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PubMed1997

Dietary wheat bran modulates proliferating cell nuclear antigen-labeling index of the rat colorectum after treatment with 1,2-dimethylhydrazine.

We investigated whether dietary wheat bran (Wb) influences the proliferating cell nuclear antigen (PCNA)-labeling index (LI) of the colorectum of rats after the injection of 1,2-dimethylhydrazine (DMH). Male Wistar/ST rats were divided into four groups and given either a fiber-free diet or diets supplemented with Wb at the expense of the whole diet (5, 10 or 20 g/100 g diet). Then, they were subcutaneously injected with a single dose of DMH (20 mg/kg body weight) or the vehicle. At four weeks after the treatment, frozen sections of the colorectum were immunostained with anti-PCNA antibody (19F4). In the fiber-free group, DMH treatment significantly increased the PCNA-LI of the distal colon and rectum. Among the DMH treatment groups, the PCNA-LI of the distal colon in the Wb 5 g/100 g diet group was significantly lower than that in the fiber-free group. The PCNA-LI of the distal colon tended to increase as the amount of Wb supplemented was increased in the DMH-treated groups except for the fiber-free group. A similar trend was observed for the rectum. In conclusion, the ingestion of Wb diminished the increase in PCNA-LI in rat colorectum induced by DMH injection.

1,2-Dimethylhydrazine↗
PubMed2026

Hypoimmune platforms: from rejection to immune evasion and regulatory implications.

The growing gap between organ demand and clinical availability has renewed interest in immune-evasive graft strategies, yet rejection and lifelong immunosuppression remain major barriers to durable success. Advances in genome editing enable immune-evasive cell platforms designed to avoid immune recognition while replacing missing function in allogeneic settings. This review summarizes current strategies for engineering immune-evasive grafts that simultaneously suppress adaptive and innate immune responses. We discuss how coordinated modulation of antigen presentation and immune checkpoint pathways can protect transplanted allogeneic cells and tissues from T, NK, and macrophage-mediated rejection. We also present the emerging concept of integrating hypoimmune engineering with genetically modified porcine donors, where extensive genome editing has reduced, but not eliminated, xenogeneic immune barriers. Combining donor genome modification with immune-evasive graft design represents a promising conceptual advance toward xenograft survival, though whether full elimination of systemic immunosuppression is achievable remains to be established clinically. We further examine how the regulatory landscape for these products is evolving across major jurisdictions, and how differences in approval pathways, manufacturing standards, and long-term surveillance requirements shape the path to clinical translation. Finally, we outline the safety considerations and remaining limitations in immune evasion that must be addressed to enable clinical implementation.

Graft Rejection↗
PubMed1976

[Prolonged survival of xenogeneic grafts after organ culture].

Organ culture of xenogeneic thyroids leads to a prolonged survival time. This effect can be reversed when donor-specific cells are injected at the time of transplantation. The results of this experiment disprove the assumption that target antigens are modulated or masked by organ culture.

Animals↗
PubMed1999

Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells.

We show that interleukin-18 is constitutively produced by dendritic cells; synthesis and secretion are poorly affected by maturative stimuli. Challenge of dendritic cells with autologous anti-tetanus toxoid T lymphocytes results in a secretory switch, with induction of secretion of biologically active interleukin-18 and decrease of its intracellular content. Similarly, when dendritic cells are challenged with allospecific T cells a dramatic decrease of intracellular interleukin-18 content occurs, whereas no effects are observed after co-culture with autologous activated T cells. The induction of secretion call be mediated by engagement of CD40 on dendritic cells, as indicated by the increased amount of interleukin-18 in dendritic cell supernatants after CD40 triggering by anti-CD40 antibodies. However, CD40 engagement, unlike from antigen-specific T cells, does not result in reduced intracellular interleukin-18 content, suggesting that this decrease may be mediated by structure(s) involved in antigen recognition.

Antigen Presentation↗
PubMedDate not supplied

Site-specific immunosuppression: mechanisms of cellular immunosuppression that are operative at local and systemic levels.

The cellular mechanisms by which topical cyclosporine A (tCsA) induces site-specific immunosuppression were investigated. Experiments were designed to elucidate how cyclosporine A (CsA) suppresses activated immunocytes in animals that are undergoing local alloactivation and concomitant tCsA immune suppression. Lewis rats received dual Lewis x Brown Norway rat skin allografts; the rats were treated with systemic CsA (sCsA) at 8 mg/kg/day for 10 days after grafting and then tCsA and vehicle thereafter. CsA added to mixed lymphocyte reactions 24 hours after culture initiation modeled the local effects of CsA on alloactivated immunocytes, and tCsA in conjunction with limited sCsA prolonged local skin allograft survival. CsA inhibited both antigen-specific and nonspecific activated alloresponses of immunocytes from animals that had received allografts and that underwent limited sCsA treatment only in a dose-dependent manner. When tCsA had been applied, immunocyte responses to a nonspecific antigen were extremely CsA-resistant as compared with those induced by antigen-specific suppression. However, this nonspecific alloresponse was fully suppressible with the use of elevated CsA doses (66 microg/mL); thus alloresponding immunocytes were significantly more sensitive to CsA if they were challenged with the donor antigen and preexposed to limited sCsA followed by tCsA in vivo.

Administration, Topical↗
PubMed1999

Nuclear medicine therapy of neuroblastoma.

Specific targeting of radionuclides to neuroblastoma, a neural crest tumour occurring predominantly in young children and associated with a relatively poor prognosis, may be achieved via the metabolic route (MIBG), receptor binding (peptides) or immunological approach (antibodies). The clinical role of 131I-MIBG therapy and radioimmunotherapy in neuroblastoma is discussed. In recurrent or progressive metastatic disease after conventional treatment modalities have failed, 131I-MIBG therapy, with an overall objective response rate of 35%, is probably the best palliative treatment, as the invasiveness and toxicity of this therapy compare favourably with that of chemotherapy, immunotherapy and external beam radiotherapy. In patients presenting with inoperable stage III and IV neuroblastoma, 131I-MIBG therapy at diagnosis is at least as effective as combination chemotherapy but is associated with much less toxicity. In patients with recurrent disease 131I-MIBG therapy in combination with hyperbaric oxygen therapy proved feasible and encouraging effects on survival have been observed. Attempts to intensify the treatment in relapsed patients by combination of 131I-MIBG therapy with high dose chemotherapy and/or total body irradiation have met with considerable toxicity. Developments in MIBG therapy aiming at improving the therapeutic index are mentioned. Early results of radioimmunotherapy using 131I-UJ13A or 131I-3F8 monoclonal antibodies have shown moderate objective response and considerable side effects in patients with stage IV neuroblastoma, who had relapsed or failed conventional therapy. New developments in radioimmunotherapy of neuroblastoma include the use of chimaeric antibodies, the enhancement of tumour uptake by modulation of antigen expression or by increasing the tumour perfusion/vascularity/permeability, the use of other labels and multistep targeting techniques, e.g. using bispecific monoclonal antibodies.

3-Iodobenzylguanidine↗
PubMedDate not supplied

[Major aphthous stomatitis (Sutton's disease): etiopathogenesis, histological and clinical aspects].

Major aphthous stomatitis (Sutton's disease) is a clinical variant of recurrent aphthous stomatitis differentiated by its high level of morbidity. It is generally found in areas of non-keratinized mucosa and is characterised by the presence of necrotic giant ulcers accompanied by intense pain. While this pathology has been the subject of molecular studies, its etiopathogenesis is still unknown. The most widely accredited hypothesis is that it represents an immune mechanism, namely the immunological response of mucosa with antigenic anomalies, modulated by altered local reactivity and influenced by triggering factors. After an extensive review of the various etiopathogenetic hypotheses, clinical and pathological aspects, the authors outline a number of therapeutic protocols including the use of topical and systemic cortisone, immunomodulators and alternative therapies like laser and ultrasound, or medications to protect the ulcers. They stress that the lack of etiopathogenetic uniformity precludes any specific treatment.

Adjuvants, Immunologic↗
PubMed2002

[Modulation of lianbizi injection (andrographolide) on some immune functions].

OBJECTIVE: To study the effects of andrographolide on immune functions and the immune mechanism of its clinical application. METHOD: The amounts of IFN-alpha, IFN-gamma, TNF-alpha, IL-8 in the peripheral blood mononuclear cells(PBMCs) culture supernatants deal with by different concentrations of LianBiZhi (LBZ) injection made of andrographolide were detected by biological activity test or ELISA in vitro. The effects of LBZ injection on macrophage phagocytotic function and natural killer cells cytotoxicity were examined by means of macrophage to phagocytize cock erythrocyte and measurement of lactate dehydrogenase(LDH) activity released from the damaged cells, respectively. RESULT: The LBZ injection could promote IFN-alpha, IFN-gamma, TNF-alpha inductions of PBMCs, but had no effect on IL-8. At the same time, the LBZ injection could not only enhance the phagocytosis activity of peritoneal macrophage from guinea pig to phagocytosis cock erythrocyte, but also augment the cytotoxicity mediated by natural killer cells from PBMCs to damage the K562 cell lines. CONCLUSION: Andrographolide is an immunostimulant agent which can modulate both antigen specific and nonspecific immune function by means of its natural killer cells and macrophage and cytokines induction.

Animals↗
PubMed2003

Selection and characterization of anti-MUC-1 scFvs intended for targeted therapy.

PURPOSE: The selection and characterization of anti-MUC-1 single-chain antibody fragments (scFv) is a first step toward the construction of new anticancer molecules designed for optimal blood clearance and tumor penetration. The mucin MUC-1 was chosen as an antigen because it is abundantly expressed on epithelial cancers in an aberrantly glycosylated form, making it structurally and antigenically distinct from MUC-1 expressed on normal cells. EXPERIMENTAL DESIGN: A previously constructed anti-MUC-1 phage display library from hyperimmunized mice, with 5 x 10(5) calculated variants, was screened for the selection of anti-MUC-1 scFvs. Selection criteria were high binding to a MUC-1 peptide containing 4 tandem repeats of 20 amino acids and to MUC-1-positive MCF-7 (human breast cancer) cell lysates in ELISA. RESULTS: Six anti-MUC-1 scFv clones were selected and characterized. Nucleotide sequencing showed that four of them were full length scFv genes (variable heavy chain + variable light chain), whereas the remaining two contained either a variable heavy chain or a variable light chain alone. Their binding affinities (K(a)) range between 8 x 10(7) and 10(9) M(-1). Immunohistopathology demonstrated reactivity with breast cancer cells (MCF-7 and BT20) and human breast biopsy tissue. Molecular modeling revealed high structural similarity of the anti-MUC-1 scFvs with the X-ray-determined structure of the anti-CEA scFv (MFE-23). CONCLUSIONS: In vitro antigen binding was demonstrated for the selected anti-MUC-1 scFvs. The binding affinities of these scFvs are in a promising range for efficient in vivo antigen binding. These anti-MUC-1 scFvs will be evaluated as antigen-binding modules in new multifunctional agents for the detection and therapy of cancer.

Amino Acid Sequence↗
PubMed2003

Celecoxib modulates the expression of cyclooxygenase-2, ki67, apoptosis-related marker, and microvessel density in human cervical cancer: a pilot study.

PURPOSE: We investigated whether a short treatment with the cyclooxygenase-2 (COX-2) inhibitor celecoxib could modulate Ki67 antigen and the caspase cleavage product of keratin 18, recognized as a marker of early apoptosis. The activity of celecoxib on microvessel density (MVD) and angio-power Doppler sonography-derived indices of tumor vascularization was also assessed. Serum levels of squamous cell carcinoma antigen and the proliferative potential and subsets of peripheral T cells before and after celecoxib treatment were also analyzed. EXPERIMENTAL DESIGN: Tumor biopsy specimens from 14 patients with cervical cancer were obtained at baseline and after 10 days of celecoxib treatment (400 mg twice daily). Tumor and stroma COX-2 expression, Ki67, apoptosis, and MVD were assessed by immunohistochemistry, whereas prostaglandin E(2) levels were measured by RIA. RESULTS: At baseline, COX-2 integrated density values in tumor compartment ranged from 10.7 to 60.1 (median, 26.5) and were significantly higher than tumor COX-2 integrated density values after celecoxib treatment (range, 0.6-42.3; median, 12.6; P = 0.0043). The percentages of Ki67-positive tumor cells in pre-celecoxib cases ranged from 39.3 to 87.4 (median, 50.8) and were significantly higher than the percentage in the corresponding posttreatment samples (range, 27.7-83.8; median, 43.1; P = 0.0092). MVD values in pre-celecoxib biopsies ranged from 28.0 to 55.0 (median, 38.5) and were significantly higher than the corresponding values in posttreatment samples (range, 16.0-49.5; median; 27.6; P = 0.012). Also, prostaglandin E(2) levels showed a trend to be reduced after celecoxib treatment (range: 4.7-386.6 pg/mg wet tissue in pretreated cases versus 4.8-91.9 pg/mg wet tissue in posttreated cases (P = 0.092). CONCLUSIONS: In cervical cancer, celecoxib treatment decreases tumor COX-2 expression and markers of proliferation and neoangiogenesis, while being uneffective on stroma COX-2 levels, thus suggesting that selective COX-2 inhibitors may be a promising strategy not only for chemopreventive approaches but also for therapeutic approaches in this neoplasia.

Adenocarcinoma↗
PubMed2003

Retinoids act as multistep modulators of the major histocompatibility class I presentation pathway and sensitize neuroblastomas to cytotoxic lymphocytes.

The current therapeutic modalities achieve low response rates in human neuroblastoma, a frequent extracranial malignancy of the early childhood. We have assessed the effect of retinoids, used presently for the treatment of neuroblastoma, on the discrete steps of the MHC class I processing machinery and susceptibility of neuroblastoma cells to CTL-mediated killing. We demonstrate that retinoic acid derivatives induce the expression of proteolytic and regulatory subunits of the immunoproteasome, increase the half-life of MHC class I complexes, and enhance the sensitivity of neuroblastoma cells to both MHC class I-restricted peptide-specific and HLA nonrestricted lysis by CTLs. Importantly, effects of retinoids on the MHC class I pathway appear to be independent of IFN-gamma and/or TNF-alpha as intermediate messengers. To our knowledge, this is the first demonstration of inflammation-unrelated biological molecules that induce systemic modulation of antigen presentation in nonprofessional antigen presenting cells. Our findings suggest that the application of retinoids and T cell-based immunotherapy may be an effective combination for the treatment of neuroblastoma.

Antigen Presentation↗
PubMed1991

Interferon alpha-induced modulation of leukocyte cell surface antigens: immunocytofluorometric study with human leukaemia/lymphoma cell lines.

Recombinant interferon alpha enhanced the MHC class I antigen density on human leukaemia/lymphoma cell lines REH, U-937 and HL-60, as measured by immunocytofluorometry using specific monoclonal antibodies. A similar effect was induced (as demonstrated in REH cells), also by human leukocyte interferon-alpha. The latter, however, caused no major alterations in the expression of leukocyte common antigen (ICA; CD45) and transferrin receptor (CD71) in the cell lines examined. In REH cells, there was no interferon-induced alteration of CD10 antigen (CALLA), which in this cell line is markedly down-regulated by 12-0-tetradecanoyl-phorbol-13-acetate (TPA). A decrease of CD4 antigen density on the cell membrane was induced by interferon-alpha in monoblastoid U-937 cells. No induction of MHC class I and II antigens by interferon-alpha was found in K-562 cell subline.

Antigens, CD↗
PubMed2006

[Chemical modification of chymopapain with monomethoxypolyethylene glycol and its effect on enzymic activity and antigenicity].

OBJECTIVE: To study the effect of chemical modification of chymopapain with monomethoxypolyethylene glycol on enzymic activity and antigenicity. METHODS: Under the substrate protecting and non-substrate protecting, the chymopapain (Cp) was modified with two types of mPEG derivatives mPEG1 and mPEG2. The average ratio of modified-NH2 was tested by trinitrobenzenesulfonic acid (TNBS) method, the enzymic activity was tested with macromolecular casein and ATEE as substrates, the antigenicity of modified enzyme was determined by ELISA method. RESULTS: (1) Both mPEG1 and mPEG2 can reduce and eliminate antigenicity of Cp, the mPEG2 was better than mPEG1. (2) The enzymic activities of modified Cp were reduced, the enzymic activities of mPEG1-modified Cp were higher than that of mPEG2-modified Cp (especially macromolecular protein as its substrate). (3) The enzymic activities in present of ATEE were obviously higher than that in absent of substrate. CONCLUSION: When mPEG1 as the modifier and in present of ATEE, the antigenicity of Cp was completely eliminated, and the enzymic activities were still higher.

Antigenic Modulation↗
PubMed1992

Radioimmunolocalization of neuroblastoma xenografts with chimeric antibody chCE7.

This study was performed to evaluate the tumor targeting ability of chCE7 with a view to clinical applications in neuroblastoma imaging and therapy. A chimeric (mouse/human) monoclonal antibody (chCE7) of gamma 1/kappa isotype directed against a neuroblastoma-associated cell-surface glycoprotein is described. In vitro chCE7 binds with high affinity (KD approximately 1 x 10(-10) M) to SKN-AS human neuroblastoma cells. Binding studies with 125I-labeled chCE7 show temperature-dependent modulation of antigen binding and indicate that a proportion of the bound antibody is internalized due to rapid antigen turnover. In vivo biodistribution of radioiodinated chCE7 in nude mice bearing SKN-AS tumors shows optimal tumor uptake after 24 hr with about 30% of the injected dose per g. Optimal tumor/blood ratios (3.4:1) are reached after 4-5 days. Uptake in other organs including the reticuloendothelial system is low with tumor/organ ratios of 10 and more. Tumor uptake of chCE7 and the parent murine CE7 are found to be similar. Stability of chCE7 during and after radiolabeling is good with no loss of immunoreactivity in preparations labeled with 123I up to 100 mCi/mg and 80% immunoreactivity after labeling with 13 mCi/mg of 131I. Neuroblastoma xenografts can be imaged by radioimmunoscintigraphy with 123I- and and 131I-labeled chCE7.

Animals↗
PubMedDate not supplied

Enkephalins-modulation of Plasmodium cynomolgi antigens-induced colony-stimulating factors elaboration by macrophages.

Methionine-enkephalin (M-Enk) and its analogue compound 82/205 (10(-5) and 10(-6) M) inhibited elaboration of Plasmodium cynomolgi total antigens soluble in culture medium (P.c.SA)-induced colony-stimulating factors (CSFs) by monkey blood monocyte-derived macrophages, in vitro. Paradoxically, lower concentrations (10(-7)-10(-9) M) of both the peptides greatly augmented CSFs elaboration; 82/205 appeared to be nearly 2.3-fold more potent. Naloxone (10(-5) M) pretreatment of macrophages inhibited only the M-Enk- and 82/205-induced enhanced CSFs elaboration, suggesting an opiate receptors-mediated mechanism of action. None of the peptides or naloxone (10(-5)-10(-9) M) had any direct effect on the CSF elaboration by unstimulated macrophages.

Animals↗
PubMed1990

Modulation of expression of the antigen identified by FMC7 upon human B-lymphocyte activation: evidence for differences between activation in vivo and in vitro.

The antigen detected by the monoclonal antibody (mAb) FMC7 is expressed by a proportion of B lymphocytes, and previous information, based on leukaemias, cell lines and some normal cell studies, suggested that FMC7 reacts with relatively differentiated B cells. In this study, it is shown that cells in the high-density 'resting' fraction of tonsil B lymphocytes have a lower expression of FMC7 than cells in the low-density 'activated' fraction. However, activation of 'resting' B cells with anti-immunoglobulin (anti-IgM) together with IL-4 resulted in a decrease in FMC7 reactivity, whilst recognized markers of activation showed up-regulation, as expected. Activated cells which were cultured for an extra 3 days to allow return to a 'resting' stage showed an increase in FMC7 expression. Culture of activated B cells with low molecular weight B-cell growth factor (LMW-BCGF), tumour necrosis factor (TNF) or interleukin-6 (IL-6), did not lead to further changes in FMC7 reactivity, but stimulation with phorbol ester had an effect similar to that of anti-IgM + IL-4. These results suggest that FMC7 is a marker of differentiation rather than activation, and identifies a relatively mature subfraction of the pool of functionally mature B cells. Consistent with this interpretation, FMC7 and surface IgD tended to be expressed by reciprocal B-cell subpopulations.

Antibodies, Anti-Idiotypic↗