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PubMed2006

REducing Deaths due to OXidative Stress (The REDOXS Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients.

Critically-ill patients experience an extent of hyperinflammation, cellular immune dysfunction, oxidative stress and mitochondrial dysfunction. Supplementation with key nutrients, such as glutamine and antioxidants, is most likely to have a favourable effect on these physiological derangements, leading to an improvement in clinical outcomes. The results of two meta-analyses suggest that glutamine and antioxidants may be associated with improved survival. The purpose of the present paper is to report the background rationale and study protocol for the evaluation of the effect of high-dose glutamine and antioxidant supplementation on mortality in a large-scale randomized trial in 1200 mechanically-ventilated, critically-ill patients. Patients admitted to an intensive care unit (ICU) with clinical evidence of severe organ dysfunction will be randomized to one of four treatments in a 2 x 2 factorial design: (1) glutamine; (2) antioxidant therapy; (3) glutamine and antioxidant therapy; (4) placebo. The primary outcome for this study is 28 d mortality. The secondary outcomes are duration of stay in ICU, adjudicated diagnosis of infection, multiple organ dysfunction, duration of mechanical ventilation, length of stay in hospital and health-related quality of life at 3 and 6 months. A novel design feature is the combined use of parenteral and enteral study nutrients dissociated from the nutrition support. The therapeutic strategies tested in the randomized trial may lead to less morbidity and improved survival in critically-ill patients. The trial will be conducted in approximately twenty tertiary-care ICU in Canada and the first results are expected in 2009.

Antioxidants↗
PubMed1998

Impairment of phagocytic and T-cell-mediated antibacterial activity and plasma endotoxins in patients with untreated gastrointestinal cancer.

BACKGROUND: Cancer patients have multiple immune deficits, and mediators, such as prostaglandins, transforming growth factor-beta, and interleukin (IL)-10, may play a role in the pathogenesis of these immune dysfunctions. METHODS: Fifty-six patients with gastrointestinal cancer (11 gastric cancer, 7 papilla of Vater cancer, and 38 colorectal cancer) were enrolled for this study, before starting conventional treatments. Phagocytosis and killing exerted by polymorphonuclear cells and monocytes, peripheral blood mononuclear cell absolute numbers, T-cell-mediated antibacterial activity, serum levels of IL-10 and interferon (IFN)-gamma, and plasma bacterial endotoxin concentration were evaluated. RESULTS: Data show an impaired phagocytic and T-cell-mediated antibacterial activity in all cancer patients, whereas only in subjects with gastric cancer were IFN-gamma serum levels reduced. Circulating endotoxins were detected in 17 patients. CONCLUSIONS: In untreated gastrointestinal cancer patients the capacity of phagocytes and T-cells to clear pathogens is reduced. This dysfunction may increase the risk of becoming infected and may account for the presence of endotoxin in 30% of patients.

Adult↗
PubMed1985

Zinc metabolism in malabsorption syndromes.

Zinc deficiency may complicate many gastrointestinal malabsorptive states. Zinc deficiency may manifest itself in a myriad of ways, ranging from skin lesions to immune dysfunction. This paper reports many of the ways in which zinc deficiency may appear in malabsorption syndromes and possible mechanisms for the development of this zinc deficiency.

Acrodermatitis↗
PubMed1995

Intestinal immune function is unaffected by parenteral nutrition in man.

BACKGROUND: Animal studies have demonstrated intestinal immunoglobulin production is decreased when luminal nutrition is withheld and nutrition is provided solely on the basis of total parenteral nutrition (TPN). METHODS: Eight normal volunteers were hospitalized in the Clinical Research Center for three weeks. The subjects received TPN as an exclusive means of nutritional support for 14 days followed by 5 days of enteral feeding with either standard or a glutamine- and arginine-supplemented formula in which the protein source was primarily free amino acids and peptides. Endoscopic jejunal biopsies obtained before and after TPN and following enteral refeeding were evaluated by immunofluorescence for the number of IgA, IgM and IgG-producing cells; T and B cells as well as intraepithelial and lamina propria lymphocytes were also counted. Serum immunoglobulins and the molecular forms of serum IgA were determined at the same intervals. RESULTS: The number of intestinal IgA-, IgM- and IgG-producing cells was unaffected by TPN (676 +/- 58 vs. 643 +/- 38, 101 +/- 14 vs. 98 +/- 18, 10 +/- 1 vs. 11 +/- 2 per low power field). The total number of intestinal lymphocytes, and CD3+ lymphocytes in the intraepithelial area was unaffected by TPN (10.4 +/- 0.4 vs. 10.2 +/- 1.3, 7.3 +/- 0.8 vs. 8.6 +/- 1.6 per 100 epithelial cells). Similarly, the total number of lymphocytes and CD3+ lymphocytes in the intestinal lamina propria was unaffected by TPN (4.4 +/- 0.2 vs. 6.2 +/- 0.8, 3.3 +/- 0.7 vs. 4.5 +/- 0.8). A small, but statistically significant increase in serum IgA and IgM was seen with TPN 314 +/- 11 vs. 342 +/- 16 mg/dL and 154 +/- 25 vs. 226 +/- 47 mg/dL, although IgG remained unchanged (1262 +/- 69 vs. 1207 +/- 57 mg/dL). The proportion of polymeric and monomeric serum IgA remained unchanged after TPN (19.2 vs. 22.1% polymeric). CONCLUSIONS: The use of TPN is not associated with intestinal immune dysfunction in man. A small, but statistically significant increase in serum IgM, and a borderline statistically significant increase in serum IgM were associated with TPN. The etiology and clinical significance of these observations is unclear.

Adult↗
PubMedDate not supplied

T-cell and neuronal apoptosis in HIV infection: implications for therapeutic intervention.

The pathogenesis of HIV infection involves the selective loss of CD4+ T cells contributing to immune deficiency. Although loss of T cells leading to immune dysfunction in HIV infection is mediated in part by viral infection, there is a much larger effect on noninfected T cells undergoing apoptosis in response to activation stimuli. In the subset of patients with HIV dementia complex, neuronal injury, loss, and apoptosis are observed. Viral proteins, gp120 and Tat, exhibit proapoptotic activities when applied to T cell and neuronal cultures by direct and indirect mechanisms. The pathways leading to cell death involve the activation of one or more death receptor pathways (i.e., TNF-alpha, Fas, and TRAIL receptors), chemokine receptor signaling, cytokine dysregulation, caspase activation, calcium mobilization, and loss of mitochondrial membrane potential. In this review, the mechanisms involved in T-cell and neuronal apoptosis, as well as antiapoptotic pathways potentially amenable to therapeutic application, are discussed.

Apoptosis↗
PubMed2002

Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood.

Telomere length can be used to predict the replicative capacity of haematological progenitor cells and may be an important prognostic factor for the onset of cellular immune dysfunction. However, such measurements require invasive bone marrow (BM) biopsies and laborious stem cell isolations that are impractical in a clinical setting. Previous studies have used peripheral blood (PB) cells as an indicator of stem cell telomere length without demonstrating a correlation. In this study, we examined the telomere length in PB, isolated mononuclear cells (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81 years. Correlation analysis confirmed that mean telomere length of BM aspirates was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001). Since BM is a heterogeneous population of cells, we have also shown in 13 separate patients that the mean telomere length in isolated peripheral blood stem cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r = 0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be determined from that of whole or fractionated PB in future studies of haematological disorders.

Adolescent↗
PubMed2004

Novel mutations and hot-spots in patients with purine nucleoside phosphorylase deficiency.

Purine nucleoside phosphorylase (PNP) deficiency results in severe immune dysfunction and early death from infections. Lymphopenia, reduced serum uric acid, and abnormal PNP enzymatic activity assist in the diagnosis of PNP-deficient patients. Analysis of the gene encoding PNP in these patients reveals several recurring mutations. Identification of these hot-spots for mutation may allow faster confirmation of the diagnosis in suspected cases.

CpG Islands↗
PubMed1985

Impaired measles virus-specific cytotoxic T cell responses in multiple sclerosis.

To assess whether an virus-specific immune defect may be associated with multiple sclerosis (MS), we have examined the ability to generate measles virus-and influenza virus-specific cytotoxic T cells (CTL) in patients with MS, normal individuals, and other disease controls (ODC). The mean (+/- SEM) measles virus-specific CTL response for normal individuals and ODC was 26.9 +/- 2.9% (N = 17) and 26.7 +/- 2.8% (N = 13) specific lysis, respectively. In contrast, the capacity of MS patients to generate measles virus-specific CTL was markedly diminished. Peripheral blood lymphocytes from MS patients stimulated with measles virus lysed their measles virus-infected autologous B cell line at a group mean level of 6.0 +/- 1.4% (N = 16) specific lysis. MS patients had significantly lower measles virus-specific CTL responses than normal individuals (p less than 0.00001) or ODC (p less than 0.0001). Importantly, this lowered response did not reflect a generalized depressed cytolytic activity of MS patients, since influenza virus-specific CTL and NK activity from these patients were comparable to normals and ODC. Thus, in MS there is a significant depression of measles virus-specific CTL which suggests that this virus-specific immune dysfunction may play a role in the pathogenesis of this disorder.

Adolescent↗
PubMed1989

Human gamma interferon strongly upregulates its own gene expression in peripheral blood lymphocytes.

The product of the human IFN-gamma gene was found to be a powerful upregulatory stimulus for its own gene expression in lectin-activated human PBMC. The INF-gamma autosuperinduction response was further enhanced by "priming" PBMC with IFN-gamma. Primed cells maximally upregulated their levels of IFN-gamma specific mRNA 4-fold faster and more than 20-fold higher than mock-stimulated cells. High mRNA levels persisted for several days after stimulation, and enhanced secretion of biologically active IFN-gamma paralleled the observed upregulation of gene expression. Producer cells demonstrating this response were found to be primarily localized to the rosette E- (leu 11+) fraction of PBMC and appear to be of the LGL/NK variety. Whether the autosuperinduction phenomenon occurs through direct or indirect effects of IFN-gamma on producer cells is still unclear. These results may be important both to an understanding of the pathogenesis of immune dysfunction and to the design of more effective immunotherapy.

Gene Expression Regulation↗
PubMed2005

Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma.

Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting l-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell-produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE2. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.

Animals↗
PubMed2001

Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma).

Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger syndrome, is an X-linked dominant and male-lethal disorder. We recently demonstrated that mutations in NEMO (IKK-gamma), which encodes a critical component of the NF-kappaB signaling pathway, were responsible for IP. Virtually all mutations eliminate the production of NEMO, causing the typical skewing of X inactivation in female individuals and lethality in male individuals, possibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutations in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both of which remove the zinc (Zn) finger at the C-terminus of the protein. Two deletion mutations were also identified in the same tract in additional families. However, only the duplication mutations allowed male individuals to survive, and affected female individuals with duplication mutations demonstrated random or slight skewing of X inactivation. Similarly, NF-kappaB activation was diminished in the presence of duplication mutations and was completely absent in cells with deletion mutations. These results strongly indicate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.

Amino Acid Sequence↗
PubMed2001

Discordant HHV8 detection in a young HIV-negative patient with Kaposi's sarcoma and sarcoidosis.

Human herpesvirus 8 (HHV8), which has been suggested as the causal agent of Kaposi's sarcoma (KS), has also been implicated in the pathogenesis of sarcoidosis. We describe a patient affected concomitantly by sarcoidosis and KS. HHV8 sequences were detected with PCR only on KS lesions, whereas sarcoid tissues did not harbor HHV8 DNA. Immune dysfunction related to sarcoidosis may have facilitated the oncogenic role of HHV8 and the development of KS.

Adult↗
PubMed2002

Abacavir hypersensitivity reaction.

A hypersensitivity reaction occurs in association with initiation of abacavir therapy as part of combination antiretroviral therapy in approximately 3.7% of patients. The reaction is possibly the result of a combination of altered drug metabolism and immune dysfunction, which is poorly understood. White patients appear to be at higher risk and patients of African descent at lower risk of abacavir hypersensitivity. Clinical management involves supportive measures and discontinuation of abacavir therapy. Rechallenge with abacavir in a hypersensitive patient should be avoided because it might precipitate a life-threatening reaction.

Anti-HIV Agents↗
PubMed2005

Treatment of intestinal helminths does not reduce plasma concentrations of HIV-1 RNA in coinfected Zambian adults.

BACKGROUND: Infection with intestinal helminths may stimulate dysfunctional immune responses in human immunodeficiency virus (HIV)-infected persons. Studies have yielded conflicting results regarding the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA.Methods. We conducted a prospective study of 54 HIV-1- and helminth-coinfected and 57 HIV-1-infected, helminth-uninfected asymptomatic adults living in Lusaka, Zambia, to assess the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA. RESULTS: Median baseline viral load was 0.33 log(10) copies/mL lower in the helminth-infected group than in the uninfected group. Mean viral load between pretreatment and posttreatment visits increased in the helminth-infected (mean, 4.23 vs. 4.29 log(10) copies/mL; P=.6) and helminth-uninfected (mean, 4.39 vs. 4.52 log(10) copies/mL; P=.2) groups. Helminth-infected participants with high pretreatment viral loads had a mean 0.25-log(10) copies/mL decrease after treatment (P=.3), and helminth-uninfected participants had a mean 0.02-log(10) copies/mL decrease (P=.8). CONCLUSIONS: We did not find an overall association between treatment of intestinal helminth infections and reduction in viral load in coinfected adults. Future studies may need to focus on adults with intense helminth infections who live in rural areas or on adults or children who harbor higher helminth burdens and plasma concentrations of HIV-1 RNA.

Adult↗
PubMed1987

Quantitative immunocytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages.

HIV infection of CD4-bearing lymphocytes alone does not fully explain the immune dysfunction of AIDS. Monocyte/macrophages infected with HIV may serve as a reservoir of HIV, may function abnormally and may transmit infection to other susceptible cells, thus playing a central role in the development of the immunodeficiency of AIDS. Quantitative analysis of surface antigens and measurement of HIV antigens in infected cells have been difficult using the conventional approach of immunofluorescent staining of cells on slides. We have developed a system that maintains monocyte/macrophages in suspension culture for at least four months. Through immunocytofluorographic single cell analysis we have shown that CD4 antigen is present on monocytes, and that a tenfold increase in expression occurs during the first two weeks in culture. In contrast, LeuM3 antigens decreased to background levels in the course of long-term culture. Using anti-HIV p24 antibody, we have demonstrated that monocyte/macrophages can be infected with HIV. Up to 70% of cells from individual donors could be infected. The techniques herein described allow in vitro quantitation of some of the mechanisms by which HIV infection of monocyte/macrophages may contribute to the immunodeficiency states associated with AIDS.

Antibodies, Monoclonal↗
PubMed1987

Transmission of HIV by antigen presenting cells during T-cell activation: prevention by 3'-azido-3'-deoxythymidine.

Tetanus toxoid (TT) reactive CD4+ cells were infected with HTLV-IIIB and exposed to TT at various times throughout a 7-day interval. Acute infection per se failed to produce overt cytopathology. However, exposure of infected cells to TT resulted in a rapid loss of cell viability, an increase in viral p24 expression, and a decline in T-cell blastogenesis. To determine whether HIV infection of antigen presenting cells (APC) could impact on T-cell activation, virus infected APC were utilized to present TT to responsive CD4+ cells. Use of infected APC produced effects similar to antigen stimulation of infected T-cells. These results suggest that the conditions of antigen presentation during T-cell activation may provide an excellent opportunity for virus transmission which may produce maximal immune dysfunction. However, preincubating antigen specific T-cells with the virostatic agent 3'-azido-3'-deoxythymidine (AZT) could prevent most of these effects.

Antigen-Presenting Cells↗
PubMed1991

Characterization of rhesus macaque B-lymphoblastoid cell lines infected with simian type D retrovirus.

A simian type D retrovirus designated SRV induces a fatal immunosuppressive disease in rhesus macaques. This syndrome shows many clinical similarities to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-infected individuals. To investigate the mechanisms of immune dysfunction in SRV infection, we have focused on the interactions of SRV serotype 1 (SRV-1) with macaque B-lymphoblastoid cell lines (B-LCL). Procedures were optimized for establishing B-LCL by immortalization of macaque B lymphocytes with rhesus Epstein-Barr virus (EBV). These cell lines express B-cell surface markers, secrete immunoglobulins of the IgG or IgM isotypes, and release EBV which transforms monkey B cells. In vitro cultures of B-LCL supported replication of SRV-1. Several B-LCL infected with SRV-1 showed downregulation of major histocompatibility complex (MHC) class II antigen expression whereas levels of MHC class I antigen remained unchanged. Infection of B-LCL with SRV-1 did not alter the level of secreted immunoglobulin. Rhesus EBV was also used to obtain B-LCL from macaques infected with SRV-1; these cell lines were found to release infectious SRV-1. Investigations on the interactions of SRV-1 with B cells will be useful for elucidating mechanisms involved in the immunopathogenesis of primate retroviruses.

Animals↗
PubMed1992

The dilemma of AIDS vaccine and therapy. Possible clues from comparative pathogenesis with measles.

AIDS viruses, because of their unique properties, are extraordinary. Past successes achieved with vaccines against ordinary viruses do not provide the guidelines needed to develop successful vaccines against HIV. Neither vaccines nor drugs can be relied upon to provide an answer to AIDS. AIDS is a disease of immune dysfunction and destruction, and an alternative to prevention of infection or cure might lie with elimination of the clinical consequences of infection. This might find a basis in precise definition of its pathogenesis. The enormity of possible pathogenetic changes in HIV infection invites simplification, and might be aided by a search for clues among ordinary viruses in which there is a less complicated biology and spontaneous recovery from infection. Measles virus infection presents analogies to AIDS, especially in the induction of anergy and increased mortality, in the long term, from diseases other than measles as observed in children infected during early life. This was demonstrated recently in increased deaths, all causes, during a three-year period among infants who were given live measles virus vaccine of high infectivity titer during early infancy, sometimes in the presence of maternal antibody. AIDS and measles may be diseases of similar pathogenesis, but with the difference that AIDS immunopathology is progressive while that for measles is regressive.

AIDS Vaccines↗