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Biomedical subjects

R A Robins

Publications and source records attributed to R A Robins.

At least 19 recordsLinked to original sources
PubMed2006

Vaccination therapy in malignant disease.

Improvement in survival among patients with early malignancy is well established in various cancers. However, long-term survival in those with advanced malignancy has changed little and this poses a major therapeutic challenge to clinicians. Anti-cancer immunotherapy is a novel approach, which is still experimental, but offers a new therapeutic strategy. In this review, we discuss the basic immunological interplay between the host immune system and the tumour, mechanisms of anti-tumour immune responses induced by immunotherapy and key in vivo pilot studies of active specific immunotherapy in various sold cancers, carried out during the last five years.

Cancer Vaccines↗
PubMed2005

Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A.

OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.

Adult↗
PubMed2005

Vaccination and malignant disease: promising therapeutic approach.

Immunotherapy of cancer is now entering its second century. Much of our understanding of the complex interaction between tumours and the host immune system has come about because of technological and immunobiological advances in very recent years. For some malignancies, such as bladder cancer and malignant melanoma, immunotherapy is becoming an accepted form of adjuvant therapy. However, for most types of cancer, immunotherapy remains experimental and the majority of surgeons will have had little experience of immunotherapy in the clinical setting. This review provides a background to the scientific basis of immunotherapy, how different forms of immunotherapy are delivered and how their effects are monitored.

Antigens, Neoplasm↗
PubMed2005

Responses to free lipopolysaccharide and Escherichia coli by normal human intestinal macrophages, following their migration out of the lamina propria.

Intestinal macrophage responses to luminal bacteria and their constituents are important in mucosal inflammatory responses. We investigated the responses of intestinal macrophages to free lipopolysaccharide (LPS) and Escherichia coli. Macrophages were isolated from normal terminal ileum and colon by allowing them to migrate out of the lamina propria of mucosal samples denuded of epithelial cells. Following exposure to free LPS or fluorescein-labelled E. coli, responsiveness was studied by intracellular expression of tumour necrosis factor-alpha (TNF-alpha). CD14, CD33, CD68, TLR2 and TLR4 expression was studied by fluorescence-activated cell sorter (FACS). TLR and NOD2 expression was confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). CD14 was expressed by 36.5 +/- 4.0% of the macrophages obtained following migration out of the lamina propria. These cells also expressed TLR2, TLR4 and NOD2. Of cells exposed to free LPS or those that had taken up E. coli, a greater proportion of CD14(+) than CD14(-) macrophages expressed intracellular TNF-alpha. Moreover, a greater proportion of macrophages (CD14(+) and CD14(-)) demonstrated responses to E. coli than free LPS. In conclusion, a proportion of macrophages obtained following migration out of the lamina propria of normal terminal ileal and colonic mucosal samples express CD14, TLR2 and TLR4. These cells respond to free LPS and E. coli, as demonstrated by the expression of TNF-alpha.

Aged↗
PubMed2005

Autoantibodies to GAD and IA-2 in Saudi Arabian diabetic patients.

AIMS: To determine the prevalence of autoantibodies in sera of Saudi diabetic patients including Type 1 and Type 2 diabetes mellitus (DM) and gestational diabetes mellitus (GDM) living in Jeddah, Saudi Arabia. Apart from data on the prevalence of islet-cell antibodies in patients in Ryhadh (Al-Attas et al. Frequency of islet cell antibodies in adult newly diagnosed diabetic patients. Ann Saudi Med 1990; 10: 369-373) immunological markers of autoimmune diabetes have not been explored in Saudi Arabians. METHODS: Autoantibodies to GAD65 (GADA) and IA-2 (IA-2A) were determined using radio-immunoprecipitation assays. RESULTS: In Type 1 DM patients, 54% were GADA+ and 27% were IA-2A+. A greater negative effect of disease duration was noted for IA-2A than for GADA positivity. Autoantibodies were more prevalent with younger age of onset. GADA were slightly more common in female Type 1 DM patients. In Type 2 DM, 8/99 patients were GADA+, and three of these patients with shorter disease duration were also IA-2A+. GADA, and particularly IA-2A, were associated with a younger age of onset of Type 2 DM and all the autoantibody-positive Type 2 DM patients were insulin-treated. GADA were detected in 2.2% of GDM patients, but none of these patients possessed IA-2A. CONCLUSIONS: The prevalence and associations of autoantibodies in Saudi diabetic patients are very similar to those reported for diabetic patients in other ethnic groups.

Adult↗
PubMed2005

Monocytes are highly sensitive to clostridium difficile toxin A-induced apoptotic and nonapoptotic cell death.

In this study we investigated the in vitro responses of peripheral blood mononuclear preparations and purified monocytes to Clostridium difficile toxin A. In contrast to the responses of T and B cells, exposure to toxin A led to a rapid loss of monocytes in a time- and dose-dependent fashion (the majority of cells were lost within 24 h of exposure to >100 ng of toxin per ml). Transmission electron microscopy, flow cytometry, and fluorescence microscopy after propidium iodide and Hoechst staining showed that cell death in purified preparations of monocytes following exposure to 100 and 1,000 ng of toxin A per ml occurred by apoptosis. Further studies showed that 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazole-carbocyanine iodide aggregates were retained within toxin A-exposed monocyte mitochondria, but cytochrome c was released, suggesting that the apoptotic cascade was triggered in the absence of mitochondrial permeability transition. There was also an increase in caspase-3 activity in toxin A-stimulated monocytes. Following exposure to very high concentrations of toxin A (30 microg/ml), monocyte cell death was predominantly of the necrotic type, with rapid extracellular release of lactate dehydrogenase. These studies demonstrated that C. difficile toxin A has a cell-specific effect, in which monocytes exhibit greater susceptibility than lymphocytes and their death is induced in a concentration-dependent manner.

Apoptosis↗
PubMed2004

Endothelial monocyte-activating polypeptide-II (EMAP-II): a novel inducer of lymphocyte apoptosis.

The novel, proinflammatory cytokine endothelial monocyte-activating polypeptide-II (EMAP-II) was first found in tumor cell supernatants. EMAP-II is closely related or identical to the p43 auxiliary protein of the multisynthase complex, which is involved in protein synthesis. In vitro, EMAP-II induces procoagulant activity, increased expression of E- and P-selectins and tumor necrosis factor receptor-1, and ultimately, programmed cell death (apoptosis) in cultured endothelial cells. EMAP-II is also chemotactic for monocytes and neutrophils. However, the role of the p43/EMAP-II cytokine form in tumors is not understood. We hypothesized an immune-regulatory role within neoplastic tissues and investigated its effects on lymphocytes. EMAP-II causes a dose-dependent inhibition of proliferation and apoptosis in Jurkat T cells and mitogen-activated peripheral blood mononuclear cells. Coculture with DLD-1 colorectal cancer cells or media conditioned by these cells induces apoptosis in Jurkat cells, which is partially reversed by antibodies against EMAP-II. Our data suggest that EMAP-II constitutes a component of a novel, immunosuppressive pathway in solid tumors, which is not normally expressed outside the cell but in tumors, may be subject to abnormal processing and released from tumor cells.

Adjuvants, Immunologic↗
PubMed2004

Immunological aspects of head and neck cancer: biology, pathophysiology and therapeutic mechanisms.

Advanced cancer and head and neck cancer, in particular, remains a major clinical challenge with its associated morbidity and inevitable mortality. Local control of early disease is achievable in many solid tumours with current surgical and radiotherapeutic techniques but metastatic disease is associated with poor outcome and prognosis. It is known that, by the time of presentation, many patients will already have occult microscopic metastatic disease, and surgery and radiotherapy will not result in long-term survival. What little effect modern chemotherapeutic agents have on microscopic disease is, however, limited by systemic toxicity and multi-drug resistance. Immune surveillance is postulated to be operative in man. There is evidence, however, that patients with progressive tumour growth have failure of host defences both locally and systemically. Various possible defects and tumour escape mechanisms are discussed in the review. Immunotherapy and, in particular adoptive T cell therapy and DC therapy, show promise as putative tumour-specific therapy with clinical benefits. These techniques are undergoing development and evaluation in phase 1 clinical trials. Preliminary data suggest that the treatments are well tolerated. Unfortunately, there is limited evidence of significant and prolonged improvements in clinical outcome. Further developments of beneficial protocols (adjuvants, mode and frequency of vaccination etc) and multicentre studies of the use of immunotherapy in cancer are now required.

Head and Neck Neoplasms↗
PubMed2003

Enhanced expression of the complement regulatory protein CD55 predicts a poor prognosis in colorectal cancer patients.

This study prospectively correlated the level of expression of CD55 on tumours with 7-year survival in 136 colorectal cancer patients. Patients with tumours expressing high levels of CD55 had a significantly worse survival (24%) than patients with low CD55 levels (50%, p<0.02). A similar difference was seen for patients (Duke's B or C) with a high risk of recurrence (29% vs 58%, p<0.05). Furthermore, there was a progressive deterioration in prognosis with increasing antigen expression ( p=0.01). It remains unclear if CD55 is overexpressed by tumours to protect them from complement or if it is related to the recent observation that CD55 is a ligand for the T-cell activation antigen CD97. However, it is a marker of aggression, as colorectal cancer patients whose tumours overexpress CD55 have a significantly reduced 7-year survival.

Aged↗
PubMed2002

Loss of cytomegalovirus-specific immunological memory in a patient with thymoma.

Cytomegalovirus (CMV) retinitis is a re-activation infection associated with severely impaired T cell-mediated immunity. We describe a patient with long-standing Crohn's disease and thymoma who developed severe CMV retinitis. While thymoma can be associated with impaired humoral immunity and a quantitative CD4+ T helper cell deficiency, these were not evident in our patient. However, more detailed investigation of anti-CMV responses showed absence of specific T cell responses to CMV antigen. Normal CMV seropositive controls have detectable proliferation and interferon-gamma production by T cells in response to stimulation with CMV antigen, but this was absent in this patient both during the acute infection and in convalescence. Other measures of T cell function were normal. Since CMV retinitis is due to reactivation of latent CMV infection, it appears that selective loss of CMV-specific immunity had occurred, perhaps secondary to a thymoma. The causes of thymoma-associated immune impairment are not understood, but this case demonstrates that selective defects can occur in the absence of global T cell impairment. Opportunistic infections should therefore be suspected in patients with thymoma even in the absence of quantitative immune deficiencies.

Aged↗
PubMed2002

S antigen specific effector T cell activation detected by cytokine flow cytometry.

BACKGROUND/AIMS: Effector T cell activation is particularly important in the initiation of autoimmune uveitis. This pilot study seeks to demonstrate activation of human peripheral effector T cells in response to the uveitis candidate autoantigen, retinal S antigen (SAg), using cytokine flow cytometry (CFC). METHODS: Peripheral blood mononuclear cell (PBMC) suspensions from uveitis patients and controls were stimulated with bovine SAg. Activation responses were detected by CFC. RESULTS: Electronic gating enabled analysis of CD69+, IFN-gamma+ CD4+ lymphocytes. An SAg specific response was detectable in four of 13 patients and four of eight controls. CONCLUSION: SAg specific, peripheral, effector T cell activation can be detected by CFC. Similar levels of responsiveness were seen in patient and control groups. More detailed cytokine profiling may demonstrate functional differences between the groups.

Arrestin↗
PubMed2001

Randomized double-blind phase II survival study comparing immunization with the anti-idiotypic monoclonal antibody 105AD7 against placebo in advanced colorectal cancer.

The cancer vaccine 105AD7 is an anti-idiotypic monoclonal antibody that mimics the tumour-associated antigen 791T/gp72 (CD55, Decay Accelerating Factor) on colorectal cancer cells. Phase I studies in patients with advanced disease confirmed that 105AD7 is non-toxic, and that T cell responses could be generated. A prospective, randomized, double-blind, placebo-controlled survival study in patients with advanced colorectal cancer was performed. 162 patients were enrolled between April 1994 and October 1996. Patients attended at trial entry, and at 6 and 12 weeks, where they received 105AD7 or placebo. Study groups were comparable in terms of patient demographics, and time from diagnosis of advanced colorectal cancer (277.1 v 278.6 days). Baseline disease was similar, with 50% of patients having malignancy in at least 2 anatomic sites. Compliance with treatment was poor, with only 50% of patients receiving 3 planned vaccinations. Median survival from randomization date was 124 and 184 days in 105AD7 and placebo arms respectively (P = 0.38), and 456 and 486 days from the date of diagnosis of advanced disease (P = 0.82). 105AD7 vaccination does not prolong survival in patients with advanced colorectal cancer. The reasons for lack of efficacy are unclear, but may reflect the high tumour burden in the patient population, and poor compliance with immunization. Further vaccine studies should concentrate on patients with minimal residual disease.

Adult↗
PubMed2001

Direct ex vivo comparison of the breadth and specificity of the T cells in the liver and peripheral blood of patients with chronic HCV infection.

The role of intrahepatic lymphocytes in the control of hepatitis C virus (HCV) infection and the pathology associated with it is not understood; most studies of the immunology of this infection use peripheral blood lymphocyte populations. To address this further, we examined in detail the IHL from HCV-infected patients and controls, focusing on the antigen-specific CD8(+) T lymphocyte component. Individual T cells from needle liver biopsies and peripheral blood were isolated from patients with chronic HCV infection and examined directly ex vivo. We used RT-PCR spectratyping to compare the breadth of the T cell receptor usage in the liver in comparison with the peripheral blood, and applied MHC class I tetramer technology to investigate the numbers of HCV-specific CD8(+) cells in the two compartments. T cell receptor usage in the liver of HCV-infected patients was broad, comparable with that in the peripheral blood of the same patients. A much higher proportion of liver CD8(+) cells expressed receptors specific for HCV antigens compared with paired peripheral blood CD8(+) cells. A greater proportion of the liver tetramer-positive cells expressed the activation marker CD69, compared with those in the periphery or other CD8(+) cells in the liver. In the course of chronic HCV infection, HCV-specific CD8 cells, which have been recently activated, appear to accumulate specifically in the livers of infected patients but are present in much lower numbers in the peripheral circulation. Further studies are needed to determine the function of these cells and their role in protection and immunopathology.

CD8-Positive T-Lymphocytes↗
PubMed2000

Vaccine-induced apoptosis: a novel clinical trial end point?

The functional end point of immunotherapy is to induce tumor regression. Because immune effector mechanisms usually result in apoptosis, the aim of this study was to determine whether measurement of tumor apoptosis ex vivo is a good end point to evaluate the efficacy of cancer vaccines. A prototype vaccine, 105AD7, was administered to colorectal cancer patients before resection of their primary tumors. There was a significant increase in apoptosis of tumor cells within immunized patients compared with control patients as assessed by immunohistochemistry (P = 0.005; n = 16) or by flow cytometry (P = 0.003; n = 34). Preoperative immunization and measurement of tumor cell apoptosis may be a valuable clinical end point for evaluation of new vaccine and other biological approaches.

Adenocarcinoma↗
PubMed2000

Preclinical evaluation of "whole" cell vaccines for prophylaxis and therapy using a disabled infectious single cycle-herpes simplex virus vector to transduce cytokine genes.

The development of genetically modified "whole" tumor cell vaccines for cancer therapy relies on the efficient transduction and expression of genes by vectors. In the present study, we have used a disabled infectious single cycle-herpes simplex virus 2 (DISC-HSV-2) vector constructed to express cytokine or marker genes upon infection. DISC-HSV-2 is able to infect a wide range of tumor cells and efficiently express the beta-galactosidase reporter gene, granulocyte-macrophage colony-stimulating factor (GM-CSF), or IL-2 genes. Gene expression occurred rapidly after infection of tumor cells, and the level of production of the gene product (beta-galactosidase, GM-CSF, or IL-2) was shown to be both time-and dose-dependent. Vaccination with irradiated DISC-mGM-CSF or DISC-hIL-2-infected murine tumor cells resulted in greatly enhanced immunity to tumor challenge with live parental tumor cells compared with control vaccines. When used therapeutically to treat existing tumors, vaccination with irradiated DISC-mGM-CSF-infected tumor cells significantly reduced the incidence and growth rates of tumors when administered locally adjacent to the tumor site, providing up to 90% protection. The prophylactic and therapeutic efficacy of DISC-mGM-CSF-infected cells was shown initially using a murine renal cell carcinoma model (RENCA), and the results were confirmed in two additional murine tumor models: the M3 melanoma and 302R sarcoma. Therapy with DISC-infected RENCA "whole" cell vaccines failed to reduce the incidence or growth of tumor in congenitally T-cell deficient (Nu+/Nu+) mice or mice depleted of CD4+ and/or CD8+ T-lymphocytes, confirming that both T-helper and T-cytotoxic effector arms of the immune response are required to promote tumor rejection. These preclinical results suggest that this "novel" DISC-HSV vector may prove to be efficacious in developing genetically modified whole-cell vaccines for clinical use.

Animals↗
PubMed2000

105Ad7 cancer vaccine stimulates anti-tumour helper and cytotoxic T-cell responses in colorectal cancer patients but repeated immunisations are required to maintain these responses.

105AD7 is a human anti-idiotypic antibody that recognises the binding site of the anti-tumour antibody 791T/36 and can thereby mimic the CD55 antigen. The molecular basis of 105AD7 mimicry has been identified with 3 CDR regions of 105AD7 showing similarity to 3 regions of CD55. These regions have been analysed for potential T-cell epitopes, and sequences that are predicted to bind to HLA/A1, 3,24 and to HLA/DR1,3,7 have been identified within the CDRH3 region of 105AD7. These epitopes should be stimulating CD8 and CD4 responses, respectively. This prediction was tested on 12 colorectal cancer patients receiving 105AD7 therapy. There was good concordance in 10 of 11 patients between accumulation of CD8RO cells or tumour killing and expression of HLA/A1,3,24. The only patient who failed to respond had a non-permissive class II haplotype and failed to show a helper response. Again 10 of 11 patients showing accumulation of CD4RO cells, in vitro blastogenesis responses, enhanced IL-2 or enhanced NK activity expressed one or more of the HLA/DR1,3,7 haplotypes. Although there was a consistent accumulation of CD45RO cells following 14 of 18 immunisations, only one patient showed a sustained memory response. Our results suggest that 105AD7 can stimulate CD4 and CD8 responses in patients with the appropriate haplotype. However, it may be necessary to continue to immunise, since few patients produce a sustained memory response.

Antibodies, Anti-Idiotypic↗
PubMed2000

Differential levels of granzyme B, regulatory cytokines, and apoptosis in Crohn's disease and ulcerative colitis at first presentation.

The mechanisms of tissue damage in ulcerative colitis and Crohn's disease may reflect disordered humoral or cell-mediated effector mechanisms, respectively. Mucosal biopsies from untreated inflammatory bowel disease patients and normal controls were analysed for the expression of granzyme B, a cytotoxic effector molecule specifically associated with cell-mediated immunity, and for regulatory cytokines. Messenger RNA (mRNA) was analysed by reverse transcription-polymerase chain reaction and enzyme-linked oligonucleotide chemiluminescence assay. Mucosal biopsies were analysed by immunohistochemistry for granzyme B protein and lymphocyte markers and for the presence of apoptotic cells by terminal deoxynucleotidyl transferase end labelling. Granzyme B mRNA was elevated in Crohn's disease, but not in ulcerative colitis or control mucosal biopsies. Granzyme B mRNA levels correlated with interferon gamma mRNA levels in Crohn's disease. Granzyme B was expressed in CD3+, CD8+ T cells in the lamina propria of Crohn's disease mucosa and there were significantly more apoptotic cells in the lamina propria in Crohn's disease. In conclusion, granzyme B-expressing T lymphocytes are present in the focal mucosal lesions of Crohn's disease, together with spatially related apoptotic cell death. These results support the hypothesis that T-cell-mediated cytotoxic effector mechanisms may play a role in Crohn's disease.

Adolescent↗