Immunotherapy for Infectious Diseases
Immunotherapy for Infectious Diseases Immunotherapy for Infectious Diseases
Principles of Vaccine Development 131 Fig. 1. Intracellular events leading to generation of class II-peptide complex expressed on the surface of professional antigen-presenting cells (APCs). After internalization, a vaccine is digested within endosomes of APCs. Class II molecules are synthesized in the endoplasmic reticulum (ER) as a trimeric complex made up of �, �, and invariant chains. It migrates to endosomes where the invariant chain is partially degraded and a short peptide called CLIP remains attached to class II molecules. After CLIP is released, DM functions as a chaperone that stabilizes the empty class II molecule, allowing the binding of peptides derived from degradation of foreign protein to class II empty molecules. Another molecule called DO stabilizes the class IIpeptide complex, which is then pulled to the membrane, where it may be recognized by CD4 T-cells. hsps, heat shock proteins. 5. It should be devoid of side effects. 6. The manufacturing should be inexpensive. CLASSICAL AND NEWLY DEVELOPED VACCINES Inactivated Vaccines The development of inactivated vaccines resulted from the development of methods to grow microbes and to purify the toxins. The preparation of inactivated vaccines is based on a golden rule emerging from Pasteur and Ramon’s studies leading to preparation of anti-rabies and toxoid vaccines, respectively: a vaccine should be devoid of pathogenicity but should preserve intact its immunogenicity.
132 Bona Fig. 2. Intracellular mechanisms leading to generation of class I-peptide complex. Endogenous proteins are degraded by lysosomes and the resulting peptides are translocated to the endoplasmic reticulum (ER) by transporter protein (TAP) molecules. In the ER, the peptides are released from TAP by chaperons such tapasin, calreticulin, and calexin and then bind to the heavy chain of class I molecules, which in turn bind � 2-microglobulin (� 2m). The class I-peptide complex is then transferred via a Golgi secretory pathway to the membrane, where it is recognized by CD 8 T-cells. The killing of bacteria can be achieved by physical means (heat) or by chemical agents. For example, currently used influenza and Salk polio vaccines are produced by inactivation with formalin. Similarly, the conversion of toxins to toxoids was obtained by treatment with formalin. Table 2 lists currently used inactivated vaccines. Immunity Inactivated vaccines can induce only a humoral response. Functional antibodies are produced subsequent to recognition by the Ig receptor of B-cells of a protective epitope on the bacterial membrane or secreted toxins. Activation and differentiation of resting B-cells into antibody-forming cells requires a second signal by cytokines produced by activated CD4 T-cells. The activation of CD4 T-cells is achieved by APCs, which take up the microbes, process them in endosomes, and present the peptide-class II complex to CD4 T-cells. Advantages Inactivated vaccines display several advantages: 1. Simple manufacturing methodology. 2. Inability of reverse mutations that might lead to pathogen microbes.
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132 Bona<br />
Fig. 2. Intracellular mechanisms leading to generation of class I-peptide complex. Endogenous<br />
proteins are degraded by lysosomes and the resulting peptides are translocated to the endoplasmic<br />
reticulum (ER) by transporter protein (TAP) molecules. In the ER, the peptides are released from<br />
TAP by chaperons such tapasin, calreticulin, and calexin and then bind to the heavy chain of class<br />
I molecules, which in turn bind � 2-microglobulin (� 2m). The class I-peptide complex is then transferred<br />
via a Golgi secretory pathway to the membrane, where it is recognized by CD 8 T-cells.<br />
The killing of bacteria can be achieved by physical means (heat) or by chemical<br />
agents. For example, currently used influenza and Salk polio vaccines are produced by<br />
inactivation with <strong>for</strong>malin. Similarly, the conversion of toxins to toxoids was obtained<br />
by treatment with <strong>for</strong>malin. Table 2 lists currently used inactivated vaccines.<br />
Immunity<br />
Inactivated vaccines can induce only a humoral response. Functional antibodies are produced<br />
subsequent to recognition by the Ig receptor of B-cells of a protective epitope on the<br />
bacterial membrane or secreted toxins. Activation and differentiation of resting B-cells into<br />
antibody-<strong>for</strong>ming cells requires a second signal by cytokines produced by activated CD4<br />
T-cells. The activation of CD4 T-cells is achieved by APCs, which take up the microbes,<br />
process them in endosomes, and present the peptide-class II complex to CD4 T-cells.<br />
Advantages<br />
Inactivated vaccines display several advantages:<br />
1. Simple manufacturing methodology.<br />
2. Inability of reverse mutations that might lead to pathogen microbes.
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