BCG (Bacille Calmette-Guérin) HspCs (heat-shock protein-peptide complexes) induce T-helper 1 responses and protect against live challenge in a murine aerosol challenge model of pulmonary tuberculosis.

The need for an effective TB (tuberculosis) vaccine remains acute, with tuberculosis still one of the major killers worldwide and 3 million new infections annually. We report here on the immune responses elicited by HspCs (heat-shock protein-peptide complexes) isolated from BCG (Bacille Calmette-Guérin) vaccine. These HspCs elicit both the appropriate cellular and protective immune responses required to merit their further development as TB vaccine candidates.

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be 'blind' to tumours, thereby challenging the theory of immune surveillance.

Towards a unified theory of immunity: dendritic cells, stress proteins and antigen capture.

In less than a decade, the archetypal view that the immune system exists primarily to distinguish "self" from "non-self" has been replaced by the paradigm that the immune system functions primarily to distinguish dangerous from non-dangerous antigens. This change is in part due to the recent reassertion of the importance of so-called innate immunity, which consists of non-specific components of the immune system such as macrophages that are active prior to exposure to antigens (In contrast, so-called acquired immunity depends upon the generation of B and T lymphocytes that are produced after exposure to the antigens and are specific for the antigens). The paradigm shift is also due to the recent proposal of the "danger model" of the immune system, which provides a conceptual mechanism by which the immune system might distinguish dangerous from non-dangerous antigens. The role of dendritic cells (DCs) in activating T lymphocytes is key to both innate immunity and the danger model. The purpose of this commentary is to add an additional piece to the emerging picture of immune-system function by suggesting that heat-shock, or stress, proteins play a central role in the activation of T lymphocytes by DCs. The uptake of stress proteins--whose expression is induced by monokines in the earliest phases of the innate immune response--by DCs might constitute a "danger" signal. However, through such a mechanism, DCs may capture antigens bound to stress proteins and improve their ability to present the antigens to other components of the immune system, such as cytotoxic T-cells. Invoking stress proteins to amplify the immune response in this manner can explain how animals can mount an effective primary immune response to an antigen despite having few T lymphocytes specific for that antigen. Finally, the "affinity-maturation" of antibody following a primary immune response would enable the much more efficient, specific antigen-capture by high affinity antibodies in a secondary immune response, resulting in a rapid and specific response or "memory" on re-exposure to the pathogen.

The role of the Maillard reaction in other pathologies: Alzheimer's disease.

Many approaches have and are being undertaken to treat Alzheimer's disease but, as yet, no therapy is available with any established efficacy. Given the heterogeneity of the aetiological factors involved in Alzheimer's disease and the difficulties encountered in the clinical diagnosis, the lack of pharmacological success is not surprising. Furthermore, the lack of an adequate animal model of Alzheimer's disease has delayed the development of novel therapeutic strategies. At present, and with the exception of the rarer forms of familial Alzheimer's disease, the need remains to treat the symptoms rather than the causes of the disease, primarily because the pathogenesis of Alzheimer's disease is still unknown. The evidence for the role of glycation and advanced glycation end-products (AGEs) in the formation of neurofibrillary tangles and neuritic plaques, the characteristic histopathological lesions of Alzheimer's disease, is briefly reviewed. While the role of glycation in the pathogenesis of Alzheimer's disease is not yet unequivocally proven, it is the only single protein modification that would explain the formation of both the characteristic histopathological lesions first described by Alois Alzheimer in 1907. With our improved understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the aetiological causes will afford more suitable targets for therapeutic intervention. In this respect it is interesting to note that the anti-inflammatory compounds indomethacin and acetylsalicylic acid, both inhibitors of the Maillard reaction, have been reported to have therapeutic potential and the nootropic agent tenilsetam inhibits protein cross-linking by AGEs.

Glycation: a pathological modification in neuropathies?: a hypothesis.

A common feature of a number of neuropathies is the formation of characteristic histopathological lesions of neural amyloid. Although the major components of many of these lesions have been identified, the nature of the modifications of these normal cellular proteins that lead to amyloidogenesis remains elusive. The purpose of this article is to introduce the hypothesis that protein glycation might account for the modifications of normal cellular proteins leading to amyloid formation neuropathogenesis.

Atherosclerosis and glycation.

Atherosclerosis is the major cause of death in the industrialised world. Though much work on the pathogenesis of atherosclerosis points to 'oxidised' low density lipoprotein (LDL) as a key aetiological feature in the generation of the atherosclerotic plaque, the nature of this 'oxidised' LDL in vivo remains an enigma. We argue here that glycated LDL shows many of the characteristics attributed to 'oxidised LDL' and may be the source of the latter in vivo. These include the increased uptake and impaired degradation of glycated LDL by macrophages and the stimulation of transendothelial chemotaxis of monocytes, cytokine secretion and platelet aggregation. We hypothesise that the covalent binding of glycated LDL to the endothelial cell wall may result in the formation of the early atherosclerotic lesion of the fatty streak and that apolipoprotein E may mediate the physiological clearance of glycated moieties. The proposed role of glycation in the pathogenesis of atherosclerosis would explain its high incidence among diabetics and the contentious epidemiological and experimental correlations between dietary sugar and atherosclerosis.

The requirements for activation of an antigen specific T-cell clone via the CD3 complex.

We have studied the requirements for the activation of the haemagglutinin peptide specific cloned T-cell HA1.7 by anti-CD3 antibodies and the mechanism of modulation of the CD3 complex. Cross-linking of the complex either by a soluble antibody second layer or an immobilized matrix of antibody is necessary for induction of a proliferative response. This proliferative response is totally dependent on exogenously added IL-2. Modulation of the cross-linked CD3 complex is by patching, capping and internalization of the antigen and is not essential for the proliferative response.

An alternative strategy for therapy of AIDS; a cure?

Present therapeutic strategies in AIDS require continuous treatment. The recognition of the major contribution of an 'autoimmune' component to the pathology of the disease opens up the possibility of ablation of specific T-cell sets as a means of preventing and reversing the disease.

Inositol is a constituent of detergent-solubilized immunoaffinity-purified rat liver 5'-nucleotidase.

myo-Inositol analysis of detergent-solubilized immunoaffinity-purified rat liver 5'-nucleotidase showed the presence of 1 mol of myo-inositol/mol of enzyme monomer. This provides unequivocal evidence that the ectoenzyme 5'-nucleotidase is attached to liver membranes by a glycosyl-phosphatidylinositol lipid anchor.

Involvement of spectrin in cell-surface receptor capping in lymphocytes.

Human and mouse lymphocytes of T- and B-cell lineages express a protein (Mr, 240,000) that crossreacts with antibodies raised against chicken erythrocyte alpha-spectrin as judged by immunofluorescence, immunoprecipitation, and immunoautoradiography; by the same criteria, antibodies raised against chicken erythrocyte beta-spectrin do not react with any lymphocyte polypeptide. In all T and B cells analyzed, before surface-directed ligand challenge with concanavalin A and surface immunoglobulins the polypeptide antigenically related to erythrocyte alpha-spectrin is distributed diffusely at the plasma membrane. Upon challenge, the redistribution of this polypeptide is concurrent with that of the cell-surface receptors initially in patches and then in a cap. Immunoprecipitation of NaDodSO4-solubilized lymphocytes with erythrocyte alpha-spectrin antiserum shows that in all cases a polypeptide with the same apparent molecular weight as erythrocyte alpha-spectrin is precipitated. Variable amounts of another polypeptide (Mr, 235,000) are also coimmunoprecipitated. Immunoprecipitations and subsequent immunoautoradiography show that the lymphocyte polypeptide doublet has a composition similar to that of (brain) fodrin, a polypeptide doublet that previously has been found mainly in the cells of nervous tissue.