The overall balance of published clinical results following 8 yr of development shows disappointing results in therapeutic areas where the greatest expectations were first hypothesized. However, such a negative statement is largely subsided by the most recent breakthrough in life-saving conditions. It is rather bewildering to note that clinical efficacy was better ascertained in the very areas where pathophysiological rationale was the most hypothetical. Conversely, asthma, which was the indication where PAF antagonists have been largely predicted to be an ideal drug, is now of much less interest. Indications, such as “prevention of acute tubular necrosis following kidney transplant” and “prevention of mortality in gram-negative documented severe sepsis,” could appear far away from each other. However, these indications are consistent with a common hypothesis, which is that PAF acts as an amplifier of the local inflammatory/immune response, although its precise interaction with other mediators (cytokines, integrins, nitric oxide [NO]) and the exact timing of sequences in the various pathological processes remain elucidated. Also, the actual limit of the potential therapeutic interest of PAF antagonists is that clinical manifestations of inflammation will still require a number of years to be elucidated, together with the potential benefit of coadministration with other drugs.

The great number of PAF antagonists reviewed in this article clearly shows the tremendous effort made in the last 20 yr to explore the complex biological background of the mechanism of action of PAF and the potential clinical benefit of its antagonists. It is obvious that now highly potent, long-acting, and perorally applicable PAF-receptor antagonists are developed, and available for preclinical and clinical research. Another important fact is that the progress in the biochemical research designed to explore the structure of PAF receptors is impressive. This work has been expected to answer numerous questions concerning the tissue specificity of several PAF antagonists. For example, among the synthetic hetrazepine PAF-receptor antagonists developed by the Beaufour-IPSEN group, BN 50727 exhibits higher efficacy in the gastrointestinal tract (67) than in other tissues; alternatively, BN 50730 exerts more potent effect in the lung (66) than in other organs. At the present state of knowledge, the interpretation of these differences is unclear. Better knowledge about the PAF-receptor structure in the gastrointestinal tract may shed more light on the background of drug-receptor interactions responsible for tissue specificity. This may lead to more successful clinical development of PAF receptor antagonists in the near future.

Platelet-activating factor (PAF) is a phospholipid mediator tha t exhibits diverse and potent effects on many cell types. In addition, these cell types possess the capability to synthesize PAF when stimulated in vitro. However, considerable quantities of PAF produced are retained within the cells, suggesting tha t this autacoid may act both as an intracellular and an extracellular mediator. PAF has also been implicated in various immunological manifestations through the regulation of cell-derived mediators. In this chapter, we focus on the role of PAF in regulating cell-derived cytokines in inflammatory responses.

Autoimmune diseases are conditions in which damage to body organs results from the presence of autoantibodies or autoreactive cells (1). Autoantibodies are the hal lmark of autoimmune diseases. Most autoimmune diseases are characterized by the production of autoantibodies and autoantibodies are often used as markers of these diseases (1). In autoimmune diseases, autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequence of tissue damage, or the footprints of an etiologic agent. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by a spontaneous production of a wide range of autoantibodies directed against constituents of nearly all cells, including the cell nucleus, notably anti-DNA antibodies. Antibodies to DNA were first described in the sera of SLE pa t ien t s in 1957 (2,3). Soon it became evident t h a t the lupus erythematosus (LE) cell phenomenon described in 1948 by Hargraves et al. (4), is caused by antibodies tha t react with constituents of the cell nucleus (5). Antibodies directed agains t DNA may bind to double-stranded (ds, native) or single-stranded (ss, denatured) DNA.

AECA represent a new family of autoantibodies detectable in systemic autoimmune diseases. Different findings support their poten-tial importance both from a diagnostic and a prognostic point of view: 1. AECA do not seem to be a mere epiphenomenon; 2. Are not related to a polyclonal B-cell activation; 3. React with surface endothelial antigens; 4. Correlate with disease activity; 5. In some cases behave as an indirect marker of in vivo endothelial damage; 6. Correlate with disease activity; and 7. In vitro experiments support a possible pathogenetic role in sus-taining autoimmune vasculitis.

ANCA are now established to be of considerable value as a tool to support the diagnosis of certain vasculitides and for monitoring disease activity. Further research is needed to clarify whether ANCA have a pathogenetic role in these diseases, and it will be interesting to study both ANCA positive and negative patients with seemingly identical diseases to clarify whether ANCA may have prognostic significance and thus be useful for the classification of vasculitis.