Biomedical subjects

Dag Kvale

Publications and source records attributed to Dag Kvale.

8 recordsLinked to original sources

PubMed2006

[Immunopathogenesis and therapeutic immunization in HIV-infection].

BACKGROUND: Modern antiretroviral treatment has improved the prognosis in chronic HIV-infection dramatically during the last decade; but the treatment is expensive, the drugs are toxic, and viral resistance is a problem. An alternative approach is therapeutic immunization. This treatment aims to improve the patients' own HIV-specific immune responses and thereby control the HIV-infection and suppress disease progression. MATERIAL AND METHODS: The article reviews therapeutic immunization in chronic HIV-infection, provides a brief overview of the immunopathogenesis of AIDS, and is partly based on studies performed at Ullevål University Hospital. RESULTS AND INTERPRETATION: Although different strategies for immune modulation in HIV-infection have shown to induce good, HIV-specific immune responses, there has been no definite documentation of clinical benefit so far. The most promising results have been obtained by immunizing patients with injections of virus-stimulated autologous dendritic cells, demonstrating a significant reduction of the viral load. The method is complex and therefore only feasible for individualised therapy in highly specialized clinics. At Ullevål University Hospital, we have in collaboration with Bionor Immuno recently conducted studies with a therapeutic immunization candidate Vacc-4x. Vacc-4x improves HIV-specific immune responses by stimulating skin dendritic cells with HIV-like peptides. Provision of efficient therapeutic immunization methods in chronic HIV-infection seems to be more realistic now than a few years ago. These methods may postpone and even reduce the need for antiretroviral treatment, and might also be beneficial if used as prophylactic immunization.

AIDS Vaccines↗

PubMed2006

Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment.

OBJECTIVES: To examine the immune modulating effects of cyclooxygenase type 2 (COX-2) inhibitors (COX-2i) in HIV-infected patients on combination antiretroviral treatment (CART). DESIGN: In-depth substudy from an approved, open, controlled, randomized study comparing the immune modulating effects of CART in combination with COX-2i after 12 weeks. METHODS: Patients (n = 38) on long-term CART with stable viral load (VL) < 50,000 copies/ml and CD4+ T-cell counts > 100/microl were randomized to CART and rofecoxib 25 mg bid (n = 12) or celecoxib 400 mg bid (n = 12), or CART only without placebo (n = 14). Routine clinical chemistry, CD4+ and CD8+ counts and VL were safety parameters. Immunological parameters included C-reactive protein, beta2-microglobulin, Ig isotypes and IgG subclasses as well as several T-lymphocyte subsets. Non-parametric analyses were used throughout. RESULTS: Prestudy experiments showed higher median intracellular expression of COX-2 in CD4+ (P = 0.048) and possibly CD8+ (P = 0.09) T cells from patients on CART compared with uninfected controls. In the clinical study, increased CD4+ T-cell counts were observed only in patients on COX-2i with VL < 50 copies/ml (P = 0.02). Decreased expression of CD38+ on CD8+ T cells and subsets as well as reductions in IgA and IgM (P < 0.03) were most pronounced in patients on COX-2i who had detectable VL (n = 6). COX-2i treatment enhanced the perforin content particularly in the differentiated CD27-/CD8+ T-cell subsets compared with controls (P = 0.05). CONCLUSIONS: COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.

ADP-ribosyl Cyclase 1↗

PubMed2006

Long-term HIV-specific responses and delayed resumption of antiretroviral therapy after peptide immunization targeting dendritic cells.

Long-term HIV-specific immune responses and clinical outcomes were evaluated in HIV-infected patients previously immunized with p24-like peptides (Vacc-4x) targeting dendritic cells (DC). Vacc-4x-induced cellular immune responses were unchanged 1.5 years after completing immunization, and 62% were still off combined antiretroviral treatment (CART). The magnitude of early Vacc-4x responses determined whether the resumption of CART was clinically indicated 2 years after enrollment. These observations encourage further exploration of both Vacc-4x and other HIV peptide-based immunization regimens targeting DC.

AIDS Vaccines↗

PubMed2005

Multiple antigen concentrations in delayed-type hypersensitivity (DTH) and response diversity during and after immunization with a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

Delayed-type hypersensitivity (DTH) testing represents a simple in vivo method for monitoring cellular immune responses. In a phase II clinical trial on HIV-infected patients (n = 38) of the peptide-based HIV-1 immunotherapy candidate Vacc-4x, we monitored DTH responses to three antigen concentrations of Vacc-4x. We have shown that DTH can be used quantitatively to measure immune reactions to Vacc-4x and its individual peptide components. Our data stress the qualities and differences of induration and erythema, both in discriminating individual antigens and in monitoring immunizations over time. The data also indicate that DTH baseline-status might have important impact on immunization kinetics.

AIDS Vaccines↗

PubMed2005

Reduced viral burden amongst high responder patients following HIV-1 p24 peptide-based therapeutic immunization.

We have previously shown that HIV p24-like peptides (Vacc-4x) via activation of skin dendritic cells induced immune responses in 90% of HIV patients on highly active antiretroviral treatment (HAART). These patients (n=38) were here subjected to a final 14-week interruption of HAART. Patients with the highest delayed type hypersensitivity (DTH) responses to Vacc-4x-peptides before treatment interruption tended to achieve lower actual HIV RNA levels at the end of the study compared to Vacc-4x DTH low-responders (p=0.08) and significantly so in terms of viral loads relative to their individual pre-HAART HIV RNA set-points (p=0.04). CD4+ lymphocyte counts were maintained only among DTH high responders but decreased in the other patients during recurrent viremia (p</=0.02). No other pre-study differences in HIV history or p24-responses were found.

AIDS Vaccines↗

PubMed2005

Divergent in vitro and in vivo correlates of HIV-specific T-cell responses during onset of HIV viraemia.

BACKGROUND: Cellular immune responses to HIV-1 have been examined mainly in peripheral blood mononuclear cells (PBMC). During onset of HIV replication and antigenaemia after discontinuation of highly active antiretroviral therapy (HAART), PBMC may theoretically contain HIV-specific T cells that are qualitatively and quantitatively different from specific T cells dominating in the tissues. PBMC responses throughout HIV immunotherapy trials may therefore be skewed during recurrent viraemia. OBJECTIVE: To compare cellular HIV-specific in vitro responses in PBMC during onset of HIV viraemia with corresponding in vivo responses, represented by classical delayed-type hypersensitivity tests (DTH). METHODS: HIV patients (n = 38), pre-immunized with four HIV-1 p24-like consensus peptides (Vacc-4x) during HAART, were subjected to a 14-week treatment interruption with recurrent HIV viraemia. Proliferative T-cell responses to Vacc-4x p24 peptides, HIV p24 protein, and cytomegalovirus (CMV) proteins were measured in PBMC. Corresponding Vacc-4x peptide DTH were expressed as skin infiltrate areas after 48 h. RESULTS: After 14 weeks without HAART, HIV-1 RNA increased to 72,500 copies/ml (median). The Vacc-4x p24 peptide- and HIV-1 p24 protein-induced T-cell proliferation concurrently decreased by 81 and 93% in PBMC during viraemia (medians, P < or = 0.03), whereas proliferative responses to CMV antigens were stable. In contrast, the Vacc-4x DTH areas, rather tended to increase by 36% (P = 0.08) and contained infiltrates dominated by proliferating T cells and macrophages. CONCLUSIONS: Divergent in vitro and in vivo HIV-specific cellular immune responses were found during recurrent HIV viraemia. The clinical relevance of both surrogate markers for HIV-related immune responses should be compared in future studies.

AIDS Vaccines↗

PubMed2005

Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host disease.

BACKGROUND AND OBJECTIVES: Bone marrow (BM) and blood stem cell (BSC) allografts differ considerably with respect to their content of progenitor cells and progenitor cell subsets as well as mature lymphocytes. The aim of this prospective, randomized study was to determine whether these differences have an impact on early post-transplant immune recovery. DESIGN AND METHODS: In a prospective randomised study, we found enhanced immune recovery in recipients of BSC allografts compared to in recipients of BM allografts despite transplantation of a lower number of lymphoid progenitors, particularly B-cell progenitors. The large number of mature lymphocytes in BSC allografts is a plausible explanation for this observation. At the progenitor cell level, we found a comparable and very high proportion of progenitor cells involved in lymphopoiesis in both study groups. RESULTS: Patients with extensive chronic GVHD, irrespective of the allograft received, had low immunoglobulin (Ig) levels in serum, low B-cell counts in blood and low numbers of B-cell progenitors in the bone marrow. They also showed high T-cell counts, particularly CD3+CD8+ T-cell counts, which was paralleled by a high number of T-cell progenitors in the bone marrow. In patients with extensive chronic GVHD we found low natural killer (NK)-cell counts which has not been reported previously. INTERPRETATION AND CONCLUSIONS: Early immune recovery is enhanced following BSC allografting compared with BM allografting. This is plausibly explained by the large inoculum of mature lymphocytes in BSC allografts. Following allografting, a higher proportion of the BM progenitor cell compartment is involved in lymphopoiesis than it is in healthy adults. However, B-lymphopoiesis is inhibited in patients with extensive chronic GVHD resulting in impaired B-cell recovery. These patients also seem to show impaired NK-cell recovery.

Adolescent↗

PubMed2004

HLA- and dose-dependent immunogenicity of a peptide-based HIV-1 immunotherapy candidate (Vacc-4x).

OBJECTIVE: The Vacc-4x immunotherapy candidate is composed of four modified peptides corresponding to conserved domains of the HIV-1 protein p24 that preferentially include HLA-A2 restricted elements. Dose-dependent safety and immunogenicity of Vacc-4x and the significance of a HLA-A2 haplotype were examined. DESIGN: Non-AIDS, HIV-1 infected healthy patients (n = 40) stable on HAART with CD4 counts > 300 x 10 cells/l were randomized to receive either low-dose or high-dose Vacc-4x over 26 weeks in an open, prospective phase II clinical trial. METHODS: Patients received a total of 10 intradermal injections, using recombinant granulocyte-macrophage colony stimulating factor as a local adjuvant. Vacc-4x-specific cellular responses were monitored in vivo by delayed-type hypersensitivity (DTH) skin test infiltrates and in vitro by both T-cell proliferation, and induction /secretion of cytokines. RESULTS: Most patients developed Vacc-4x-specific DTHs (90%) and proliferative T-cell responses (80%) that were inter-related in magnitude. High-dose Vacc-4x generally induced stronger specific immune responses than low dose in terms of DTH areas and CD4 and CD8 T-cell proliferation. Only HLA-A2 negative patients had a definite dose advantage, and this subgroup had in fact the best overall DTH and proliferative responses. In contrast, no significant dose difference was observed for HLA-A2 positive patients. No serious adverse events were reported. CONCLUSIONS: HIV-associated specific responses were safely induced in most patients by Vacc-4x in a dose-dependent manner and were also influenced by the HLA haplotype.

AIDS Vaccines↗