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Biomedical subjects

R M Victorino

Publications and source records attributed to R M Victorino.

At least 19 recordsLinked to original sources
PubMed2001

Comparison of the frequency of interleukin (IL)-2-, interferon-gamma-, and IL-4-producing T cells in 2 diseases, human immunodeficiency virus types 1 and 2, with distinct clinical outcomes.

Human immunodeficiency virus (HIV) type 2 infection is associated with a better clinical outcome, slower rates of CD4 T cell decline, and lower viremia than is HIV-1. This study compares HIV-1 and HIV-2 in regard to the percentages of interleukin (IL)-2-, interferon (IFN)-gamma-, and IL-4-producing cells at the single-cell level, as determined by flow cytometry. At a given degree of CD4 T cell depletion, the frequency of T cells able to produce IL-2 is better preserved in HIV-2 than in HIV-1 infection, particularly within the CD4 T cell subset. As described for HIV-1 immunodeficiency, HIV-2-positive patients exhibit a marked expansion of terminally differentiated effector CD8 T cells (CD28(-)CD27(-)IFN-gamma(+)). However, the proportion of CD8 T cells able to simultaneously produce IL-2 and IFN-gamma is higher in HIV-2 disease. Considering the central role of IL-2 as a lymphocyte proliferative and survival factor, these findings provide a possible immunologic basis for the distinct course of HIV-2 immunodeficiency.

Adolescent↗
PubMed2000

Marked immunosuppressive effects of the HIV-2 envelope protein in spite of the lower HIV-2 pathogenicity.

OBJECTIVE: HIV-1 envelope proteins have immunosuppressive properties and it is thought that they have a role in the establishment of immunodeficiency. This study characterizes the immunological effects of HIV-2 envelope protein gp105, a virus which is associated with a slower rate of disease progression. METHODS: The effects of recombinant baculovirus-expressed envelope proteins from HIV-IIIB HIV-1MN, HIV-2ROD and SIVmac251 on anti-CD3-stimulated peripheral blood mononuclear cells (PBMC) from healthy donors were evaluated by incorporation of 3H-thymidine, flow cytometric analysis of bromodeoxyuridine incorporation in different T cell subsets, kinetics of expression of costimulatory molecules (CD40L/OX40) and assessment of cell death by annexin V/propidium iodide staining. The effects on production of tumour necrosis factor alpha (TNF-alpha) by monocytes were assessed at the single-cell level after a 6 h culture of unstimulated PBMC. RESULTS: HIV-2 gp105 was more inhibitory than HIV-1 gp120 of T cell proliferation and the upregulation of CD40L and OX40; in the absence of signficant induction of apoptosis. This inhibition affected both CD4 and CD8 T cells and was only partially reversed by costimulation with interleukin 2 or CD28. gp105 strongly inducted TNF-alpha production by monocytes. CONCLUSION: The immunosuppressive properties of the HIV envelope proteins could be beneficial rather than detrimental to the host by interfering with the heightened state of immunocellular activation that characterizes HIV infection and by limiting the bursts of viral replication. This hypothesis could in part explain the slower decline of CD4 cell numbers in HIV-2 infection and deserves further exploration.

Apoptosis↗
PubMed2000

Bulk cytokine production versus frequency of cytokine-producing cells in HIV1 infection before and during HAART.

Cytokine imbalances play a major role in HIV immunopathogenesis. This study analyzes simultaneously the frequency of cytokine-producing cells at the single cell level by flow cytometry and the disturbances in cytokine secretion assessed by ELISA in a cohort of asymptomatic HIV1 patients in different stages of CD4 depletion and during antiretroviral therapy (HAART). Early in the disease, there is an increased frequency of IFN-gamma(+) lymphocytes and bulk IFN-gamma production, in parallel with a reduced proportion of IL4(+) cells and IL4 secreted. The two IL4 measurements are significantly correlated. No such correlation was found for IFN-gamma, which is consistent with a large variation in the amount of IFN-gamma released per individual cell. Moreover, HAART was associated with a reduction to normal levels in the bulk IFN-gamma secretion concomitant with a persistency of the overexpanded IFN-gamma(+) cell subset in the peripheral blood. This study emphasizes the importance of using a conjoint approach to assess the cytokine network in trials of antiretroviral and/or immune-based therapies to avoid missing significant effects which are possibly relevant in the clinical setting.

Adult↗
PubMed1999

Kinetics of the changes of lymphocyte subsets defined by cytokine production at single cell level during highly active antiretroviral therapy for HIV-1 infection.

The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets.

Adult↗
PubMed1999

Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery.

Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor superfamily with critical roles in T cell activation and death, B cell function, dendritic cell maturation and leucocyte traffic regulation. The aim of this study was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and Fas expression on freshly isolated peripheral blood T cells by three-colour flow cytometry and compare them with lymphoproliferative responses, peripheral blood cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially for 48 weeks. At baseline, patients exhibited significantly enhanced proportions and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load rebound during therapy in spite of increasing CD4 counts, the reduction of the levels of these costimulatory molecules was similarly maintained. Therapy induced a decrease in the over-expression of Fas, particularly in the CD4 subset where normal levels were reached at week 8. This reduction occurred in parallel with the major recovery of lymphoproliferative responses. Higher basal levels and lower reduction of Fas were associated with suboptimal suppression of viraemia. In conclusion, this previously undescribed increased expression of CD40L and OX40 may play a role in the HIV-associated pan-immune activation and represent a possible target for immunointervention, as suggested for several immunologically mediated diseases. Moreover, HAART induced an early correction of the over-expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the recovery of the cell traffic disturbances and in the T cell renewal capacity.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Single-cell analysis of lymphokine imbalance in asymptomatic HIV-1 infection: evidence for a major alteration within the CD8+ T cell subset.

In this study we investigated at single-cell level by flow cytometry the potential of T cell cytokine production in asymptomatic HIV-1-infected subjects with > 200 CD4 counts and possible correlation with T helper cell depletion and viral load. Mitogen-stimulated peripheral blood mononuclear cells from 32 HIV-1+ patients and 16 healthy subjects were intracytoplasmically stained for IL-2, interferon-gamma (IFN-gamma), IL-4 or IL-10, and the frequency of cytokine-producing cells was assessed in total T cells, CD4, CD8 and CD45RO subsets as well as in CD69+CD3+ gated lymphocytes. HIV-1+ patients, irrespective of their degree of CD4 depletion, exhibited a major increase in IFN-gamma+ CD8 T cells, largely due to CD28- cells, as well as a decrease in the capacity of CD8 T cells to produce IL-2. Patients with > 500 CD4 counts showed a diminished frequency of IL-4 expression in CD4 T cells and a negative correlation was found between this parameter and the ex vivo CD4 counts in the 32 patients. Analysis of patients stratified according to viral load revealed a significantly higher proportion of IL-2-producing CD4 cells in the group with < 5000 RNA copies/ml. In short, using single-cell analysis and an antigen-presenting cell-independent stimulus, we have not been able to find any significant cytokine imbalances in the CD4 subset, suggesting that the well described T helper defects are not due to intrinsic alterations in the potential of CD4 T cells to produce cytokines. On the other hand, the major disturbances in the CD8 T lymphocytes agree with the marked activation and possible replicative senescence of CD8 T cells and emphasize the role of this subset in HIV immunopathogenesis.

Adult↗
PubMed1997

Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis.

The objective of this study is to present and validate a clinical scale for the diagnosis of drug-induced liver injury (DILI). Five components were selected to be included in the scale: temporal relationship between drug intake and the onset of clinical picture, exclusion of alternative causes, extrahepatic manifestations, rechallenge or accidental re-exposure, and previous report in medical literature. The relative importance of each component was weighed, and arbitrary scores were attributed. The probability of the diagnosis of DILI was expressed as a final score, which could vary from -6 to 20. Content validity, criterion validity, construct validity, and inter-rater reliability were studied. To analyze validity and reliability, a random sample of 50 cases of suspected DILI was drawn from a series of 120 cases reported to our unit. The classification of the 50 cases by three experts in DILI was used as the external standard in the study of criterion validity. Agreement between the scale and the standard, and agreement between two independent raters (inter-rater reliability) was analyzed by weighted kappa coefficient. There was agreement between the scale and the standard in 42 cases (84%) with a weighted kappa coefficient of 0.90. A good discriminatory capacity of the scale was found when construct validity was studied. Agreement between raters was observed in 86% of the cases, corresponding to the weighted kappa of 0.93. In conclusion, the clinical scale was shown to have a high-level of validity and inter-rater reliability as well as a good discriminatory capacity between different levels of probability. These data suggest that the scale is suitable for use in clinical practice and may contribute to overcome the difficulties in the process of causality assessment in DILI.

Bias↗
PubMed1997

Effects of substance P on human T cell function and the modulatory role of peptidase inhibitors.

Evidence has been presented for a modulatory role of surface peptidases on substance P-mediated immune responses. In this study, we first characterized the effects of substance P and its carboxy- and amino-terminal fragments on human lymphocyte proliferative responses to investigate whether peptidase inhibitors influence the effects of the neuropeptide. Substance P at 10(-7) M and the carboxy-terminal fragment SP(4-11) slightly enhanced the lymphocyte responses to phytohemagglutinin and concanavalin A. In contrast, the amino-terminal fragment SP(1-4) failed to have any positive effect. However, in the presence of dipeptidylpeptidase IV/CD26 and neutral endopeptidase/CD10 inhibitors (diprotin A and thiorphan, respectively), the effect of substance P on mitogen-induced proliferation was significantly increased. These data support the hypothesis that lymphocyte surface peptidases play a modulatory role in the effects of substance P on T cell function.

Concanavalin A↗
PubMed1997

Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury.

BACKGROUND: Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC). AIM: To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor. PATIENTS: Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs. METHODS: Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by 3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI). RESULTS: When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI > 2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC. CONCLUSIONS: This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis.

Adult↗
PubMed1995

T-helper reactivity to simian immunodeficiency virus gag synthetic peptides in human immunodeficiency virus type 2 infected individuals.

West African populations are infected with divergent strains of human immunodeficiency virus type 2 (HIV2), some of which are closely related to simian immunodeficiency virus (SIV) and it has been postulated that the HIV2 epidemic might have arisen by cross-species spread of SIV into the human population in West Africa. To gain some insight into the possible basis for cross protection between these two closely related viruses, the T-helper responses to 15 synthetic peptides from SIV gag synthetic peptides were investigated in seven HIV2-infected subjects and in seven healthy controls. Significant reactivity to at least one of the synthetic peptides tested was found in all patients and a statistically significant correlation between CD4+ lymphocyte absolute numbers and the number of reacting peptides was observed. A marginal lymphocyte reactivity was found in two of the healthy controls studied. In conclusion, this preliminary evidence that HIV2-infected patients exhibit T-cell responses to SIV gag peptides suggests that both viruses share t-helper epitopes in the gag viral region and raises the possibility of cross protection between SIV and HIV2 which may be relevant for HIV2 vaccine research based on closely related retroviruses.

Acquired Immunodeficiency Syndrome↗
PubMed1995

[Cytomegalovirus-induced colitis in HIV infection. Considerations on its diagnosis, treatment and complications].

The diagnosis of cytomegalovirus intestinal disease in patients with HIV (human immunodeficiency virus) infection frequently raises diagnostic problems in view of the absence of definite pathological, serological or virological markers of active CMV infection. We describe the case of a 47-year-old man with a CMV colitis which illustrates several diagnostic and therapeutic problems and that was complicated by an intestinal perforation. We emphasize that in HIV+ patients with chronic diarrhea, the presence of abdominal pain should suggest the possibility of a CMV colitis and that in such cases a colonoscopy with biopsies of the right colon should be performed, in view of the higher frequency of the typical histopathological changes at this level. On the other hand, this case presented a marked thickening of the colon wall, simulating pseudotumoral images on CAT scans, as recently described in literature. The therapeutic possibilities as well as the complications of CMV colitis are discussed in the context of the occurrence of an ileal perforation, which represents the first report of this complication in Portuguese literature and which had the particularity of having a long survival after surgery in comparison with the previous cases described in international literature.

AIDS-Related Opportunistic Infections↗
PubMed1995

[The use of serological tests for detecting HIV infection in general clinical consultations and hospital consultations].

AIMS: To determine the number and type of HIV tests requested in general practice (GP) and in hospital outpatient clinics, to identify principle risk behaviors, to determine the percentage of HIV positive tests and to identify possible factors associated with the request of HIV tests. METHODS: Cross-sectional, analytical and observational study, involving 80 GPs and 45 hospital specialists in the region of Lisbon. All requests for HIV tests were analysed during a 12 month period. RESULTS: 936 HIV tests were requested, with a mean of 12.47 in GP and 0.69 in the hospital. Risk behaviors observed were mainly heterosexual contacts and intravenous drug abuse (IVDA). The motives of the requests mainly were pregnancy, risk behaviors in GP and the presence of symptoms suggesting HIV infection in the hospital. The initiative of the request came from doctors in 70% of the cases. The percentage of HIV positive tests (ELISA + Western blot) was 4.2% in GP and 32% in the hospital. According to risk behaviors, the percentage of seropositivity was 33% in homo/bisexuals, 13% in IVDA, 7% in heterosexuals with risk behaviors and 0.2% in individuals with unidentified risk behaviors. CONCLUSIONS: The patterns of request of HIV tests differ in hospital and in GP. In a significant percentage of cases, no informed consent was obtained prior to HIV testing, both in hospital and GP. This study may serve as an indicator of the need for information and education programs concerning HIV testing directed to health professionals and the general population.

Adult↗
PubMed1995

[Autoimmune hemolytic anemia and ulcerative colitis].

Although several associations of autoimmune disorders with ulcerative colitis have been reported, autoimmune hemolytic anemia is extremely rare. We report a case of a 35 year-old white woman with a twelve-year history of mild ulcerative colitis treated in the last 5 years with 5-amino-salycilic acid who developed a severe autoimmune hemolytic anemia. We discuss some particular aspects of the association of these two immunologically mediated disorders as well as the controversial aspects of autoimmune hemolytic anemia therapy in this context.

Adult↗