Designing the next-generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures

In the mid-90s, hepatitis B virus (HBV)-directed immune responses were for the first time investigated in detail and revealed suboptimal T-cell responses in chronic HBV patients. Based on these studies, therapeutic vaccination exploiting the antigen presentation capacity of dendritic cells to prime and/or boost HBV-specific T-cell responses was considered highly promising. Now, 25 years later, it has not yet delivered this promise. In this review, we summarise what has been clinically tested in terms of antigen targets and vaccine forms, how the immunological and therapeutic effects of these vaccines were assessed and what major clinical and immunological findings were reported. We combine the lessons learned from these trials with the most recent insights on HBV antigen presentation, T-cell responses, vaccine composition, antiviral and immune-modulatory drugs and disease biomarkers to derive novel opportunities for the next generation of therapeutic vaccines designed to cure chronic HBV either alone or in combination therapy

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Po

Design of TLR2-ligand-synthetic long peptide conjugates for therapeutic vaccination of chronic HBV patients

Synthetic long peptide (SLP) vaccination is a promising new treatment strategy for patients with a chronic hepatitis B virus (HBV) infection. We have previously shown that a prototype HBV-core protein derived SLP was capable of boosting CD4+ and CD8+ T cell responses in the presence of a TLR2-ligand in chronic HBV patients ex vivo. For optimal efficacy of a therapeutic vaccine in vivo, adjuvants can be conjugated to the SLP to ensure delivery of both the antigen and the co-stimulatory signal to the same antigen-presenting cell (APC). Dendritic cells (DCs) express the receptor for the adjuvant and are optimally equipped to efficiently process and present the SLP-contained epitopes to T cells. Here, we investigated TLR2-ligand conjugation of the prototype HBV-core SLP. Results indicated that TLR2-ligand conjugation reduced cross-presentation efficiency of the SLP-contained epitope by both monocyte-derived and naturally occurring DC subsets. Importantly, cross-presentation was improved after optimization of the conjugate by either shortening the SLP or by placing a valine-citrulline linker between the TLR2-ligand and the long SLP, to facilitate endosomal dissociation of SLP and TLR2-ligand after uptake. HBV-core SLP conjugates also triggered functional patient T cell responses ex vivo. These results provide an import step forward in the design of a therapeutic SLP-based vaccine to cure chronic HBV

Functional aspects of the adaptive immune system in arthritis

The adaptive immune system is the part of the immune system that is highly specific and generates memory resulting in a fast and specific immune response upon a second infection with the same pathogen. However, when this response is specific for a part of the body itself instead of a pathogen, inflammation and autoimmune disease can develop. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints leading to cartilage and bone destruction. This thesis focused on the role of the adaptive immune system in the development, treatment and diagnosis of rheumatic disorders. The cells of the adaptive immune system play a pivotal role in the development of RA as cross-reactive CD4+ T cells can provide help to B cells which subsequently produce autoantibodies leading to autoantibody-positive RA. They can be a target in therapy as the biological Abatacept inhibits activation of T-cells, however, it potentially targets several players of the adaptive immune system making it an effective treatment strategy. Cells of the adaptive immune system can also be very useful as biomarker or to monitor response to therapy, which makes them very interesting players in the development of new treatment strategies for arthritis.</p

Functional aspects of the adaptive immune system in arthritis

The adaptive immune system is the part of the immune system that is highly specific and generates memory resulting in a fast and specific immune response upon a second infection with the same pathogen. However, when this response is specific for a part of the body itself instead of a pathogen, inflammation and autoimmune disease can develop. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints leading to cartilage and bone destruction. This thesis focused on the role of the adaptive immune system in the development, treatment and diagnosis of rheumatic disorders. The cells of the adaptive immune system play a pivotal role in the development of RA as cross-reactive CD4+ T cells can provide help to B cells which subsequently produce autoantibodies leading to autoantibody-positive RA. They can be a target in therapy as the biological Abatacept inhibits activation of T-cells, however, it potentially targets several players of the adaptive immune system making it an effective treatment strategy. Cells of the adaptive immune system can also be very useful as biomarker or to monitor response to therapy, which makes them very interesting players in the development of new treatment strategies for arthritis.LUMC / Geneeskunde Repositoriu

Functional aspects of the adaptive immune system in arthritis

The adaptive immune system is the part of the immune system that is highly specific and generates memory resulting in a fast and specific immune response upon a second infection with the same pathogen. However, when this response is specific for a part of the body itself instead of a pathogen, inflammation and autoimmune disease can develop. Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joints leading to cartilage and bone destruction. This thesis focused on the role of the adaptive immune system in the development, treatment and diagnosis of rheumatic disorders. The cells of the adaptive immune system play a pivotal role in the development of RA as cross-reactive CD4+ T cells can provide help to B cells which subsequently produce autoantibodies leading to autoantibody-positive RA. They can be a target in therapy as the biological Abatacept inhibits activation of T-cells, however, it potentially targets several players of the adaptive immune system making it an effective treatment strategy. Cells of the adaptive immune system can also be very useful as biomarker or to monitor response to therapy, which makes them very interesting players in the development of new treatment strategies for arthritis.</p

Anti-carbamylated protein antibodies are present in mice with collagen induced arthritis

Pathophysiology and treatment of rheumatic disease

Altered composition and phenotype of mucosal-associated invariant T cells in early untreated rheumatoid arthritis

Pathophysiology and treatment of rheumatic disease

Tolerogenic dendritic cells impede priming of naïve CD8(+) T cells and deplete memory CD8(+) T cells

Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+) T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+) T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8(+) T cells, however, remains unknown. To investigate the interaction of CD8(+) T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+) T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8(+) T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+) T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+) T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+) T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+) T-cell immunity. Yet, Combi-DCs pulsed with CD8(+) T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies.Transplantation and autoimmunit