Human inflammatory diseases

Therapeutic Interventions in Human Inflammatory Diseases - A Cautionary Note 108... 

Multiple new series of CCR2 small molecule antagonists have been described in the recent patent and peer-reviewed literature. Importantly, the diversity of structural classes recognized as CCR2 antagonists has increased. These chemical advances should allow the scientific community to test adequately the hypothesis that CCR2 plays a key role in human inflammatory disease. 

Future studies will no doubt further assess the utility of viral chemokine inhibitors in other models of inflammation. It is interesting that products derived from pathogenic viruses hold substantial promise for the treatment of human inflammatory diseases. 

Table 3. Clinical trials involving helminth infections of patients with defined human inflammatory diseases...

Finally, I hope that this book whets the appetite for the reader, whether in academia or industry, to explore opportunities for exploiting pathogens for the discovery of new processes in irmnunobiology and, ultimately, for development of new therapies for human inflammatory diseases. 

Mason, D. (1991) Genetic variation in the stress response susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today 12, 57-60. 

Biologicals. Figure 4 Licensed human vaccines. From Immunity Immune Response in Inflammatory Disease by DeFranco, Locksley and Robertson [2]. 

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

In addition to the NOD mouse, Entelos has models for several human metabolic diseases (diabetes, obesity, and metabolic syndrome), inflammatory diseases (rheumatoid arthritis), and respiratory diseases (asthma and COPD). 

Human chronic inflammatory diseases are characterized by populations of cells with altered regulation and function. A large body of evidence suggests that many of these cellular abnormalities may be linked to an increase in the production of free radicals and/or deficiencies of antioxidant defence systems. Oxygen free radicals attack cell structures, altering their function, and are cytotoxic. They have therefore been implicated in the pathogenesis of rheumatoid arthritis as well as many other human diseases (HaUiwell, 1991). 

There is now considerable evidence suggesting a role for free radicals in the pathogenesis of inflammatory diseases and in the development of cancer. However, the effect of benefit from specific antioxidants in human disease remains to be established. Until this is done, the question of whether free radicals are yet just another inflammatory mediator, or whether their role is more central to the understanding of disease, remains open. 

Another interesting observation is that exposure of DNA to OH can render the DNA antigenic, an observation perhaps relevant to the formation of anti-DNA antibodies in some human chronic inflammatory diseases (Blount etal., 1992 Alam etal., 1993). 

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Damage to connective caused by leakage of elastases leads to damage associated with inflammatory diseases, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, carcinogenesis, chronic bronchitis, and rheumatoid arthritis. Compounds that directly inhibit elastase or its release from human neutrophils are of enormous pharmaceutical and cosmetological interest in the development of new anti-inflammatory drugs. A possible source for elastase inhibitors are the medicinal Asteraceae and Droseraceae, particularly those used as traditional medicine in Asia. 

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