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Justin Stebbing

Publications and source records attributed to Justin Stebbing.

At least 73 records · Page 4Linked to original sources
PubMed2004

Nadir B cell counts are significantly correlated with the risk of Kaposi's sarcoma.

Infection with HIV-1 is known to impair B cell function. To further elucidate the role of B cells during infection and tumorigenesis, we studied their numbers in cases of AIDS-related Kaposi's sarcoma (KS) during the HAART era. Patients with AIDS-related KS were identified from a database of 4,480 HIV-1 positive individuals and the incidence of KS and rate ratio was stratified according to nadir number of B cells, measured as the CD19 count. In an unadjusted model, we observed that lower B cell counts were associated with a statistically significant increased risk of KS development (p < 0.001). We also observed a trend toward increased counts during KS resolution. When adjusted for nadir CD4 count in a multi-variable model, higher B cell counts were protective against KS development (p = 0.015). These data highlight a potential role for B cells and therefore the humoral immune system in KS aetiopathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed2004

The evidence-based treatment of AIDS-related non-Hodgkin's lymphoma.

As we enter the third decade of the AIDS epidemic, it is apparent that a large number of cancers are more common in people with the human immunodeficiency virus type 1 (HIV). Non-Hodgkin's lymphoma (NHL) remains the second most common tumour in such patients. At the onset of the epidemic, dose-intense combination regimens were used but these were quickly abandoned in favour of dose-modified strategies because of difficulties in tolerating aggressive chemotherapy in the presence of underlying immunosuppression. With the improvements in supportive care including more effective anti-retroviral therapies, colony-stimulating factors and prophylaxis against opportunistic infections, we are returning to the traditional chemotherapeutic approaches similar to those utilised in the non-HIV infected individual including infusional regimens. In this review, we discuss the evidence for choosing particular therapies in patients with AIDS-related NHL.

Administration, Oral↗
PubMed2004

Kaposi's sarcoma as a model for cancer immunotherapy.

Physicians have, for over a century, attempted to harness the potential therapeutic power of the immune system to treat patients with cancer. The discovery that cancer regression can be achieved by immune rejection of tumour antigens theoretically allows the eradication of neoplastic cells without toxicity to normal tissues. An understanding of the mode of presentation of tumour antigens, including those complexed to heat shock proteins by major histocompatibility complex (MHC) class I and class II molecules, and their recognition by CD8(+) and CD4(+) T cells, respectively, has further delineated the potential cancer rejection pathways involved. This also enables the sustained induction and expansion of specific anti-tumour T cells with cytolytic activity.

Animals↗
PubMed2004

Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients.

There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV) co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial. We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4 count, HIV-1 RNA viral load and therapy, to HIV-1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Th1 cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1 alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.

Adult↗
PubMed2004

Resolution of AIDS-related Castleman's disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels.

A 32-year-old HIV-1 positive man was diagnosed with Castleman's disease following a long history of constitutional symptoms. Primary therapy with single agent rituximab was associated with a near complete response. During this time, his KSHV (Kaposi's sarcoma-associated herpesvirus) viral load decreased and we also observed immediate, large and sustained decreases in interleukin-6 (IL-6) and tumor necrosis factor-alpha levels (TNF-alpha). This highlights the close association between circulating cytokines such as IL-6 and virally-induced malignancy.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Antigen presentation and the role of dendritic cells in HIV.

PURPOSE OF REVIEW: As initiators of primary immune responses and one of the first cell types encountered and infected by HIV, the role of dendritic cells in retroviral infection has been the subject of intense scrutiny. We review recent publications regarding the effect of HIV-1 infection on the numbers and function of dendritic cells, as well as progress in the use of dendritic cells in immunotherapeutic protocols. RECENT FINDINGS: The numbers of both plasmacytoid and myeloid dendritic cells in the blood are reduced during HIV-1 infection. The ability of dendritic cells to stimulate T-cell proliferation is impaired, probably as a result of defective co-stimulatory molecule expression. In addition, a decreased production of IFN-alpha may reflect the loss or dysfunction of plasmacytoid dendritic cells. There is evidence that dendritic cells may promote the induction of peripheral tolerance to self peptides, and HIV may utilize this function of dendritic cells to inhibit the immune response. The data on improvements in dendritic cell numbers and function during antiretroviral therapy are conflicting, whereas current vaccine initiatives involving pulsing dendritic cells with virus proteins, infected apototic or whole inactivated virions is proving a useful tool in the induction, expansion and maintenance of antiviral cell-mediated immunity. SUMMARY: This review summarizes the current literature regarding the effects of HIV on the dendritic cell populations, with particular interest in understanding how the function of dendritic cells is affected by HIV infection.

Antigen Presentation↗
PubMed2004

Lessons for HIV from Tuskegee.

We are fortunate to live in an era in which research allows significant progress in the therapy of the major diseases that affect us. However, evaluating their efficacy and safety is expensive, laborious and involves the study of human subjects in an appropriate manner. The principles of such trials have a heterogeneous basis encompassing the principles of utilitarianism, distributive justice, the protection of individual rights and the investigators' commitment to patients. The Tuskegee study of untreated syphilis is the longest non-therapeutic experiment on human beings in medical history. It continues to cast its shadow on the relationship between black Americans and the broader biomedical community. Parallels and the relationship with the HIV pandemic are discussed.

Anti-Bacterial Agents↗
PubMed2003

An open-label assessment of TMC 125--a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance.

UNLABELLED: The development of resistance to any of the currently licensed non-nucleoside reverse transcriptase inhibitors (NNRTI) invariably leads to cross-resistance to the drugs in that class. New NNRTI, that have the promise of being active even when such 'signature' mutations are present, are in development. Such novel therapies could be effective after current NNRTI failure as there would probably be no cross-resistance. We assessed the short-term efficacy and safety of a next generation NNRTI, TMC 125, a diarylpyrimidine derivative that has in vitro activity against NNRTI resistant HIV-1. TMC 125 was studied in HIV-1 infected patients with high-level phenotypic NNRTI resistance in an open-label phase IIa trial. METHODS: Sixteen individuals receiving an NNRTI-containing antiretroviral regimen (efavirenz or nevirapine) with an HIV-1 RNA viral load of > 2000 copies/ml and phenotypic resistance to NNRTI, received TMC 125 for 7 days, as a substitute for their current NNRTI in their failing therapy. Full pharmacokinetic profiles were investigated. FINDINGS: The primary end point--viral load decay rate per day--was 0.13 log10 RNA copies/ml per day. Over 7 days, we observed a median 0.89 log10 decrease in HIV-1 viral load; seven individuals (44%) had a decrease of > 1 log10. The most significant adverse effects were grade I diarrhoea (31%) and a mild headache (25%). Steady-state drug levels were achieved by day 6. INTERPRETATION: TMC 125, a next generation NNRTI, is well tolerated and demonstrates significant and rapid antiviral activity in patients with high levels of phenotypic NNRTI resistance to current NNRTI.

Adult↗
PubMed2003

All for CD91 and CD91 for all.

Heat shock proteins interact with antigen-presenting cells through their receptor, CD91, eliciting a cascade of events including maturation, activation and representation of chaperoned foreign peptides with class I molecules on their surface. In turn, this facilitates recognition of non-self leading to induction of a cytotoxic T cell response. The abundance of heat shock proteins in tumours and their presence in virion coats makes them attractive propositions for use in antitumour and antiviral strategies.

Animals↗
PubMed2003

Antibody-targeted MHC complex-directed expansion of HIV-1- and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination.

The ability of therapeutic vaccines to generate large numbers of CD8+ T lymphocytes that have specificity for HIV-1 or other virally infected cells has enormous potential clinical value. However, approaches to produce cytotoxic T lymphocytes (CTLs) in vivo via vaccine technology have thus far been disappointing and the ex vivo production of cells for adoptive transfer is labor intensive and expensive. We describe the results of a 2-step antibody-targeting system for the production of CD8+ T lymphocytes specific for HIV-1 and Kaposi sarcoma-associated herpesvirus (KSHV), suitable for use in vivo. In 8 consecutive human leukocyte antigen-A2 (HLA-A2)-positive HIV-1-infected individuals with Kaposi sarcoma, 2 cycles of this system resulted in more than 1 Log increases of specific anti-HIV and anti-KSHV CD8+ lymphocytes. These expanded cells have an effector phenotype that includes the ability to produce interferon-gamma and CD45Ra+/CD69+ staining. We have shown that antibody-targeted B cells can function as effective antigen-presenting molecules and lead to sustained specific T-lymphocyte expansion from peripheral blood mononuclear cells (PBMCs) of immunosuppressed individuals. This approach, which offers an easy and effective protocol for the amplification of specific antiviral and antitumor CTLs, may offer significant advances for in vivo T-cell immunotherapeutic protocols.

Antigens, CD↗
PubMed2003

Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.

Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.

Antiretroviral Therapy, Highly Active↗
PubMed2003

A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma.

OBJECTIVE: To determine the incidence of Kaposi's sarcoma (KS) in a prospective longitudinal cohort of HIV-1-infected individuals before during and after the introduction of highly active antiretroviral therapy (HAART) and to compare the incidence of KS between specific HAART regimens. DESIGN: Univariate and multivariate analysis of 8640 HIV-1-infected individuals. METHODS: The protective effect of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) on the development of KS was examined in prospectively recorded data to determine whether treatments based on the two types of drug were comparable with regard to a reduction in the incidence of KS. RESULTS: A total of 1204 patients with KS were identified. The incidence of KS decreased from 30/1000 patient-years prior to 1995 to 0.03/1000 patient-years in 2001. Multivariate analysis showed that age, nadir CD4 cell count and antiretroviral class exposure were significant independent predictors of KS. NNRTI-based HAART (adjusted rate ratio, 0.42; 95% confidence interval 0.24-0.37) had a similar protective effect to PI-based HAART (adjusted rate ratio, 0.47; 95% confidence interval 0.38-0.58). Most patients who develop KS on HAART [30/35 (86%)] had evidence of virological treatment failure. CONCLUSION: PI- and NNRTI-based HAART regimens are equally effective as protection against KS. This is the first study to demonstrate a decreased incidence of an AIDS-defining disease with NNRTI-based therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor.

The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma-associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1-infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.

Acquired Immunodeficiency Syndrome↗