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Chapter: Essential Clinical Immunology: Immune Regulation


Chronic infections such as HIV and hepatitis C are characterized by an inability of the host to control viral replication.


Chronic infections such as HIV and hepatitis C are characterized by an inability of the host to control viral replication. The ability to potentiate the host immune response to control chronic infections is an important goal and is under active investi-gation. It has also been shown that at least some types of cancer can be controlled by the host immune system, so potentiation of the host immune system may prove useful in treating these cancers. There are three principal ways to potentiate the immune response in humans: through cytokines, adoptive immunotherapy, or vaccination

Cytokine Therapy

Interferons are antiviral glycoproteins, which are secreted as a result of a viral infection and have wide-ranging antitu-mor and immunomodulatory effects. They have attracted much interest as immuno-therapeutic agents. Interferons bind to cell surface receptors and activate secondary intracellular changes which inhibit viral replication. They can be divided into three groups: alpha (α), beta (β), and gamma

(γ) interferons. All three interferons have been genetically engineered, and recom-binant IFN-α, -β, and -γ are available, but IFN-α is the best studied. IFN-α is the treatment of choice for hepatitis B and C; when given systemically, it produces sig-nificant clearing of hepatitis B in chronic carriers. IFN-α has some side effects, mainly flu-like symptoms such as fever, malaise, and anorexia – all symptoms that can be tolerated. More severe effects are reversible: bone marrow depression, liver dysfunction, and cardiotoxicity.


IFN-β has been shown to be of benefit in patients with relapsing-remitting multiple sclerosis, and IFN-β1 appears to decrease the rate of progression of disability. Despite these results, the precise therapeutic role of IFN-β is still controversial.


IFN-γ is a potential activator of mac-rophages and is most often used in con-ditions in which defective macrophage function occurs. Examples of these disor-ders are lepromatous leprosy, leishmani-asis, and chronic granulomatous disease. IFN-γ works by increasing phagocytic bac-tericidal activity, but only some patients show enhanced superoxide activity, imply-ing that IFN-γ works by several different mechanisms.

IL-2 is produced by stimulated CD4 T cells and induces clonal expansion of IL-2+ T and B cells. is used in immunodeficiency states such as HIV infection where IL-2 production is defective. In patients with HIV infection and baseline counts of CD4 above 200 ml, intermittent IL-2 infusions have been shown to produce substantial and sustained increases in CD4 counts. IL-2 has side effects similar to IFN-α, with most of the effects being flu-like. The most seri-ous side effect is IL-2 action on IL-1, IFN-γ, and TNF, all mediators of vascular perme-ability, resulting in marked hypotension, pulmonary edema, and neuropsychiatric symptoms.

Adoptive Immunotherapy

Adoptive immunotherapies involve the transfer of either cells or antibodies into a host. These are also referred to as passive therapies, since the host does not actively mount its own immune response. Examples include infusion of hepatitis B immune globulin and the adoptive trans-fer of antigen-specific T lymphocytes to treat a chronic viral infection or cancer (see Gattinoni et al. 2006).


Prevention of infectious diseases depends on many factors. Foremost is the presence of a clean water supply, development of sanitary facilities, good nutrition, and good personal hygiene. More recently, immuni-zation against a particular agent has been the most effective measure in controlling infectious disease. Yet, with the emergence of new infectious agents such as hepatitis C and HIV, novel approaches will be needed to generate new and effective vaccines.


The two ways to achieve immunity are actively and passively. Active immunity is achieved when exposure to a foreign stim-ulus triggers an immunological response to the agent by the host. The best immunity to an agent is achieved by natural infection, which evolves with a clinical or subclinical response to the agent by the host. Artificial active immunization is the administration of an immunogen as a vaccine. Vaccines may be live organisms, killed organisms, or modified toxins. Although no vaccine is ideal and each has its problems, the

problems of live vaccines are generally related to their safety, while the problems of killed vaccines are related mainly to their effectiveness.


Live attenuated vaccines are useful because they infect, replicate, and immu-nize in a manner similar to natural infection but with milder clinical symptoms. Exam-ples include many of the childhood infec-tions such as measles, mumps, and rubella (MMR vaccine), chicken pox (varicella) and Bacille Calmette-Guérin (BCG) for tuberculosis. Although millions of doses have been administered with no complica-tions, if given to an immunocompromised host (such as primary immunodeficiency or secondary to HIV infection), these live vaccines may cause serious disease.


Killed vaccines consist of suspen-sions of killed organisms such as typhoid, cholera, and pertussis (although there is now an acellular vaccine) or one of the products or fractions of the organism. These include toxoids of diphtheria and tetanus and subunits of viruses such as surface hepatitis B antigen. Among the most successful of these types of vaccines has been the use of polysaccharides in the pneumococcal, meningococcal, andHaemophilus influenza vaccines. In general, the killed vaccines are not as effective as the live viruses because they do not give long-lasting immunity as a live infection does. For example, although the tetanus toxoid vaccine is effective, it requires a booster dose every ten years.


The immunological response to the killed organism or product thereof has been enhanced by the use of adjuvants. Although the most common adjuvant for animal studies has been the complete Freund’s adjuvant, it cannot be used in humans because it causes liver, skin, and spleen dys-function. The most common adjuvant for humans is aluminum compounds, which are generally safe for human use. Others include muramyl dipeptide, biodegradable polymers, and a glycoside adjuvant called Quil A from the bark of an Amazon oak tree. However, many others are being developed or will probably be given U.S. Food and Drug Administration (FDA) acceptance in the future. The key feature will be their immunogenic enhancement and their strength of safety for use in humans.

Although we have mainly been dis-cussing various forms of vaccination to protect against the invading organism, one of the most interesting new vaccines has not been developed to eliminate the infectious agent but rather to prevent the development of another far more serious disease – a complication of the initial infec-tion. This is the Gardisal vaccine manufac-tured by Merck to protect against human papilloma virus (HPV). HPV infection is usually sexually acquired, and it is esti-mated that currently 20 million people are infected in the United States. The infection has no real signs or symptoms, and HPV may lead to cervical cancer. It is estimated that ten of the thirty different serotypes of the virus can induce cervical cancer, so the vaccine has been directed at eliminat-ing those serotypes. Thus, if 10,000 women are infected with one of the high-risk viral serotypes, approximately 3,900 of them will die of cervical cancer. The new vac-cine, if given before active sexual activity in women, can prevent the viral infection and thereby markedly diminish the risk of cervical cancer. Because of the possible suc-cess of this vaccine, it may be worthwhile to look at how to prevent the Epstein-Barr virus in at-risk children to prevent or diminish the risk of Burkett’s lymphoma in children infected with the virus.

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