In the first category, the immune response is often partly responsible for the pathogenic effects. Infection by the helminth Schistosoma mansoni is associated with a powerful TH2-type response, characterized by high levels of IgE, circulating and tissue eosinophilia, and a harmful fibrotic response to schistosome ova in the liver, leading to hepatic fibrosis. Other common parasites, such as Plasmodium and Leishmania species, also cause damage in many patients because they are not eliminated effectively by the immune response. The mycobacterial agents of tuberculosis and leprosy cause a persistent intracellular infection; a TH1 response helps to contain these infections but also causes granuloma formation and tissue necrosis (see Fig. 11.13).
Among viruses, hepatitis B and hepatitis C infections are commonly followed by a persistent viral burden and hepatic injury, resulting in eventual death from hepatitis or from hepatocellular carcinoma. Infection with HIV, as we have seen in Chapter 13, also persists despite an ongoing immune response. In a preliminary trial involving HIV-infected patients, dendritic cells derived from the patients’ own bone marrow were loaded with chemically inactivated HIV. After immunization with the loaded cells, a robust T-cell response to HIV was observed in some patients that was associated with the production of IL-2 and IFN-γ (Fig. 16.29). Viral load in these patients was reduced by 80%,
Fig. 16.29 Vaccination with dendritic cells loaded with HIV substantially reduces viral load and generates T-cell immunity. Left panel: viral load is shown for a weak and transient response to treatment (pink); the red bar represents individuals who made a strong and durable response. Right panel: CD4 T-cell IL-2 and interferon-γ production for individuals who made a weak or strong response. The production of both these cytokines, indicating T-cell activity, correlates with the response to treatment.
Viral load weak response strong response weak response strong response weak response strong response IFN-˜(after 112 days of treatment) IL-2 Effect of dendritic-cell vaccination for HIV on immune function and virus production 0 1 2 3 4 5 0 10,000 20,000 30,000 40,000 50,000 Percentage of HIV-specifc CD4 cells expressing cytokine and in almost half of these patients the suppression of viremia lasted for more than a year. Nonetheless, these responses were not sufficient to eliminate the HIV infection.
In the second category of chronic infection, which is predominantly viral, the immune response fails to clear the infection because of the relative invisibility of the infectious agent to the immune system. A good example is herpes simplex virus type 2, which is transmitted venereally, becomes latent in nerve tissue, and causes genital herpes, which is frequently recurrent. The invisibility of this virus seems to be caused by a viral protein, ICP-47, that binds to the TAP complex (see Section 6-3) and inhibits peptide transport into the endoplasmic reticulum in infected cells. Thus, viral peptides are not presented to the immune system by MHC class I molecules. A similar example in this category of chronic infection is genital warts, caused by certain papilloma viruses that evoke very little immune response, particularly a cell-mediated response. As discussed previously, the results of a recent clinical trial showed that using long-peptide vaccines against HPV-16 was effective in increasing the strength of cell-mediated immune responses to viral antigens, and in reducing or eliminating precancerous lesions associated with the HPV infection (see Section 16-28). These results are a positive indication that vaccines directed at increasing cell-mediated responses to other pathogens may be similarly effective.
Summary.