures, but not those in the serum, showed a significantly positive correlation with the degree of clinical disease activity in patients with IBD. CONCLUSIONS: Enhanced IL-6/sIL-6R-mediated immune and inflammatory responses may be implicated, at least partly, in the continuation of intestinal inflammation in patients with IBD.

Adolescent↗
PubMed2001

Immuno-bacterial homeostasis in the gut: new insights into an old enigma.

The intestinal mucosa is the interface between the immune system and the massive antigenic load represented by the commensal enteric bacteria. These commensal bacteria drive the development of the mucosal immune system, and in turn most of the lymphocytes in the intestinal mucosa appear to be specific for enteric bacteria antigens. Proper regulation of the responses of these anti-bacterial lymphocytes are extremely important because T cell effectors reactive to enteric bacterial antigens have been shown to cause chronic intestinal inflammation in an adoptive transfer system. The cells and molecules important in regulating mucosal immune response are now being identified. Insights into the mechanisms of mucosal regulation have come from a number of genetically manipulated mouse strains which develop inflammatory bowel disease in response to the enteric bacterial flora. CD4(+)T cells with regulatory function in the mucosa are being identified; other cell types such as CD8(+)T cells. NK cells, and B cells may also have a role in mucosal immune regulation. A model for T cell-immune homeostasis in the intestinal mucosa is presented.

Animals↗
PubMed1990

Relationship between intestinal permeability to [51Cr]EDTA and inflammatory activity in asymptomatic patients with Crohn's disease.

The relationship between intestinal permeability to an oral dose (100 mu Ci) of [51CR]EDTA and the inflammatory activity of Crohn's disease was studied in 63 adult patients (32 unresected and 31 resected) who underwent 162 evaluations. The results of the [51CR]EDTA test were compared with the serum levels of the acute-phase reactant proteins (APRP) and with the result of the [111In]leukocyte scanning, respectively, as an indirect and direct method to assess intestinal inflammation. In a group of healthy adult controls, the upper normal value for the 24-hr urinary [51CR]EDTA excretion was 3.61 (97.5% percentile) and the mean coefficient of variation was 21%. Sensitivity and specificity of the [51CR]EDTA test in identifying active inflammation expressed by increased serum levels of APRP were, respectively, 97% and 54% in the unresected group and 68% and 52% in the resected group of patients. The low specificity of the test was due to the presence of increased [51CR]EDTA urinary excretion in about half the cases with normal serum levels of APRP. The [111In]leukocyte scanning was performed in a subgroup of 11 patients (three unresected and eight resected) with normal serum levels of APRP, six with increased and five with normal [51CR]EDTA urinary excretion. All six patients with increased intestinal permeability had a positive 111In image of mild to moderate degree of activity. A positive 111In scan was present in two of the five patients with normal permeability; these were two resected patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed2007

Lamina propria and circulating interleukin-8 in newly and previously diagnosed pediatric inflammatory bowel disease patients.

Dysregulation of interleukin-8 (IL-8) production has been proposed to contribute to intestinal inflammation in inflammatory bowel disease (IBD) patients. Previous studies, which evaluate adult patients with long-standing or steroid-modulated disease, have reported conflicting results regarding the role of IL-8 in IBD pathogenesis. The present study evaluates IL-8 in colonic organ cultures and sera of newly and previously diagnosed pediatric IBD patients with various degrees of histopathologic activity. Colon and terminal ileum biopsies were obtained from 26 patients with Crohn's disease, 12 with ulcerative colitis, 4 with indeterminate colitis, and 12 age-matched normal controls. IBD patients were additionally characterized as newly or previously diagnosed. Supernatants from organ-cultured lamina propria biopsies and sera were evaluated by ELISA for IL-8 protein. IL-8 increased with degree of histologic inflammation regardless of diagnosis (no pathologic diagnosis, 62.6 ng/ml, interquartile range [IQR] 30.4-94.6 ng/ml; mild, 92.0 ng/ml, IQR 21.9-170.0 ng/ml; moderate, 676.2 ng/ml, IQR 46.4-2967.7 ng/ml; severe, 585.6 ng/ml, IQR 149.7-1602.2 ng/ml; P < 0.01). Lamina propria IL-8 was significantly elevated in moderately and severely inflamed tissue segments (603.26 ng/ml; IQR, 72.15-2240.4 ng/ml) compared to noninflamed and mildly inflamed segments (67.70 ng/ml; IQR, 30.38-124.1 ng/ml; P = 0.0009). There was no significant trend in IL-8 concentration when compared by clinical diagnosis. No significant difference was found in IL-8 concentrations in organ cultures from newly diagnosed patients versus those from previously diagnosed patients. There was no significant correlation between serum IL-8 concentration and organ culture IL-8 concentration. We conclude that higher concentrations of IL-8 are found in more histologically inflamed tissue segments from pediatric IBD patients. IL-8 does not appear to be associated with clinical IBD subtype. IL-8 appears to be an integral part of both early and established mucosal inflammation in pediatric IBD patients. These findings suggest that IL-8-specific therapies may universally modify inflammatory activity in IBD patients.

Adolescent↗
PubMed1996

Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12.

There is now increasing evidence that hyperresponsiveness towards intestinal flora is a crucial event in the pathogenesis of inflammatory bowel disease (IBD). In support of this hypothesis, we recently described in humans that tolerance exists towards indigenous intestinal flora but is broken in active IBD lesions. In the present study, we have attempted to transfer this model into mice from different genetic backgrounds (BALB/c, SJL/J, C3H/HeJ). We found that mononuclear cells from spleen, small bowel and large bowel of mice do not proliferate, i.e. are tolerant when exposed to bacterial sonicates derived from autologous intestine (BsA) but do proliferate, i.e. are immune when exposed to bacterial sonicates derived from the heterologous intestine of syngenic littermates (BsH). Furthermore, we demonstrate that both local and systemic tolerance to BsA is broken in a murine model of chronic intestinal inflammation induced by the hapten reagent 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics several important characteristics of Crohn's disease. Tolerance to BsA was restored and TNBS-induced colitis was abrogated in mice systemically treated with interleukin (IL)-10 or antibodies to IL-12. Treatment specifically restored tolerance to BsA, but did not suppress proliferation to BsH. In summary, we here report a new model for the study of immunity and tolerance towards bacterial products. Our data suggest that tolerance to BsA is an important protective mechanism and that restoration of tolerance intestinal flora by IL-10 and antibodies to IL-12 may be of potential therapeutic utility in patients with inflammatory bowel disease.

Animals↗
PubMed1984

Intestinal permeability and inflammation in rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs.

The suggestion that the intestinal mucosa may be abnormally permeable and a site of absorption of antigens in rheumatoid arthritis was tested by the use of a 51Cr-EDTA (edetic acid) absorption test. 24 patients with rheumatoid arthritis excreted significantly more 51Cr-EDTA than did 34 controls. Intestinal permeability was normal in untreated patients but almost invariably abnormal in patients treated with non-steroidal anti-inflammatory drugs. Studies in patients with osteoarthritis showed that the permeability abnormalities were due to an effect of NSAIDs on both the proximal and the distal intestine and that the effect was systemically mediated. Indium-111-labelled leucocyte scans showed ileocaecal inflammation in 6 of 9 patients on or recently on NSAIDs. Although increased intestinal permeability does not seem to be important in the pathogenesis of rheumatoid arthritis, the administration of NSAIDs may lead to loss of intestinal integrity, thus facilitating antigenic absorption and perhaps contributing to persistence of the disease.

Anti-Inflammatory Agents↗
PubMed2000

Interleukin 16 is up-regulated in Crohn's disease and participates in TNBS colitis in mice.

BACKGROUND & AIMS: Interleukin (IL)-16 is a T lymphocyte- derived cytokine that uses CD4 as its receptor and hence selectively recruits CD4-bearing cells. Infiltrating CD4(+) T cells are a feature of Crohn's disease; however, the role of IL-16 in intestinal inflammation is unknown. The aim of this study was to determine whether IL-16 production is increased in inflammatory bowel disease and whether IL-16 participates in trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. METHODS: IL-16 messenger RNA and protein levels in inflammatory bowel disease tissues were determined by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. C57BL/6 or BALB/c mice were treated with vehicle, TNBS alone, TNBS + anti-IL-16 monoclonal antibody (mAb), TNBS + control mAb, or were untreated. Colonic injury and inflammation were evaluated after 3 or 10 days. RESULTS: Colonic IL-16 protein levels were increased in patients with Crohn's disease (P<0.05) but not ulcerative colitis. Anti-IL-16 mAb treatment significantly reduced TNBS-induced weight loss (P< 0.001), mucosal ulceration (P<0.05), myeloperoxidase activity (P< 0.001), and TNBS-mediated increases in mucosal levels of IL-1beta (P<0.05) and tumor necrosis factor alpha (P<0.01). CONCLUSIONS: Anti-IL-16 mAb reduced colonic injury and inflammation induced by TNBS in mice. Colonic mucosal IL-16 levels were elevated in Crohn's disease, suggesting a role for IL-16 in the pathophysiology of inflammatory bowel disease.

Animals↗
PubMed1999

Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats.

Reactive oxygen metabolites (ROMs) contribute to the pathophysiology of intestinal inflammation. Our aim was to ascertain the involvement of ROMs in experimental ileitis in rats produced by toxin A of Clostridium difficile. Intraluminal toxin A caused a significant increase in hydroxyl radical and hydrogen peroxide production by ileal microsomes starting 1 h following toxin exposure and peaking at 2-3 h, and this was inhibited by pretreatment with DMSO, a ROM scavenger, or superoxide dismutase (SOD), which inactivates ROMs. In contrast, mucosal xanthine oxidase increased only slightly after toxin A exposure, and allopurinol, an inhibitor of xanthine oxidase, had no effect on toxin A-associated intestinal responses. Induction of neutropenia resulted in reduction of toxin-mediated free radical formation, fluid secretion, and permeability. The enterotoxic effects of C. difficile toxin A were associated with increased ROM release in ileal tissues, and the ROM inhibitors DMSO and SOD inhibited these effects. This suggests that ROMs released during toxin A enteritis are released primarily from neutrophils invading the inflamed bowel segment.

Animals↗
PubMed1997

A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease.

Recent clinical studies of Crohn's disease patients demonstrated dramatic clinical responses following one i.v. infusion of a chimeric mAb to TNF-alpha (cA2). To assess the role of TNF-alpha in mucosal cytokine regulation, the effects of TNF-alpha on lamina propria mononuclear cell (LPMC) Th1 production were determined. Increased IFN-gamma production was demonstrated in anti-CD2-stimulated LPMC cultured in TNF-alpha. To determine the effects of cA2 on cytokine production, TNF-alpha- and IFN-gamma-producing cells were quantitated in LPMC from five Crohn's disease patients treated with cA2. In all four patients who demonstrated clinical and endoscopic improvement, decreased numbers of LPMC producing IFN-gamma and TNF-alpha following CD2/CD28 activation paralleled improvement in disease activity over 8 wk. In one patient who did not improve, increased numbers of TNF-alpha- and IFN-gamma-secreting LPMC were observed. In three of four responding patients, CD2/CD28-activated PBMC demonstrated increased IFN-gamma production over 8 wk. These observations suggest that TNF-alpha may be a cofactor for mucosal Th1 responses, and improvement in clinical parameters and intestinal inflammation induced by cA2 in Crohn's disease may be mediated by down-regulation of mucosal Th1 cytokines.

Adjuvants, Immunologic↗
PubMedDate not supplied

Gut mucosal mast cells and goblet cells during acute graft-versus-host disease in rats.

Intestinal inflammation occurs in both nematode infections and graft-versus-host disease (GVHD). In nematode infections, this involves the proliferation of mucosal mast cells (MMC) and goblet cells (GC). To examine MMC and GC responses in GVHD, female Lewis rats were given allogeneic bone marrow (BM). Each animal received 1,020 rads and, one day later, 6 X 10(7) ACI BM cells plus 2 X 10(7) ACI spleen cells i.v. Control rats received 6 X 10(7) BM cells. On days 4, 8, 12, 16 and 20 post-transplant, rats were sacrificed and their intestines removed and prepared for histological examination of MMC and GC. Cells in 10 villus-crypt units (VCU) of the gut were counted for each animal. Skin and tongue were also removed and examined to determine the degree of GVHD. GVHD was first evident on day 8 in allogeneic BM recipients and progressed thereafter. No evidence of GVHD was seen in syngeneic BM recipients. Rats receiving allogeneic BM showed a 10-fold increase from day 12 to day 20 (p less than 0.01). Rats receiving syngeneic BM showed no significant change in MMC through the 20th day. In animals with GVHD, GC decreased by day 12 and remained lower than control animals during the subsequent 8 days. It was concluded that, similar to nematode infection, MMC proliferation is a feature of GVHD. In contrast, GC do not appear to proliferate in an acute GVHD.

Animals↗
PubMed2003

Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis.

The IL-7/IL-7R-dependent signaling pathway plays a crucial role in regulating the immune response in intestinal mucosa. Here we demonstrate the pivotal role of this pathway in the development and treatment of chronic colitis. T cells expressing high levels of IL-7R were substantially infiltrated in the chronic inflamed mucosa of TCR alpha-chain knockout mice and IL-7 transgenic mice. Transfer of mucosal T cells expressing high levels of IL-7R, but not T cells expressing low levels of IL-7R, from these mice into recombinase-activating gene-2(-/-) mice induced chronic colitis. Selective elimination of T cells expressing high levels of IL-7R by administrating small amounts of toxin-conjugated anti-IL-7R Ab completely ameliorated established, ongoing colitis. These findings provide evidence that therapeutic approaches targeting mucosal T cells expressing high levels of IL-7R are effective in the treatment of chronic intestinal inflammation and may be feasible for use in the therapy of human inflammatory bowel disease.

Adoptive Transfer↗
PubMed1991

Gamma delta T cell receptor-positive cells of the human gastrointestinal mucosa: occurrence and V region gene expression in Heliobacter pylori-associated gastritis, coeliac disease and inflammatory bowel disease.

T cells expressing the gamma delta heterodimer of the T cell receptor (TCR) were studied with respect to their occurrence and expression of gamma delta TCR variable region (V) genes in the normal gastrointestinal mucosa and in a variety of inflammatory conditions. In controls, gamma delta TCR+ cells were a minority population confined to the epithelial compartment of stomach, small bowel and colonic mucosae. Unlike in the periphery, gastro-intestinal gamma delta TCR+ intraepithelial lymphocytes (IEL) were mainly V delta 1+ (89.98 +/- 17.70%); few were V delta 2+ (6.04 +/- 13.8%) or V gamma 9+ (11.38 +/- 10.73%). All gamma delta TCR+ IEL were CD5low; nearly half were CD8+ and the remainder were CD4-CD8- 'double negatives'. There was no significant change from normal in percentages of gamma delta TCR+ IEL in H. pylori-associated gastritis, Crohn's disease and ulcerative colitis. However, in coeliac disease, gamma delta TCR+ IEL were elevated from 2.54% (+/- 1.71) in controls to 29.6% (+/- 16.1) in untreated patients (P less than 0.001) and 18.5% (+/- 7.2) in treated patients (P less than 0.001) and more were CD4-CD8-. Otherwise, gamma delta TCR+ IEL phenotypes were little changed: the majority remained V delta 1+V delta 2-V gamma 9- and all were CD5low. These data suggest that increased gamma delta TCR+ IEL are not a generalized response to intestinal inflammation or to stress proteins, although the typical V delta 1+V delta 2-V gamma 9- CD5low phenotype is retained.

Adult↗
PubMed2003

Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease.

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.

Adult↗
PubMed1999

Lessons for human inflammatory bowel disease from experimental models.

Experiments carried out in new rodent models of chronic intestinal inflammation provide important clues about the pathogenesis of human inflammatory bowel disease (IBD). Genetic factors and enteric microflora are driving forces regulating mucosal immune responses, some of which are pathogenic and lead to colitis. CD4(+) T cells are the major pathogenic cells in colitis, and the type of injury depends on the nature of the cytokine imbalance. The cytokine network controlled by CD4(+) T cells dictates the outcome of the mucosal immune responses. Certain cytokines, such as transforming growth factor-beta and interleukin-10, have a suppressive role, and immunoregulatory T cells capable of secreting these cytokines may be induced at intestinal mucosal sites. Lessons learned from these experimental models are leading to new strategies for the treatment of IBD.

Journal Article↗
PubMed2003

IL-6 and Crohn's disease.

Interleukin-6 (IL-6) is a pleiotropic cytokine with central roles in immune regulation, inflammation, hematopoiesis, and oncogenesis. Its biological activities are shared by IL-6-family of cytokines such as leukemia inhibitory factor and oncostatin M. When IL-6 binds to IL-6R, the IL-6/IL-6R complex then associates with gp130, the common signal transducer of cytokines related to IL-6. IL-6R does not have to be expressed on the cell surface for IL-6 signaling because soluble form of IL-6R (sIL-6R) can bind to IL-6 and function through gp130. Increased levels of IL-6 and sIL-6R have been demonstrated in both serum and intestinal tissues of the patients with active Crohn's disease. In animal model studies, anti-IL-6R monoclonal antibody (mAb) successfully prevented intestinal inflammation and systemic wasting disease by suppressing adhesion molecule expression by vascular endothelium. It also reduced colonic expression of tumor necrosis factor alpha, IL-1beta, and interferon gamma mRNA without affecting the production of transforming growth factor beta, IL-10, and IL-4. Moreover, the treatment displayed therapeutic efficacy against established colitis through the induction of lamina propria T-cell apoptosis. These results strongly suggest that specific targeting of IL-6/sIL-6R pathway will be a promising new approach for the treatment of Crohn's disease, and the clinical trial of humanized anti-IL-6R mAb has been carried out.

Animals↗
PubMed1999

Health effects among workers in sewage treatment plants.

OBJECTIVES: To further assess the presence of fatigue, symptoms of diarrhoea, and inflammation of airways among people working in sewage plants and the relation to airborne bacterial endotoxin at the workplace. METHODS: 34 Employees in sewage treatment plants and 35 controls were selected. They underwent a questionnaire investigation, and spirometry and airway responsiveness were measured. Measurements were made of airborne endotoxin at different workplaces. RESULTS: The amount of airborne endotoxin varied between 3.8 and 32,170 ng/m3. Workers reported significantly higher nose irritation, tiredness, and diarrhoea. Airway responsiveness was increased among sewage workers, but no differences between the groups were found for spirometry. CONCLUSIONS: The results confirm previous studies on the presence of airways and intestinal inflammation among workers in sewage treatment plants. The most likely causative agent is endotoxin, and at 14 of 23 workplaces, concentrations exceeded recommended guidelines.

Bronchial Hyperreactivity↗
PubMed2006

[The intestinal flora: the scales without the sword].

The intestine is colonised by a vast population of resident bacteria which have established mutualistic relationships with their host throughout evolution, progressing from commensalism to symbiotic interactions. Intestinal bacteria benefit from resources available in their host, but reciprocally provide advantages to their host, by supplying enzymatic activities not encoded in the host genome, by promoting maturation of the intestine and of the gut associated immune system as well as by modifying the host metabolism. The commensal bacteria, although deprived of pathogenic attributes, might however become a danger for the host in case of translocation, acquisition of pathogenic features or via the inappropriate activation of intestinal inflammation. Remarkably, the commensal flora promotes the onset of innate and adaptive immune defences which, in turn, allow to set up a subtle balance between the host and the flora that promotes the symbiosis.

Adult↗
PubMed2004

CD4+ T cells mediate murine syngeneic graft-versus-host disease-associated colitis.

Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA). Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver. Although nonspecific effector cells and Th1 cytokines have been shown to participate in disease induction, the role of T cells has not been fully elucidated. Initial studies demonstrated significant increases in CD4+ T cells, but not other T cell populations in the colons of diseased animals relative to transplant control animals. To demonstrate a functional linkage between increases in colonic CD4+ T cells and disease induction, in vivo T cell depletion studies were performed. Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days. Treatment with anti-CD4, but not anti-CD8, eliminated clinical symptoms and colon pathology. Interestingly, neither anti-CD4 nor anti-CD8 therapy affected the development of liver pathology associated with SGVHD. These findings demonstrated that CD4+ T cells initiate development of the intestinal inflammation associated with murine SGVHD.

Animals↗