A randomised trial of subcutaneous intermittent interleukin-2 without antiretroviral therapy in HIV-infected patients: the UK-Vanguard Study

Objective: The objective of the trial was to evaluate in a pilot setting the safety and efficacy of interleukin-2 (IL-2) therapy when used without concomitant antiretroviral therapy as a treatment for HIV infection. Design and Setting: This was a multicentre randomised three-arm trial conducted between September 1998 and March 2001 at three clinical centres in the United Kingdom. Participants: Participants were 36 antiretroviral treatment naive HIV-1-infected patients with baseline CD4 T lymphocyte counts of at least 350 cells/mm(3). Interventions: Participants were randomly assigned to receive IL-2 at 15 million international units (MIU) per day ( 12 participants) or 9 MIU/day ( 12 participants) or no treatment ( 12 participants). IL-2 was administered by twice-daily subcutaneous injections for five consecutive days every 8 wk. Outcome Measures: Primary outcome was the change from baseline CD4 T lymphocyte count at 24 wk. Safety and plasma HIV RNA levels were also monitored every 4 wk through 24 wk. The two IL-2 dose groups were combined for the primary analysis. Results: Area under curve (AUC) for change in the mean CD4 T lymphocyte count through 24 wk was 129 cells/mm(3) for those assigned IL-2 ( both dose groups combined) and 13 cells/mm(3) for control participants (95% CI for difference, 51.3 - 181.2 cells/mm(3); p = 0.0009). Compared to the control group, significant increases in CD4 cell count were observed for both IL-2 dose groups: 104.2/mm(3) ( p = 0.008) and 128.4 cells/mm(3) ( p = 0.002) for the 4.5 and 7.5 MIU dose groups, respectively. There were no significant differences between the IL-2 (0.13 log(10) copies/ ml) and control (0.09 log(10) copies/ml) groups for AUC of change in plasma HIV RNA over the 24-wk period of follow- up ( 95% CI for difference, - 0.17 to 0.26; p = 0.70). Grade 4 and dose-limiting side effects were in keeping with those previously reported for IL-2 therapy. Conclusions: In participants with HIV infection and baseline CD4 T lymphocyte counts of at least 350 cells/mm(3), intermittent subcutaneous IL-2 without concomitant antiretroviral therapy was well tolerated and produced significant increases in CD4 T lymphocyte counts and did not adversely affect plasma HIV RNA levels

Immunomagnetic t-lymphocyte depletion (ITLD) of rat bone marrow using OX-19 monoclonal antibody

Graft versus host disease (GVHD) may be abrogated and host survival prolonged by in vitro depletion of T lymphocytes from bone marrow (BM) prior to allotransplantation. Using a mouse anti-rat pan T-lymphocyte monoclonal antibody (0×19) bound to monosized, magnetic, polymer beads, T lymphocytes were removed in vitro from normal bone marrow. The removal of the T lymphocytes was confirmed by flow cytometry. Injection of the T-lymphocyte-depleted bone marrow into fully allogeneic rats prevents the induction of GVHD and prolongs host survival. A highly efficient technique of T-lymphocyte depletion using rat bone marrow is described. It involves the binding of OX-19, a MoAb directed against all rat thy-mocytes and mature peripheral T lymphocytes, to monosized, magnetic polymer spheres. Magnetic separation of T lymphocytes after mixing the allogeneic bone marrow with the bead/OX-19 complex provides for a simple, rapid depletion of T lymphocytes from the bone marrow. In vitro studies using flow cytometry and the prevention of GVHD in a fully allogeneic rat bone marrow model have been used to demonstrate the effectiveness of the depletion procedure. © 1989 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

High Interleukin-6, Low Cd4+ and Cd8+ T-lymphocytes Expressions as Risk Factors of Cervical Carsinoma Infected by Human Papilloma Virus Type-52

In Indonesia cervical carcinoma is the most common cancer in women and one of the leading cause of mortality. High risk human papillomavirus (HPV) is the major risk factor of cervical cancer. This study aims to know the role of IL-6, CD4+ and CD8+ T-lymphocyte for the risk of cervical carcinoma infected by HPV52. This study was a case control study, specimens of cervical carcinoma patients infected by HPV type-52 as the case group and HPV type-16 or 18 as the control group. HPV genotyping used SPF10 primer and type specific E7 primer by LiPA. Immunohistochemistry method was used to know expression of IL-6, CD4+ and CD8+ T lymphocyte. Pearson's c2 test was applied with statistical significance was set at the 2-sided 0.05 level. The odds ratios (OR) were calculated for the risk, with 95% confidence intervals on SPSS 16.0 for windows. PCR examination was performed in 185 paraffin-embedded tissue. The risk of high IL-6 expression in cervical carcinoma infected by HPV type-52 was statistically significant 6-fold higher compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05) and HPV type 18 (OR = 6.00 ; CI 95% = 1.13-31.99; p = 0.03; p < 0.05). The risk of low CD4+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 6-fold higher and 7.43-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 6.00 ; CI 95% = 1.003-35.91; p = 0.04; p < 0.05) and HPV type 18 (OR = 7.43 ; CI 95% = 1.23-45.01; p = 0.02; p < 0.05). The risk of low CD8+ T lymphocyte expression in cervical carcinoma infected by HPV type 52 was statistically significant 13.5-fold higher and 11-fold higher respectively compare with cervical carcinoma infected by HPV type 16 (OR = 13.50 ; CI 95% = 1.42-128.26; p = 0.01; p < 0.05) and HPV type 18 (OR = 11.00 ; CI 95% = 1.16-103.94; p = 0.02; p < 0.05). No significance different between cases and controls group in mean-age, parity and sexual activity (p > 0.05). In conclusion, this study found that high IL-6 expression, low CD4+ and CD8+ T lymphocyte expression were the risk factors of cervical carcinoma infected by HPV type 52

Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes

Although the relative contribution of different immune effector functions to clearing tissues of cytomegalovirus is controversial, the contribution of CD8+ T lymphocytes has generally been accepted as essential. In this report, we show that under certain conditions the CD8+ T-lymphocyte subset can be dispensable for clearance of cytomegalovirus. Mice depleted of the CD8+ T-lymphocyte subset eliminated infectious virus with a clearance kinetics similar to that of normal mice. Adoptive transfer studies revealed that the limitation of virus spread required the cooperation between the CD4+ subset and other cells. Comparison between protective functions generated in fully immunocompetent and in CD8- mice demonstrated that elimination of the CD8+ subset before infection altered the quality of the antiviral immune response. The compensatory protective activity gained by CD4+ cells in CD8- mice was absent in normal mice recovering from virus infection

The cytolytic T lymphocyte response to the murine cytomegalovirus

Limiting dilution (LD) analysis with two modifications, the expansion and the restimulation LD assay, led to the detection and quantification of two distinct in vivo maturation stages within the lineage of virus- specific self-restricted CTL after infection of mice with the murine cytomegalovirus (MCMV). A low frequency set, representing an average of 15% of the specifically activated CTL-P in a draining lymph node, generated virus-specific lytic activity in the absence of antigen, solely under expansion conditions provided by growth and differentiation interleukins. These cells were considered to be active and were denoted antigen-independent or interleukin-receptive CTL-P (IL- CTL-P). A high frequency set required additional antigen in vitro to generate functionally active clones, and therefore the cells were termed antigen-dependent. Both sets are present in vivo simultaneously at the peak of the acute immune response and represent antigen- activated cells because their existence strictly depends on a preceding priming event. IL-CTL-P disappear quickly after acute infection and are absent during the memory state. It is proposed that the isolation of IL- CTL-P could serve to detect viral antigen expression during persistent and/or recurrent herpes virus infections

T-cell responses in oiled guillemots and swans in a rehabilitation setting

This article has been accepted for publication in the Archives of Environmental Contamination and Toxicology. The final version can be accessed from the link below.This article has been made available through the Brunel Open Access Publishing Fund.Aquatic birds are commonly affected by oil spills. Despite rehabilitation efforts, the majority of rehabilitated common guillemots (Uria aalge) do not survive, whereas mute swans (Cygnus olor) tend to have higher post-release survival. Polyaromatic hydrocarbons (PAHs) present in crude oil and diesel are immunotoxic in birds affecting cell-mediated responses to immunogens. Because it is a target of PAH toxicity, T-lymphocyte response to controlled mitogen administration (phytohemagglutinnin test) was investigated in a scoping study as a potentially useful minimally invasive in vivo test of cell-mediated immunity. The test was performed on 69 mute swans and 31 common guillemots stranded on the Norfolk and Lincolnshire coastline and inland waterways in England (UK)either due to injury or to contamination with crude or diesel oil. T-lymphocyte response was significantly decreased in swans with greater oil scores. T-lymphocyte responses were also decreased in guillemots, but this finding was not statistically significant

Anti-CTLA-4 (CD 152) monoclonal antibody-induced autoimmune interstitial nephritis

Targeted immune-modulating agents are entering clinical practice in many specialties, providing novel therapeutic possibilities but introducing new potential toxicities. We present the first reported case, to our knowledge, of immune-mediated nephritis following the administration of Tremelimumab (CP-675, 206), an anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody. High-dose steroid therapy led to a rapid improvement in renal function, avoiding the need for renal replacement therapy.Peer reviewe

In vitro immunosuppressive effects of FR 900506 on human T lymphocyte alloactivation

FR 900506 (FR) is a new immunosuppressive drug which prolongs allograft survival. Our studies have compared the in vitro inhibitory effects of FR and cyclosporine (CsA) on human lymphocyte proliferation. Considerably lower doses of FR were required to induce inhibition of lymphocyte proliferation induced by concanavalin A (Con A) stimulation or in primary mixed lymphocyte reactions (MLR). Similar differences between FR and CsA were observed with the secondary stimulation of alloactivated T cells generated in MLR or propagated from liver transplant biopsies. These observations provide further evidence that FR is about 500 fold more potent than CsA and may be a useful immunosuppressive agent in organ transplantation