Compound E5 (Nanjing University)

Major histocompatibility complex (MHC) class II antigens are expressed on human foreskin keratinocytes (HFKs) following exposure to interferon gamma. The expression of MHC class II proteins on the cell surface may allow keratinocytes to function as antigen-presenting cells and induce a subsequent immune response to virus infection. Invariant chain (Ii) is a chaperone protein which plays an important role in the maturation of MHC class II molecules. The sequential degradation of Ii within acidic endocytic compartments is a key process required for the successful loading of antigenic peptide onto MHC class II molecules. Since human papillomavirus (HPV) 16 E5 can inhibit the acidification of late endosomes in HFKs, the E5 protein may be able to affect proper peptide loading onto the MHC class II molecule. To test this hypothesis, HFKs were infected with either control virus or a recombinant virus expressing HPV16 E5 and the infected cells were subsequently treated with interferon-gamma. ELISAs revealed a decrease of MHC class II expression on the surface of E5-expressing cells compared with control virus-infected cells after interferon treatment. Western blot analysis showed that, in cells treated with interferon gamma, E5 could prevent the breakdown of Ii and block the formation of peptide-loaded, SDS-stable mature MHC class II dimers, correlating with diminished surface MHC class II expression. These data suggest that HPV16 E5 may be able to decrease immune recognition of infected keratinocytes via disruption of MHC class II protein function.

The role of the pharmacist in defining and implementing criteria for selection of patients who are most likely to benefit from monoclonal antibody therapy is discussed. The introduction of new biotechnology products has raised concerns about rationing of health-care services, particularly in view of the costs of drug research and development. Traditional antimicrobial therapy has not reduced morbidity and mortality from gram-negative sepsis. Early clinical trials indicate that immunotherapy with new agents that supplement the host immunological response to these infections may be effective. Criteria must be developed to identify patients who will obtain maximum benefits from these newer interventions. Severity-stratification systems (e.g., the APACHE II scoring system) have been used to classify disease and monitor treatment outcome. These techniques have been applied in clinical trials assessing E5 monoclonal antibody therapy in patients with gram-negative sepsis and in others evaluating the use of imipenem versus tobramycin and clindamycin in the treatment of intraabdominal infection. Pharmacists with a knowledge of infectious-disease processes and pharmacotherapeutics can play a major role in developing criteria for identifying patients who are most likely to benefit from the products of biotechnology and thereby ensuring the cost-effective use of these products.