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PubMed1992

Chronic intestinal lymphocytic microphlebitis.

The authors report two cases of a peculiar microphlebitis of the intestines, similar to that described by Saraga and Costa quite recently [5]. The patients had undergone hemicolectomy because of evolving ileus caused by cecal polyps or lipohyperplasia, respectively. Pseudomembranous-ulcerative inflammation of the cecum and variously intense lymphocytic infiltrates of numerous small submucosal veins and venules of the intestines were found in both cases. Thrombosis occurred very rarely in the affected vessels, although sometimes it was found in deeper and larger veins. Arteries, lymphatics, mesenterial veins and lymph nodes were normal. Parts of the distal ileum and ascending colon displayed the phlebitic changes without mucosal alterations. The authors hypothesize that it was not the abnormal local circulation, but some hitherto not fully clarified immunological disorder that resulted in the disease. In contrast to the claim of Saraga and Costa [5], it is suggested that thrombosis of the small veins does not have a significant role in the development of the lesions, but a complex process that includes the entry of antigens via the altered mucosa followed by an immunogenic inflammatory response of the small veins is responsible for the pathogenesis.

Adult↗
PubMed1984

Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat.

Experiments were performed to investigate the immunological consequences associated with the persorption of poorly degradable carregeenans from the diet. Using an inbred strain of rat it was demonstrated histochemically, by the carrageenan-specific Alcian blue staining technique, that small quantities of food-grade carrageenans given at 0.5% in drinking-water for 90 days could penetrate the intestinal barrier of adult animals. This apparently occurred via an intact mucosa in the absence of inflammatory or pathological lesions. The carrageenan was demonstrated in macrophage-like cells present within the villi and lamina propria of the small intestine. The oral administration of kappa, lambda or iota food-grade carrageenans did not affect local (biliary) or systemic antibody responses to gut commensal microorganisms, or to orally-administered sheep erythrocytes. However, when sheep red blood cells were administered parenterally the ensuing anti-sheep red blood cell haemagglutinating antibody response was temporarily suppressed in carrageenan-fed rats. lambda-Carrageenan and iota-carrageenan both significantly (P less than or equal to 0.01 and P less than or equal to 0.05, respectively) reduced the mid-phase (14-28 days) haemagglutinin response; kappa-carrageenan (L100) was less effective but caused significant depression at day 21 (P less than or equal to 0.01). Individual responses were, however, within the control range 35 days after sheep erythrocyte administration, thus indicating the temporary nature of this effect. Although carrageenan administration depressed the anti-sheep erythrocyte antibody response, it did not affect T-cell immune competence as measured by the popliteal lymph node assay for graft-versus-host reactivity.

Administration, Oral↗
PubMed2003

Expression of ets-related transcriptional factor E1AF is associated with tumor progression and over-expression of matrilysin in human gastric cancer.

Expression of E1AF/PEA3 (ETV4), an ets family transcriptional factor, has been implicated in tumor progression through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human gastric cancer. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we analyzed 100 gastric cancer tissues for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets-1 and Ets-2 was also analyzed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 64% of the 100 gastric cancer tissues, but was undetectable or only faintly detected in adjacent non-tumor tissues. E1AF expression was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumor-node-metastasis stage and recurrence. Patients with E1AF-positive tumors had significantly shorter overall and disease-free survival periods than did those with E1AF-negative tumors (P < 0.0001 and P < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (P = 0.0082 and P = 0.0096, respectively). Among the MMPs analyzed, expression of matrilysin (MMP-7) was significantly correlated with E1AF expression. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of matrilysin was often co-localized. Antisense E1AF-transfected MKN45 gastric cancer cells expressed reduced levels of matrilysin and were less invasive in vitro than mock-transfected MKN45 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of matrilysin, plays a key role in the progression of gastric cancer.

Adenovirus E1A Proteins↗
PubMed1999

Changes in gut mucosal nitric oxide synthase (NOS) activity after thermal injury and its relation with barrier failure.

This study was designed to investigate changes in mucosal NOS activity after burns and its relation to barrier failure. In Experiment 1, female specific pathogen free (SPF) Sprague-Dawley rats underwent 35% total body surface area (TBSA) burn. One to six days after burn, intestinal permeability was determined from the plasma leakage of fluorescein isothiocyanate (FITC)-dextran 4400, intestinal mucosal cNOS and iNOS activity were assayed using Griess' reagent, and the cellular localization of iNOS was examined using immunostaining. In Experiment 2, S-methylisothiourea (SMT) was given (5 mg/kg, i.p. every 12 h) for 2 days to suppress inducible NOS (iNOS) activity after thermal injury. On postburn Day 2, the effect of SMT on gut mucosal NOS activity, intestinal permeability, and barrier function were evaluated. The activity of iNOS increased 24 h after the injury and up to a maximum of twofold on postburn Day 2, and decreased thereafter. The increase in iNOS activity in gut mucosa correlated well with the increase in intestinal permeability, an index for barrier failure (r = .776, p = .0002). Results from iNOS immunostaining showed that changes in mucosal iNOS activity after the burn occurred mainly in the enterocytes rather than in the macrophages. Administration of SMT decreased mucosal iNOS activity, intestinal permeability, and bacterial translocation incidence to mesenteric lymph node concurrently. In conclusion, thermal injury induces intestinal mucosal iNOS, which is principally in the enterocytes. The increased intestinal iNOS activity was closely related to barrier failure. SMT inhibited intestinal mucosal iNOS activity and prevented barrier failure as demonstrated by a decrease in BT occurrence and intestinal permeability.

Animals↗
PubMed2003

Platelet-derived endothelial cell growth factor predicts of progression and recurrence in primary epithelial ovarian cancer.

We investigated the clinical significance of platelet-derived endothelial cell growth factor (PD-ECGF) as measured by enzyme-linked immunosorbent assay in primary epithelial ovarian cancers (EOC), finding amounts to be significantly greater in cancers than in normal ovarian tissue (p<0.01). PD-ECGF was significantly more abundant in stages III and IV than in lower stages (p<0.05), and also was high in tumors with macroscopically evident metastases in the peritoneal cavity (p<0.05), or pelvic (p<0.01) or paraaortic (p<0.01) lymph node metastases. Further, PD-ECGF was significantly lower in mucinous than in serous adenocarcinomas (p<0.05). No significant correlation was seen between PD-ECGF and histologic grade, maximum intraperitoneal metastatic tumor diameter (<2 vs.>2 cm), or presence of demonstrable malignant cells in peritoneal fluid. In stage III disease, PD-ECGF exhibited significant correlation with recurrence (p<0.05). Our data suggested that results of PD-ECGF assays in primary tumors can predict progression and recurrence of EOC.

Adult↗
PubMed1994

Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in nude mice.

Matrix metalloproteinases have been implicated in the growth and spread of metastatic tumors. This role was investigated in an orthotopic transplant model of human colon cancer in nude mice using the matrix metalloproteinase inhibitor BB-94 (batimastat). Fragments of human colon carcinoma (1-1.5 mm) were surgically implanted orthotopically on the colon in 40 athymic nu/nu mice. Administration of BB-94 or vehicle (phosphate buffered saline, pH 7.4, containing 0.01% Tween 80) commenced 7 days after tumor implantation (20 animals/group). Animals received 30 mg/kg BB-94 i.p. once daily for the first 60 days and then 3 times weekly. Treatment with BB-94 caused a reduction in the median weight of the primary tumor from 293 mg in the control group to 144 mg in the BB-94 treated group (P < 0.001). BB-94 treatment also reduced the incidence of local and regional invasion, from 12 of 18 mice in the control group (67%) to 7 of 20 mice in the treated group (35%). Six mice in the control group were also found to have metastases in the liver, lung, peritoneum, abdominal wall, or local lymph nodes. Only two mice in the BB-94 group had evidence of metastatic disease, in both cases confined to the abdominal wall. The reduction in tumor progression observed in the BB-94-treated group translated into an improvement in the survival of this group, from a median survival time of 110 days in the control group to a median survival time of 140 days in the treated group (P < 0.01). Treatment with BB-94 was not associated with any obvious toxic effect, and these results suggest that such agents may be effective as adjunctive cancer therapies.

Adenocarcinoma, Mucinous↗
PubMed1995

Specific tumor memory induced by polyethylene-glycol-modified interleukin-2 requires both helper and cytotoxic T cells.

Local polyethylene-glycol (PEG)-modified interleukin-2 (IL-2) immunotherapy of the guinea pig Line 10 (L10) tumor was previously demonstrated to evoke long-lasting systemic immunity after cure of the tumor and metastases. T cells, most likely the helper T cell subpopulation, were demonstrated to be crucial to the antitumor effects. Here we show that systemic immunity is induced within 7 days after the start of PEG-IL-2 therapy, indicating a rapid systemic priming of L10-specific T cells. No in vitro cytotoxic activity was detected in cell suspensions obtained from the primary tumor site, the regional lymph node or the spleen when isolated during (days 21 and 28) intratumoral treatment with 200,000 IU PEG-IL-2. These data confirm our earlier results obtained with 60,000 IU PEG-IL-2. Moreover, no cytolytic activity was observed in the chromium-release assay after in vitro restimulation with irradiated tumor cells. Specific L10 immunity can be transferred using spleen cell suspensions. Depletion of such a suspension of helper T cells resulted in rejection of the primary tumor in two out of four animals, but all the guinea pigs developed lymph node metastases. Removal of the cytotoxic/suppressor phenotype caused rejection of the dermal tumor in four of eight guinea pigs, but the capacity to prevent lymph node metastases was retained in all animals. Thus, depletion of either subtype reduces, but does not abrogate, the capacity to transfer L10 immunity with spleen cells. In conclusion, our data suggest that tumor cell killing through direct T cell cytotoxicity is not the main mode of action in PEG-IL-2-induced L10 tumor regression. PEG-IL-2 therapy induces early systemic immunity, resulting in rejection of a distant tumor, and the transfer of this immunity depends mainly on the presence of helper T cells, although cytotoxic T cells may also play a role.

Animals↗
PubMed1980

Abrogation of T cell homing by alloantibody.

Utilizing a dual isotope assay, the effect of passively transferred enhancing alloantibody on the specific accumulation of cytotoxic T cells in murine skin allografts were examined. (C57BL/6 x A/J)F1 (B6AF1) mice hyperimmunized with weekly injections of B10.D2 and B10.BR lymphoid cells served as a source of anti-B10.D2 and anti-B10.BR alloantibody. Intraperitoneal injections of alloantibody in B6AF1 hosts on days 0,2, and 4 significantly prolonged skin allograft survival. Dually skin allografted B6AF1 mice with or without the administration of enhancing alloantibody received differentially labeled (3H/14C) cytotoxic T cells on day 5. On day 7, a "homing index" derived from the comparison of 3H to 14C ratios was calculated for the skin allografts and draining axillary lymph nodes of each mouse. In unenhanced, normal mice significant preferential homing of cytotoxic T cells to skin allografts was demonstrated. However, enhanced mice receiving cytotoxic T cells had significantly dimished homing to skin allografts. Preferential localization of effector cells to the draining axillary lymph nodes was not present in either unenhanced or enhanced mice. These data demonstrate that enhancing alloantibody interferes with the specific accumulation of cytotoxic T cells in skin allografts and may be an important previously undescribed mechanism of immunological enhancement.

Animals↗
PubMed1997

Inhibition of head and neck squamous cell carcinoma growth and invasion by the calcium influx inhibitor carboxyamido-triazole.

Local invasion and lymph node metastasis are correlated with a decreased overall survival in head and neck cancer patients and warrant new strategies to intervene in the metastatic cascade. One approach is to focus on the intracellular signaling pathways underlying the metastatic process. A common regulatory point in several signal transduction pathways is intracellular calcium homeostasis. We assessed the effect of a novel calcium influx inhibitor, carboxyamido-triazole (CAI), on the growth and invasive phenotype of cell lines derived from head and neck squamous cell carcinoma (HNSCC). CAI inhibited the growth of FaDu and EVSCC17M cells in a dose-dependent (IC50, 13-15 microM) and reversible manner. CAI also caused a generalized attenuation of receptor-mediated calcium elevation to several calcium mobilization agonists, including epidermal growth factor and bradykinin. The effects of CAI on the invasive phenotype of HNSCC cell lines were assessed by a chemo-invasion assay. HNSCC cell lines exhibited a range of invasive potential as measured by the capacity of tumor cells to penetrate a reconstituted basement membrane of Matrigel. HNSCCs were classified as highly invasive (EVSCC14M and EVSCC17M) or weakly invasive (EVSCC18, EVSCC19M, UMSCC10A, and FaDu). Treatment of HNSCC cell lines with 10 microM CAI for 24 h reduced invasion 2-14-fold in a dose-dependent manner. HNSCCs also exhibited different motilities as measured by a chemotaxis assay. EVSCC14M and EVSCC17M were highly motile, whereas EVSCC18, EVSCC19M, UMSCC10A, and FaDu were less motile. CAI reduced the migration of all cell lines. Conditioned medium from HNSCC cell lines was analyzed by zymography for production of Mr 72,000 type IV collagenase [matrix metalloproteinase (MMP)-2)] and Mr 92,000 type IV collagenase (MMP-9). All HNSCC cell lines secreted MMP-2 and/or MMP-9 into conditioned medium. Treatment of cells with 10 microM CAI for 24 h resulted in a reduction of both MMP-2 and MMP-9 production. The results demonstrate that CAI blocks cellular proliferation, migration, chemoinvasion, and MMP production by HNSCC in vitro and identify calcium-dependent signaling as a new target for inhibition of the malignant phenotype of HNSCC.

Antineoplastic Agents↗
PubMed2002

Antibody responses in sheep vaccinated against Staphylococcus aureus mastitis: a comparison of two experimental vaccines containing different adjuvants.

A double-blind, placebo-controlled study was conducted to compare two vaccines using different adjuvants with regard to their ability to stimulate antibody production against the alpha- and beta-toxins and the exopolysaccharide of Staphylococcus aureus. The vaccines contained identical antigens, consisting of inactivated whole bacteria of two strains of S. aureus in addition to alpha- and beta-toxoid. One vaccine contained mineral oil, while the other used a water-soluble acrylic acid polymer resin (Carbopol) as adjuvant. Saline served as the placebo. One hundred and forty ewes were vaccinated twice before lambing, by subcutaneous injection with vaccine or placebo in the region of the supramammary lymph node, and were observed and sampled over a period of 6 months. The vaccine containing mineral oil as adjuvant induced significantly greater immune responses to the alpha- and beta-toxins than did the vaccine containing Carbopol. The latter vaccine induced higher levels of antibodies to exopolysaccharide. The degree of local adverse reactions did not differ between the two groups. The results indicate differences between the oil-adjuvanted and Carbopol-adjuvanted vaccines with regard to their ability to stimulate antibody production against S. aureus protein antigens in sheep.

Acrylic Resins↗
PubMed1994

Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids.

CD22 beta is a B cell-restricted phosphoprotein expressed on the surface of mature resting B cells. It mediates interactions with other cells partly or exclusively via recognition of alpha 2-6-linked sialic acids on glycoconjugates. The sialylated N-linked oligosaccharides recognized best by CD22 beta are common to many glycoproteins, suggesting that additional regulatory mechanisms may exist. Since the exocyclic side chain of sialic acid is required for recognition, we explored the effects of a naturally occurring modification of the side chain, 9-O-acetylation. Semisynthetic N-linked oligosaccharides terminating with 9-O-acetylated, alpha 2-6-linked sialic acids showed markedly reduced binding to CD22 beta relative to their non-O-acetylated counterparts. Murine lymphoid cells were probed for natural CD22 beta ligands that might be O-acetylated using recombinant soluble forms of CD22 beta (CD22 beta Rg) and influenza C esterase (CHE-Fc, which specifically removes 9-O-acetyl esters from sialic acids). By flow cytometry analysis, CD22 beta Rg binding to splenic B cells and a subset of T cells was increased by pretreatment with CHE-Fc, indicating that some potential CD22 beta ligands are naturally "masked" by 9-O-acetylation. Unmasking of these CD22 beta ligands by removal of 9-O-acetyl esters from intact splenocytes substantially increases their CD22 beta-dependent adhesion in an in vitro adhesion assay. Probing of murine lymphoid tissue sections by CD22 beta Rg and CHE-Fc treatment demonstrates regionally restricted and differentially expressed patterns of distribution between masked and unmasked ligands. For example, lymph node-associated follicular B cells express high levels of CD22 beta ligands, none of which are masked by 9-O-acetylation. In contrast, the ligands on lymph node-associated dendritic cells are almost completely masked by 9-O-acetylation, suggesting that masking may regulate interactions between CD22 beta-positive B cells and dendritic cells. In the thymus, only medullary cells express CD22 beta ligands, and a significant portion of these are masked by 9-O-acetylation, particularly at the cortical-medullary junction. Thus, 9-O-acetylation of sialic acids on immune cells is in a position to negatively regulate CD22 beta adhesion events in a manner depending on both cell type and tissue localization.

Acetylation↗
PubMed2004

Unique characteristics of the intestinal immune system as an inductive site after antigen reencounter.

BACKGROUND: Immunization prepares the body for a reencounter with the microbe. Information on the targeting of immune effector cells during secondary immune response--that is, lymphocyte homing--is scarce. In the present study, the homing potentials of lymphocytes are examined after antigen reencounter at mucosal versus nonmucosal sites. METHODS: Orally or parenterally immunized volunteers were reimmunized orally or parenterally with Salmonella typhi Ty21a, and the expression of the gut homing receptor (HR), alpha(4)beta(7), and of the peripheral lymph node HR, L-selectin, was investigated in circulating antigen-specific antibody-secreting cells (ASCs). Lymphocytes were sorted by HR expression and examined for antibody production, by use of an enzyme-linked immunospot assay. RESULTS: After oral reimmunization, 90% of ASCs were alpha(4)beta(7) positive and 88% were L-selectin positive, an expression profile that differed significantly from that found after oral primary immunization. After parenteral reimmunization, 45% of ASCs were alpha(4)beta(7) positive and 79% were L-selectin positive, similar to the results after parenteral primary immunization. The route of priming had no effect on HR patterns in either case. CONCLUSIONS: Homing potentials of lymphocytes depend on the site of antigen reencounter. Whereas the HR profile after parenteral reimmunization resembles that after primary immunization, the profile after oral reimmunization is uniquely characterized by high expression of both HRs, suggesting gut-localized memory and effective homing ability to both the mucosal and systemic immune system. These data may prove valuable in the search for the most effective immunization route in humans.

Administration, Oral↗
PubMed2003

Preoperative plasma soluble E-cadherin predicts metastases to lymph nodes and prognosis in patients undergoing radical cystectomy.

PURPOSE: We have previously reported that high urinary levels of soluble E-cadherin (sE-cadherin) are associated with an increased risk of bladder cancer. We determined whether plasma levels of sE-cadherin are associated with bladder cancer stage and prognosis. MATERIALS AND METHODS: The study group consisted of 50 patients who underwent radical cystectomy for muscle invasive cancer or intravesical therapy refractory Tis, Ta, or T1 bladder cancer; and 40 men without cancer. Preoperative plasma levels of sE-cadherin were measured using a commercially available enzyme-linked immunosorbent assay kit. RESULTS: Plasma sE-cadherin was higher in patients with bladder cancer than in healthy subjects (p <0.0001) and it was elevated in patients with metastases to regional and distant lymph nodes (p = 0.019 and 0.024, respectively). When adjusted for the effects of clinical stage and grade, preoperative sE-cadherin was independently associated with metastases to regional lymph nodes (p = 0.028) and disease progression (p = 0.006) but not with bladder cancer mortality. In postoperative models preoperative sE-cadherin and lymph node metastases were associated with disease progression (p = 0.017 and 0.042, respectively) after adjusting for the effects of pathological stage, grade and lymphovascular invasion but only lymph node metastases were associated with cancer specific mortality (p = 0.007). CONCLUSIONS: Higher plasma sE-cadherin is associated with bladder cancer. Higher preoperative plasma sE-cadherin has the potential to identify patients with metastases to regional and distant lymph nodes who are at increased risk for failure of local therapy with curative intent. These patients may benefit from more extensive lymph node dissection and/or combined modality treatment regimens.

Adult↗
PubMed2004

Inhibitory p41 isoform of invariant chain and its potential target enzymes cathepsins L and H in distinct populations of macrophages in human lymph nodes.

Activation of the CD4(+) T-cell mediated immune response relies on the proteolytic capacity of enzymes involved in modulating major histocompatibility complex (MHC) II-associated antigen presentation in antigen-presenting cells (APC). The MHC II-associated chaperone molecule p41 isoform of invariant chain (inhibitory p41 Ii) has been suggested to regulate stability and activity of cathepsin L in these APC. In the present study the human lymph node distribution of non-inhibitory p31 Ii and inhibitory p41 Ii have been compared by differential labelling, using two specific monoclonal antibodies. The distribution of p41 Ii, but not p31 Ii, matched the distribution of cathepsins L and H in subcapsular and cortical sinuses and germinal centres. Co-localization of p41 Ii with cathepsin H was confirmed in strongly CD68(+) sinus-lining macrophages, acting as APC. Furthermore, p41 Ii was determined together with cathepsins L and H in tingible body macrophages, highly phagocytic, but not antigen-presenting cells inside germinal centres. With respect to the physiological function that these two populations of macrophages have in human lymph nodes, our results support a regulatory function of p41 Ii towards cathepsins L and H in human macrophages, associated with the processes of phagocytosis rather than antigen presentation.

Animals↗
PubMed1993

Production of a monoclonal antibody against canine GMP-140 (P-selectin) and studies of its vascular distribution in canine tissues.

Rapid upregulation of the adhesion molecule GMP-140 (P-selectin) on endothelial cells is believed to play an important role in the initial binding of leukocytes to endothelium, a very early step in the inflammatory response. Activated platelets that are involved in the coagulation system and in inflammatory processes also express GMP-140 on their surfaces. The objectives of the present study were to develop a monoclonal antibody against this adhesion molecule in the dog and to use this antibody to study platelet-neutrophil interactions in whole blood and to characterize the in vivo localization of GMP-140 in canine tissues. Five Balb/c mice were immunized with thrombin-stimulated dog platelets, and clones were screened using an enzyme-linked immunosorbent assay. The clone MD3 (IgG1) showed preferential binding to activated as compared with resting platelets. Flow cytometric analysis using MD3 revealed that 27% of circulating neutrophils in unstimulated blood had platelets bound to their surfaces; stimulation with platelet activating factor increased this percentage to 85%. Immunoblot analysis of solubilized dog platelets resolved by sodium dodecyl sulfate polyacrylamide gel electrophoresis indicated that the antibody MD3 recognized an approximately 140-kd protein. Immunohistochemical study of normal dog tissues with MD3 revealed that the antigen was present in endothelial cells of arteries, capillaries, and veins, depending on the specific tissue examined. Blood vessels staining positively with MD3 were most abundant in the digestive system (liver, stomach, small and large intestines), moderate in the lungs, kidneys, spleen, lymph nodes, and endocrine glands, and minimal in the brain, myocardium, skeletal system, and skin. Based on its presence on stimulated but not resting platelets, its molecular weight, and its vascular distribution, the antigen recognized by MD3 appears to be the selectin GMP-140 of the dog. This study documents that the cellular and tissue distribution of GMP-140 in dogs is very similar to that in human beings.

Animals↗
PubMed1996

Radioimmunoguided surgery after primary treatment of locally advanced breast cancer.

PURPOSE: To assess the role of radioimmunoguided surgery (RIGS) using a handheld intraoperative gamma-detecting probe (GDP) to identify neoplastic disease after primary chemotherapy in locally advanced breast cancer (LABC) patients injected with iodine 125-labeled monoclonal antibodies (MAbs). PATIENTS AND METHODS: Twenty-one patients with histologically documented LABC were treated with a combined modality approach. After three courses of primary chemotherapy and before modified radical mastectomy, the 125I-radiolabeled MAbs B72.3 (anti-TAG72) and FO23C5 (anti-carcinoembryonic antigen [CEA]) were administered to 11 patients (group A) and 10 patients (group B), respectively. At surgery, a GDP was used to locate the primary tumor and to assess possible tumor multicentricity and the presence of ipsilateral axillary metastases. Routine pathologic examination was performed in neoplastic and normal tissue specimens of all 21 patients. In addition, immunohistochemical assay for TAG72 and CEA expression was performed. RESULTS: In group A patients, RIGS identified primary tumor in seven of 11 patients (63.3%) and unpalpable multicentric tumor lesions were located in two of four (50%). Positive axillary lymph nodes were histologically documented in eight of 11 patients (72.7%) and RIGS identified three of eight (37.5%). In group B, RIGS located the primary tumor lesion in four of 10 patients (40%); in two cases, the tumor was not clinically evident. Multicentricity was observed in one of two patients and lymph node involvement in three of nine (33.3%). No false-positive results were observed in either group A or B. CONCLUSION: RIGS appears to be a safe and reliable technique. However, the MAbs used in this study are not sufficiently specific. RIGS represents a technique for which the full potential for intraoperative assessment of breast cancer lesions can be reached when more specific antibodies become readily available.

Aged↗
PubMed2005

A novel mechanism of immune regulation: interferon-gamma regulates retention of CD4 T cells during delayed type hypersensitivity.

The local immune response is characterized by an increase in the rate of entry of lymphocytes from the blood into regional lymph nodes and changes in the output of cells in lymph. While significant data are available regarding the role of inflammation-induced vascular adhesion processes in regulating lymphocyte entry into inflamed tissues and lymph nodes, relatively little is known about the molecular processes governing lymphocyte exit into efferent lymph. We have defined a novel role for lymphatic endothelial cells in the regulation of lymphocyte exit during a delayed type hypersensitivity (DTH) response to mycobacterial purified protein derivative (PPD). Soluble, pro-adhesive factors were identified in efferent lymph concomitant with reduced lymphocyte output in lymph, which significantly increased lymphocyte binding to lymphatic endothelial cells. While all lymphocyte subsets were retained, CD4+ T cells appeared less susceptible than others. Among a panel of cytokines in inflammatory lymph plasma, interferon (IFN)-gamma alone appeared responsible for this retention. In vitro adhesion assays using physiological levels of IFN-gamma confirmed the interaction between recirculating lymphocytes and lymphatic endothelium. These data demonstrate a new level of immune regulation, whereby the exit of recirculating lymphocytes from lymph nodes is selectively and sequentially regulated by cytokines in a manner equally as complex as lymphocyte recruitment.

Animals↗
PubMed1981

Cellular immunity during pregnancy. II. Response to T and B cell mitogens.

Immune reactivity of primiparous pregnant C57Bl/6J mice was investigated using in vitro assays of mitogen reactivity. The response to the T cell mitogens phytohemagglutinin (PHA) and concanavalin A of cells from the paraaortic (PA) lymph nodes, which drain the uterus, was decreased in pregnant animals. Reactivity to lipopolysaccharide, a B cell mitogen, was normal. The decreased PHA response was seen with PA cells from mice bearing syngeneic or allogeneic (to DBA/2J) fetuses. It was not due to a change in sensitivity to PHA dose or to active suppression (as demonstrated by mixing experiments). Phytohemagglutinin reactivity of cells from inguinal nodes of pregnant mice showed a more variable depression of response in comparison to that seen with cells from the draining PA nodes. The response of axillary and brachial node cells was similar to virgin values. Statistical analysis revealed no differences in the average number of PA lymphocytes or fetuses per mouse between mice bearing syngeneic or allogeneic fetuses. This parallels the similarities found between syngeneic and allogeneic matings in in vitro functional assays. This study demonstrates that pregnant mice (syngeneic or allogeneic) show only a decrease in T proliferative capacity localized to the area of the uterus, while such responses in the rest of the body are left essentially intact.

Animals↗