Springer Seminars in Immunopathology

CGD is a rare inherited immunodeficiency syndrome, caused by the phagocytes' inability to produce (sufficient) reactive oxygen metabolites. This dysfunction is due to a defect in the NADPH oxidase, the enzyme responsible for the production of superoxide. It is composed of several subunits, two of which, gp9lphox and p22phox, form the membrane-bound cytochrome b558, while its three cytosolic components, p47phox p67phox and p40phox, have to translocate to the membrane upon activation. This is a tightly and intricately controlled process that involves, among others, several low-molecular weight GTP-binding proteins. Gp91phox is encoded on the X-chromosome and p22phox, p47phox and p67phox on different autosomal chromosomes, and a defect in one of these components leads to CGD. This explains the variable mode of inheritance seen in this syndrome. Clinically CGD manifests itself typically already at a very young age with recurrent and serious infections, most often caused by catalase-positive pathogens. Modern treatment options, including prophylaxis with trimethoprim-sulfamethoxazole and rIFN-γ as well as early and aggressive anti-infection therapy, have improved the prognosis of this disease dramatically. CGD, as a very well-characterized inherited affection of the hematopoietic stem cells, is predestined to be among the first diseases to profit from the advances in cutting-edge therapeutics, such as gene therapy and in utero stem cell transplantation.

The clarification of the precise locus within HLA responsible for at least the majority of the MHC-encoded susceptibility has allowed insights into the pathogenesis of RA which could have therapeutic implications. The HLA-DR molecules associated with RA (DR4Dw4, DR4Dw14, DR4Dw15, DR1 and DRw10) have shared epitopes which are likely to influence their ability to bind and present particular antigenic peptides to T lymphocytes. It appears likely, therefore, that a disease-related antigen which can be bound and presented preferentially by these susceptibility molecules is responsible for triggering the disease in the great majority of cases. However, it is clear that environmental or chance events are of fundamental importance to the development of RA and that other genes contribute significantly to both susceptibility and progression of the disease. Based on what we now know of the HLA-related susceptibility, we can develop therapeutic strategies based on blocking the immune response at the HLA/peptide/TCR level. By designing high affinity-binding peptides or other molecules which bind preferentially to those HLA-DR molecules associated with RA, particularly DR4Dw4 and DR4Dw14, competitive blocking of the antigen-binding site may be achieved and the abnormal immune response abolished. This approach has recently been outlines in the mouse EAE model [92]. Alternatively, if it can be shown that a limited TCR repertoire is involved in recognising the diseasecausing peptide/HLA configuration, it may be possible to achieve the same effect with monoclonal antibodies against the variable regions on the TCR. The former approach would have effect on immune recognition mediated by DRβ but this could be limited by local application within the synovial joints. In contrast, blocking specific T cell clones offers the exciting possibility of highly specific immunosuppressants for RA. Finally, if other genes involved in susceptibility and progression of RA can be identified, this may allow further insights into the pathophysiology of the disease. This may directly lead to further novel therapeutic possibilities and the eventual eradication of this common disease.

The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1β has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

Rheumatoid arthritis (RA) is well known to be a chronic autoimmune/inflammatory disease which leads to progressive joint damage and destruction. Less well known is the fact that in severe cases of RA, with extra-articular manifestations and multiple joint involvement, there is also a significant reduction in life expectancy [28]. Hence the need for new therapeutic agents. With the cloning of cDNAs encoding cytokines in the early to mid 1980s, it became possible to use new assays to evaluate cytokine expression in the local site of autoimmunity, the rheumatoid synovium. There were two goals. First would understanding cytokine expression help us understand the pathogenesis of RA? Secondly, would it be possible to learn enough about the cytokine network to establish possible therapeutic targets? While a complete understanding of either of these questions remains elusive, here we review the state of knowledge in early 1998, which shows that much progress has been made and that these goals have been partly reached. The clinical benefits of this knowledge are documented elsewhere in this compilation, as is the role of chemokines, anti-inflammatory cytokines and the cytokines involved in neovascularisation.

Recombinant vesicular stomatitis virus (rVSV) is currently under evaluation as a human immunodeficiency virus (HIV)-1 vaccine vector. The most compelling reasons to develop rVSV as a vaccine vector include a very low seroprevalence in humans, the ability to infect and robustly express foreign antigens in a broad range of cells, and vigorous growth in continuous cell lines used for vaccine manufacture. Numerous preclinical studies with rVSV vectors expressing antigens from a variety of human pathogens have demonstrated the versatility, flexibility, and potential efficacy of the rVSV vaccine platform. When administered to nonhuman primates (NHPs), rVSV vectors expressing HIV-1 Gag and Env elicited robust HIV-1-specific cellular and humoral immune responses, and animals immunized with rVSV vectors expressing simian immunodeficiency virus (SIV) Gag and HIV Env were protected from AIDS after challenge with a pathogenic SIV/HIV recombinant. However, results from an exploratory neurovirulence study in NHPs indicated that these prototypic rVSV vectors might not be adequately attenuated for widespread use in human populations. To address this safety concern, a variety of different attenuation strategies, designed to produce a range of further attenuated rVSV vectors, are currently under investigation. Additional modifications of further attenuated rVSV vectors to upregulate expression of HIV-1 antigens and coexpress molecular adjuvants are also being developed in an effort to balance immunogenicity and attenuation.