Immunotherapy for Infectious Diseases
Immunotherapy for Infectious Diseases Immunotherapy for Infectious Diseases
Humoral Immunity 11 ficity. In light chains, these are the J genes, which link V to C, i.e., we have V-J-C. Joining is imprecise, causing further variation, or combinatorial diversity. In the case of H chains, there is yet another region interposed between V and J, the D (for diversity) gene segment. Thus, in H chains, we have V-D-J-C, again with combinatorial diversity. So, if there are 25 � light chain V genes, and 5 J genes, constituting light chain variable regions, there are already 125 possible combinations, disregarding imprecision of joining. For � light chains, there are 5 V genes and 70 J genes, yielding 350 combinations. For H chains, there are 100 V genes, 50 D genes, and 6 J genes, giving 30,000 combinations. Overall, disregarding combinatorial diversity, this yields more than 109 combinations. When we multiply this by joining imprecision, plus a heightened mutation rate of genes in the hypervariable region, we can see that from 261 genes, we can easily exceed 1018 variations. The C regions are also genetically encoded, there being four genes for � light chains, one for � light chains, and nine H chain C genes (IgM, IgD, IgG1–4, IgA1, IgA2, and IgE). IgG is the only class of immunoglobulin capable of crossing the placenta (an Fcmediated event) (Table 1). The mechanisms for generating antibody diversity may be summarized as follows: 1. Multiple germline V genes 2. V-J and V-D-J recombinations 3. Combinatorial diversity (� recombinational inaccuracies) 4. Somatic point mutation 5. Pairing of heavy and light chains. Millions of antibody genes come from diverse combinations of gene parts. (Fig. 5). Antibodies have a variable region (binding site) and a constant region (holds binding sites together, interacts with cells). B-cell maturation joins V (variable), D (diversity), and J (segments) to form a variable gene region, connected to a constant region. Posttranscriptional processing removes introns (and extra J regions) to form mRNA. Class switching changes the constant region type (Fig. 6). Each stem cell produces an antibody with a different specificity, because it combines a different combination of V, D, and J exons for both light and heavy chains (Fig. 7). ANTIBODY ENGINEERING YESTERDAY AND TODAY The discovery of monoclonal antibody (MAb) technology in the late 1970s and early 1980s opened a new era in human therapeutics (3). The economic promise of MAbs was said to be limitless. In fact, MAbs, could be selected with exquisite specificity. They were found to orchestrate various components of the immune system such as ADCC and complement, and they showed a high biologic half-life in blood and tissues, rendering them effective for prophylactic use. The toxicity of infused MAbs was expected to be low because of their biologic nature. This concept was further supported by the successful clinical results of mouse antiidiotypic MAbs in the treatment of lymphoma and leukemias and by U.S. Food and Drug Administration (FDA) approval in 1986 of the OKT3 and anti-CD3 mouse MAb for acute renal transplant rejection.
12 Nara Fig. 5. Diagram showing how antibody genes are combined (see text). Fig. 6. Diagram of class switching. This excess of optimism was soon followed by a period of skepticism after adverse clinical and laboratory findings with rodent MAbs when they were used clinically in humans: up to 50% of treated patients developed antimurine antibody responses. In addition, the effector functions and biologic half-life were much less efficient. Adding to the skepticism were the additional failures of the clinical trials of the anti-lipopolysaccharide (LPS) mouse IgME5 MAb from Zoma, which was completed between 1992 and 1993, and the human IgM HA-1A (for septic shock) from Stanford/Centocor. However, in 1994, the FDA approved the antiplatelet mouse MAb ReoPro to treat the complications of angioplasty. This modest success was followed by FDA approval of six other engineered antibodies between 1997 and 1999. The resurgence of interest in antibody-based therapeutics was the direct consequence of the introduction of genetically engineered immunoglobulins and the refinement of targets for antibody therapy. MAbs or their recombinant derivatives now account for the single largest group of biotechnology-derived molecules in clinical trials and have a prospective market of several billion dollars. Their applications include the prophylaxis, therapy, or control of allergic and autoimmune diseases; complications of angioplasty; sepsis; a variety of inflammatory diseases; many viral and bacterial infections; organ transplantation rejections; and solid and hematologic tumors (4–10).
- Page 1 and 2: Immunotherapy for Infectious Diseas
- Page 3 and 4: In f e c t i o u s . D i s e a s e
- Page 5 and 6: © 2002 Humana Press Inc. 999 River
- Page 7 and 8: vi Preface I am grateful to all of
- Page 9 and 10: viii Contents 11 Passive Immunother
- Page 11 and 12: x Contributors BARBARA G. MATTHEWS,
- Page 14 and 15: From: Immunotherapy for Infectious
- Page 16 and 17: Humoral Immunity 5 Fig. 1. Humoral
- Page 18 and 19: Humoral Immunity 7 Table 1 Properti
- Page 20 and 21: Humoral Immunity 9 minal complement
- Page 24 and 25: Humoral Immunity 13 Fig. 7. VDJ joi
- Page 26 and 27: Humoral Immunity 15 Fig. 9. Messeng
- Page 28 and 29: Humoral Immunity 17 In contrast to
- Page 30 and 31: Humoral Immunity 19 advantage to tr
- Page 32 and 33: Humoral Immunity 21 32. Allman DM,
- Page 34 and 35: Some Basic Cellular Immunology Prin
- Page 36 and 37: Cellular Immunology Principles 25 i
- Page 38 and 39: Cellular Immunology Principles 27 s
- Page 40 and 41: Cellular Immunology Principles 29 d
- Page 42 and 43: Cellular Immunology Principles 31 f
- Page 44 and 45: Cellular Immunology Principles 33 F
- Page 46 and 47: Cellular Immunology Principles 35 R
- Page 48 and 49: Cellular Immunology Principles 37 1
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12 Nara<br />
Fig. 5. Diagram showing how antibody genes are combined (see text).<br />
Fig. 6. Diagram of class switching.<br />
This excess of optimism was soon followed by a period of skepticism after adverse<br />
clinical and laboratory findings with rodent MAbs when they were used clinically in<br />
humans: up to 50% of treated patients developed antimurine antibody responses. In<br />
addition, the effector functions and biologic half-life were much less efficient. Adding<br />
to the skepticism were the additional failures of the clinical trials of the anti-lipopolysaccharide<br />
(LPS) mouse IgME5 MAb from Zoma, which was completed between 1992<br />
and 1993, and the human IgM HA-1A (<strong>for</strong> septic shock) from Stan<strong>for</strong>d/Centocor. However,<br />
in 1994, the FDA approved the antiplatelet mouse MAb ReoPro to treat the complications<br />
of angioplasty. This modest success was followed by FDA approval of six<br />
other engineered antibodies between 1997 and 1999.<br />
The resurgence of interest in antibody-based therapeutics was the direct consequence<br />
of the introduction of genetically engineered immunoglobulins and the refinement<br />
of targets <strong>for</strong> antibody therapy. MAbs or their recombinant derivatives now<br />
account <strong>for</strong> the single largest group of biotechnology-derived molecules in clinical trials<br />
and have a prospective market of several billion dollars. Their applications include<br />
the prophylaxis, therapy, or control of allergic and autoimmune diseases; complications<br />
of angioplasty; sepsis; a variety of inflammatory diseases; many viral and bacterial<br />
infections; organ transplantation rejections; and solid and hematologic tumors<br />
(4–10).