Vaccines for the 21st Century A Tool for Decisionmaking (2000) / Chapter Skim
Currently Skimming:
Appendix 28: Summary of Workshops
Appendix 28: Summary of Workshops
Pages 325-434
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 325... ...
APPENDIX 28 Summary of Workshops Herpes Simplex 326 Epstein-Barr Virus 329 Hepatitis C Virus 334 Human Papillomavirus 338 Dengue Hemorrhagic Fever 342 Chlamydia trachomatis 347 Tuberculosis 351 Histoplasmosis and Coccidioidomycosis 355 Group A Streptococci 359 Helicobacter pylori 363 Neisseria gonorrhoea 367 Adjuvants 372 Antigen Delivery Systems 377 DNA Vaccines 381 Preventive Vaccine for Diabetes 386 Cytokine Modification of Autoreactivity 389 T-Cell Subset Choice on the Outcome of Autoimmune Disease 392 Antigen-Induced Programmed T-Cell Death as a New Approach to Immune Therapy 395 Induction, Propagation, and ImmunoreguIation of Autoimmune Diseases of the Central Nervous System 399 Peptide-Mediated Regulation of Autoimmunity 403 Stimulation and Costimulation 407 Viral Therapeutic Vaccines Hepatitis B 412 CD8 CTL to Mutated Oncoproteins and Fusion Proteins 415 CTL Screening for Tumor Antigens Immunity to Oncogenic Self-Proteins Cytokines and Their Local Environments 325 .....
|
From page 326... ...
infection occurs through mucosal surfaces, followed by Kaposi's varicelliform eruption. Immune host responses control this primary infection within 14 to 21 days.
|
From page 327... ...
Subunit Vaccines. Clinical trials are currently evaluating monoclonal antibody therapy using glycoprotein B and D combinations to treat neonatal HSV infection and HSV encephalitis.
|
From page 328... ...
Animal Models. Two new animal models have emerged from this work.
|
From page 329... ...
Both neutralizing antibodies and cell-mediated immune responses have been investigated and eliminated.
|
From page 330... ...
EBV can establish both permissive infection in epithelial cells and lymphocytes and latent, nonpermissive transforming infections in lymphocytes. Pathogenesis involves introduction of the virus into the oral epithelial cells, which are usually permissive to viral infection, and virus is then secreted into the saliva.
|
From page 331... ...
EBV Gene Functions. As noted, EBV gene products are expressed by infected cells, and researchers have identified the function of many of these products.
|
From page 332... ...
The glycoproteins of EBV are much less complex than those of HSV, and one in particular gp350/220 is the main target of neutralizing antibodies and hence the principal focus of research attention. Approaches for Vaccine Development.
|
From page 333... ...
Animal Models. Animal models are somewhat limited.
|
From page 334... ...
What used to be known as "non-A and non-B hepatitis" was recognized in the mid-1970s with the development of serological tests for the hepatitis A and B viruses, and the cause was identified and named in 1988. Researchers are only beginning to understand the interaction of HCV with the host and the ensuing immune responses.
|
From page 335... ...
An otherwise conserved epitope in nonstructural protein 3 (NS3) , which is the target for a strong CTL response, mutated over time, leading researchers to speculate that escape variants might emerge.
|
From page 336... ...
As a result, there are only three approaches available at present: recombinant subunit vaccines, naked DNA vaccines, and vector DNA vaccines. Researchers are pursuing all three approaches in order to produce a very complete immune response.
|
From page 337... ...
. Researchers have not yet identified major differences in the antibody or CTL response of patients who resolve following acute infection compared with those who develop chronic infection.
|
From page 338... ...
In a study of viral DNA in 1,000 cervical cancers from around the world, HPV-16 is by far the most common type, although HPV-18 is also common in Southeast Asia. However, the DNA of multiple HPV types is found in both benign and malignant genital lesions, for which reason a vaccine against genital HPV will need to be polyvalent.
|
From page 339... ...
In addition, there is no animal model of HPV infection the productive infection is species-specific, although there are several animal systems that might eventually be used as models. Approaches to Vaccine Development.
|
From page 340... ...
One drawback of this CRPV model is that it involves a cutaneous infection, whereas the genital HPV infections associated with cervical cancer are mucosal infections. However, an experiment with BPV type 4, which causes oral mucosal disease in cows, showed protection similar to that seen in the CRPV cutaneous system.
|
From page 341... ...
Data published about 20 years ago indicated that incubation with BPV causes agglutination of mouse red blood cells. Researchers found the same response to L1 and L1-plus-L2 VLPs, and that the response is sensitive to differing concentrations and combinations and BPV proteins.
|
From page 342... ...
Some pharmaceutical companies may try to go into Phase I clinical trials in the next couple of years, but it will take a period of time to demonstrate immunological reactivity and safety, and a longer time following women to demonstrate efficacy. Controlled Phase III trials might be completed in more than 5 but less than 10 years.
|
From page 343... ...
Recent research has emphasized the immunopathogenesis of dengue, and specifically the concept of antibody-dependent enhancement, rather than vaccine development per se. The current hypothesis is that, during secondary infection, previously existing crossreactive antibodies are binding the dengue virus and helping it into FC receptor-bearing cells.
|
From page 344... ...
Following primary infection with dengue type 1, stimulated peripheral blood monocytes will respond most strongly to the dengue-1 antigen, but there is also a lesser response to the three other serotypes. Analysis shows that about 1 cell in 1,000 will be positive for dengue-1, and about 1 cell in 10,000 will be positive for dengue-2, 3, and 4.
|
From page 345... ...
A group in Thailand has performed Phase I immunogenicity studies in adults, using live attenuated strains of dengue-1 through 4. They believe that there is adequate immunogenicity in terms of neutralizing antibody response, although enhancing antibody response has not been measured.
|
From page 346... ...
Hence, dengue vaccines should have a very solid long-term memory, with the ability to induce both B-cell and T-cell responses, as well as good antibody response. One of the biggest barriers to vaccine development is that there is no suitable animal model for DHF.
|
From page 347... ...
biovariant, which consists of three serotypes that proliferate in the lymph nodes; and (c) the trachoma biovariant, which consists of 15 different serotypes that cause epithelial infections of the eye or of the genital tract.
|
From page 348... ...
Adhesion Molecules and Analogues. Researchers believe that the parasite attaches and enters the host cell using a carbohydrate-like ligand that is synthesized on the surface of the chlamydia and somehow mediates entry.
|
From page 349... ...
Immunology. Epidemiological data, animal models, and early vaccine trials demonstrate serotype-specific immunity to the 15 known serotypes of C
|
From page 350... ...
Issues in Vaccine Development. Unlike some of the viral infections, there are several animal models for chlamydia, including mice, guinea pigs, and monkeys.
|
From page 351... ...
These studies need to be repeated in light of new understanding of antibody response at mucosal sites.
|
From page 352... ...
Four major mycobacteria-specific antigens have been studied as potential vaccine candidates over the past 20 years:
|
From page 353... ...
Animal models provide strong evidence that Th-1 CD4-positive cells are important in protective immunity. These cells produce interleukin 2 (IL-2)
|
From page 354... ...
Among potential subunit vaccines, Ag85 is the best-characterized. It is known to protect guinea pigs, and it is going into clinical trials in humans.
|
From page 355... ...
. There is data on crossreactive immune responses to other mycobacterial species such as M
|
From page 356... ...
Both organisms pose the biggest threat to immunocompromised hosts, in the form of a reactivation disease. Primary infection is followed by a dormant phase that is held in check until a perturbation in the immune system allows the organism to flourish.
|
From page 357... ...
capsulatum G2 1 7-B, the standard strain used in all animal models. Researchers were able to demonstrate (1 )
|
From page 358... ...
Currently, they are trying to identify the smallest fragment of rHIS-62 that can confer protective immunity, using 4 overlapping fragments of about 250 to 300 amino acids in length. Unfortunately, the hierarchy of proliferation response has been totally different for BALB/c mice immunized with whole H
|
From page 359... ...
immitis is HPPD, an enzyme that is involved in the degradation of aromatic amino acids and the production of pigments. The gene for HPPD is highly conserved from bacteria to humans, and that of coccidioides is about 50 percent identical to the human gene.
|
From page 360... ...
There are several potential antigens for vaccines, but over the years the surface M protein has produces the best evidence for protective immune responses. The surface M protein is a major virulence factor of Group A streptococci, since organisms that are rich in M protein are able to resist phagocytosis in the nonimmune host.
|
From page 361... ...
To resolve this uncertainty, researchers added another four fragments toward the carboxy terminus 35 amino acids each from M1, M3, M18, and M2 and injected another set of rabbits with the resulting octavalent protein. Again, the immunized rabbits produced significant levels of antibodies against all of the serotypes, and again the level of opsonic antibodies tended to decline toward the carboxy terminus.
|
From page 362... ...
; this combination might afford the broadest protective immunity in ultimate vaccine trials. In response to questions from the audience, Dr.
|
From page 363... ...
Once established, it is a lifelong persistent infection that is not cleared by host immune response. The result of chronic infection is inflammation of the gastric epithelium leading ultimately to atrophy and destruction of the gastric glands, lymphoid follicles, and a massive accumulation of T and B cells.
|
From page 364... ...
Urease is an abundant protein on the surface of the bacteria and makes up over 6 percent of its total soluble protein. It is highly conserved across strains of HP and even across different species of Helicobacter that can be used in animal models (see below)
|
From page 365... ...
Without the mucosal adjuvant, however, doses as high as 5 milligrams provided no protection: 100 percent of the animals became infected. Analysis of antibody response indicate that secretory IgA correlates best with protection: animals that were fully or partially protected had IgA in their saliva; those that became infected might have IgG in their serum but had no IgA in their saliva.
|
From page 366... ...
Immunocytochemistry reveals a marked increase in the number of IgA-secreting cells in immunized animals and a much lower response in infected controls. In fact, up to 20 percent of the IgA-secreting cells in the gastric mucosa of immunized mice were urease-specific.
|
From page 367... ...
APPENDIX 28 367 quite safe and well tolerated. Researchers are currently in the middle of an appropriate Phase II study of the safety and immunogenicity of this vaccine, using an appropriate adjuvant.
|
From page 368... ...
This relative lack of a protective immune response to uncomplicated genital infection is surprising, at first glance, because such infection does result in a very vigorous systemic and mucosal antibody response against a number of gonococcal antigens. The mechanisms by which gonococci escape what might otherwise be an effective immune response include rapid antigenic variation of key surface proteins, masking of surface antigens by sialylation of gonococcal lipooligosaccharide (LOS)
|
From page 369... ...
Several companies are pursuing this strategy, and there may well be Phase I clinical trials of such a Por liposome vaccine within 12 to 18 months. Another strategy has been to focus on the LOS itself.
|
From page 370... ...
However, sequencing of two gonococcal genes and one meningococcal gene show that this protein is highly conserved at the amino acid level, even in the surface exposed domains. Further research remains to be done, but this protein might also be included in an "bull's eye" component vaccine.
|
From page 371... ...
. The target population would be, at the least, young people as soon as they've had their first incident of any sexually transmitted disease.
|
From page 372... ...
Most adjuvants induce a protective or neutralizing antibody response, and over the years this has been the focus of most adjuvant research. Fewer adjuvants have been looked at for delayedtype hypersensitivity (DTH)
|
From page 373... ...
, it produces very strong antibody and CMI response, and it is effective for mucosal immunization, which also produces CTL responses. A formulation called QS-21 is in Phase 1 trails in humans.
|
From page 374... ...
The lymphoid follicles in the gastrointestinal tract and the nose are important entry or inductive sites for mucosal immune responses. Cells that are induced in one site are transported to other mucosal surfaces, making it possible to immunize the respiratory epithelium (for example)
|
From page 375... ...
Researchers have also achieved interesting effects by varying the sequence in which antigen-presenting cells are stimulated. Using bone marrow macrophages grown in vitro with M-CSF, for example, they found that both IFN and CT stimulate IL-6, and the combination stimulates better than either alone.
|
From page 376... ...
Another limiting factor, however, will be the necessity of testing new vaccines on cancer patients; after all, is their immune system so normal? In response to questions from the audience, Dr.
|
From page 377... ...
. In both monkeys and mice, for example, intranasal immunization produces a greater antibody response in the genital tract than any other route.
|
From page 378... ...
Other researchers are developing new mucosal adhesives, which increase absorption by extending the period of time during which antigen is exposed to the mucosal surface. Substances such as carboxymethylcellulose adhere very nicely to the mucosal surfaces and could be used to deliver antigen to those tissues.
|
From page 379... ...
DNA vaccines are covered in greater detail in the following summary. However, this is a difficult route of immunization because of generally poor reproducibility and low uptake of DNA.
|
From page 380... ...
These delivery systems might be used to introduce proteins that would treat or protect against autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Another possible application might be in the control of fertili~researchers working with rats have found that the sperm antigen SP-10, introduced orally, produces specific secretory antibodies against sperm in the female genital tract.
|
From page 381... ...
Muscle cells aren't usually thought of as antigen-presenting cells, but the DNA vaccine approach did provide a way to have the antigen produced endogenously by a host cell. Viral DNA Vaccines.
|
From page 382... ...
This is an important issue in diseases like influenza, where the elderly are the population at greatest risk. To determine whether is would also be possible to get efficacious B-cell and antibody responses, as well as CTL response, researchers repeated the experiment using the gene encoding for influenza hemagglutin, a surface glycoprotein that is the antigen against which the major neutralizing antibody is directed.
|
From page 383... ...
Researchers hope to improve antibody titers in the future. To look for CTL responses, researchers also vaccinated monkeys with a DNA vaccine based on envelope proteins with known CTL epitopes.
|
From page 384... ...
One group has used the technique to construct "expression libraries," in which an organism's genome is broken into perhaps 2,000 fragments and then used to immunize experimental animals that are subsequently challenged. A decoding process identifies which antigens elicited protective immune responses.
|
From page 385... ...
Subcutaneous injection produces good antibody response but no CTL or helper T-cell response. They have also applied DNA directly to mucosal tissues; the result was IgG antibody response without IgA, and no CTL response.
|
From page 386... ...
. The influenza vaccine is the most advanced candidate, even though it may not be the best choice for a DNA vaccine because of antigenic drift.
|
From page 387... ...
Most of the antibodies in the NOD mouse are of the IgG-B2 variety, and oral feeding doesn't suppress the animal's ability to make antibodies, or switch the subtype of antibodies made. Two cytokines of interest are induced: tumor necrosis factor beta (TNFbeta)
|
From page 388... ...
The A chain provided insignificant protection, but animals immunized with B chain developed marked protection that was transferrable to irradiated animals. The protective epitope turns out to be amino acids 9 through 23 on the B chain of the insulin molecule.
|
From page 389... ...
It is well known that Th-1 and Th-2 cells counterregulate each other. Th-1 cells are thought to promote autoimmune disease, but their action can be counte~Tegulated by Th-2 cytokines, particularly IL-10 and IL-4 and, to a lesser extent, tumor growth factor beta (TGF-beta)
|
From page 390... ...
NOD disease differs from other autoimmune diseases in its diversity many new antigens are still being identified, and a corresponding variety of T cells mediate and regulate the disease. Hence, the progression of the disease seems to involve three stages: 1.
|
From page 391... ...
B7-1 and B72 are in the infiltrates in the NOD mouse, but they have not looked at whether that is down-regulated. It would be a good experiment.
|
From page 392... ...
T-CELL SUBSET CHOICE ON THE OUTCOME OF AUTOIMMUNE DISEASED Transgenic T-cell models allow researchers to ask questions that cannot be asked in clinical disease, primarily because they limit the dramatic diversity of diabetes. In both humans and NOD mice, diabetes involves a plethora of antiens and T-cells and cytokines.
|
From page 393... ...
Experiments have show that genetic influences may establish "default pathways" in certain individuals or strains—predispositions that researchers will need to consider when developing vaccine strategies. In response to the leishmarliasis pathogen, for example, B10.D2 mice produce an initial burst of IL-4, followed by rising levels of IL-12 and ultimately a Th-1 response with rising levels of IFN-gamma; while BALB/c mice produce a sustained level of IL-4 with rising levels of IL-12 and ultimately a Th-2 response with low levels of IFN-gamma.
|
From page 394... ...
NOD mice and waited 14 to 28 days to see if insulitis and diabetes developed. The results indicated that within 3 or 4 days after transfer, there is infiltraion of the islets by both Th-1 and Th-2 cells, with resulting peri-insulitis and insulitis.
|
From page 395... ...
ANTIGEN-INDUCED PROGRAMMED T-CELL DEATH AS A NEW APPROACH TO IMMUNE THERAPY18 Another new class of vaccines has an intended effect the opposite of all currently available vaccines that is, to extinguish rather than activate an immune response by means of eliminating the catalytic cell of immune responses the T-cell by using antigen to specifically program those T-cells to die. Such vaccines could play an important role in the treatment of disease in which Tcells play an important role in pathogenesis, including autoimmune diseases, graft rejection, allergies, and some others.
|
From page 396... ...
On the molecular level, active programmed death requires strong engagement of the T-cell receptor, which stimulates high-level production of deathinducing cytokines, including tumor necrosis factor (TNF) and Fas ligand.
|
From page 397... ...
Controlled Use of Programmed T-Cell Death in Autoimmune Therapy. To determine whether the active programmed cell death pathway could be used in a controlled way, to eliminate T-cells that were causing T-cell disease, researchers used an animal model experimental allergic encephalomyelitis (EAE)
|
From page 398... ...
Histology revealed that untreated animals show severe disruption of myelin architecture and inflammatory cell infiltrate in the subarachnoid space, while treated animals show little or no disruption of the normal architecture. Researchers also wondered whether there is a fundamental immunoregulatory problem that might prohibit apoptosis and thus lead to autoimmune disease.
|
From page 399... ...
or proteolipid protein MOG (another myelin antigen) , or by transferring T-cells specific for those epitopes; it develops into a relapsingremitting form of autoimmune disease.
|
From page 400... ...
Potential for Peptide Immunotherapy in Relapsing Autoimmune Disease. Building on these findings, researchers discovered that if it was possible to induce EAE by injecting mice with MBP-specific T-cells at day 0, it was also possible to effectively turn off that response by tolerizing the animals anywhere from 7 days prior to 5 days after injection i.e., prior to initial clinical tissue damage either with whole MBP (in a mouse spinal cord homogenate or MSCH)
|
From page 401... ...
Potential for Peptide Immunotherapy in Progressive Autoimmune Disease. Researchers believe that tissue damage in TMEV is at least initiated because the virus is trophic for the CNS, where it lives in APC-like cells and can persist for long periods of time.
|
From page 402... ...
T-cell responses in MS and other Thl-mediated autoimmune diseases appear to evolve dynamically during the course of both relapsingremitting and chronic-progressive types of disease. Autoimmune reactivity in MS may in part be a secondary consequence of chronic CNS damage initiated by some putative persisting virus.
|
From page 403... ...
In at least three different animal models of autoimmune disease (EAE, diabetes, and type 2 collagen-induced arthritis) , whether spontaneous or induced, it is possible to use peptides of major dominant autoantigens in a "tolerogenic" fashion to turn off the disease.
|
From page 404... ...
In the clonal transfer experiment cited above, peptide A administered when disease has progressed to stage 2 will turn the disease off; but if anti-IL-4 is administered at the same time, it completely blocks the therapeutic effect of the peptide. This suggests, but by no means proves, that regulatory cytokines might be a central focus in efforts to bypass peptide vaccination immunotherapy and treat autoimmune diseases more directly.
|
From page 405... ...
In the future when funding becomes available researchers would like to pursue this approach using a retrovirus that is targeted to OX40, a TNF-family receptor that is expressed on the surface of activated T-cells in lesions of EAE. OX40 is also expressed in rheumatoid arthritis and possibly in diabetes as well, although researchers have not yet looked for it in NOD mice.
|
From page 406... ...
There have been anecdotal reports of patients whose autoimmune diseases were cured when they received autologous bone marrow transplants for other reasons, such as cancer therapy, but this approach is far too radical to use pre-ventively for example, in prediabetic children that aren't yet sick. An alternative that may be much simpler is stem cell rescue: if the patient becomes heterozygous, this protects against diabetes, although it may allow other diseases to be induced.
|
From page 407... ...
At a more complex level, the costimulatory signal appears to be particularly important in activating the CD4 helper cells, which in either the Th-1 or Th-2 form—plays a critical role in activating other cells of the immune system. And while the signal it transits to the B-lymphocyte may be antigen-nonspecific (e.g., cytyokines such as IL-4)
|
From page 408... ...
When researchers knocked out the gene for CD28, however, the data were more ambiguous. IgG antibody responses were impaired, but there were normal cytotoxic responses to L, C, and V viruses.
|
From page 409... ...
IL-1 was the first costimulatory molecule to be defined, and there is good evidence that it participates in initiating events in the immune response. The best-characterized of the family is the CD40-ligand interaction antibodies that block this interaction will also impair immune responses, and researchers are now waiting for the combination studies and knockout studies that will demonstrate whether this is the "missing component." IL-12 helps initiate Th-1 responses, and GM-CSF helps initiate macrophages.
|
From page 410... ...
Programmed cell death was described above. However, the resting T-cell has on its surface the CD95 molecule, which is fast When the cell is activated through antigen stimulation and costimulation, one result is the production of additional fas ligands on the surface.
|
From page 411... ...
In tumor immunity, the APC must activate cytotoxic T-cells in order to eliminate tumor cells. Tonally, this is done by stimulating T-helper cells, using both signals and producing IL-2 to encourage T-cell proliferation (as in A)
|
From page 412... ...
The strategy adopted by the researchers—identifying the epitopes that are most capable of inducing CTL responses required them first to identify the binding motifs responsible for peptide-MHC interaction, then to investigate their immunogenicity, both in vitro and in vivo. Peptide-MHC Binding Motifs.
|
From page 413... ...
When researchers repeated this analysis for known epitopes of viral and tumor antigens, however, they found that 90 percent of viral epitopes are high-affinity binders for MHC, while less than half of tumor epitopes are high-affinity binders. Because tolerance tends to favor high-affinity, immunodominant peptides, a possible vaccine in situations of significant tolerance would be to shift to subdominant, lower-affinity peptides as potential immunogens.
|
From page 414... ...
Like TT, pan-DR represents a helper epitope that may be very useful in conjunction with CTL epitopes to augment the immune response. It also shows considerable usefulness in helping antibody responses, and it might be an interesting peptide to add to some of the prophylactic vaccines that are currently used to generate carbohydrate antigen antibodies.
|
From page 415... ...
The problem with this approach, from the point of view of conventional tumor vaccine work, is that most tumor antigens have been described using antibodies, which can only recognize proteins on the surface of tumor cells. The products of these oncogenes and tumor suppressor genes are generally intracellular proteins, often nuclear proteins, that are not expressed on the surface of the cell.
|
From page 416... ...
Researchers transfected mouse tumor cells with mutant pS3 and found that they were killed, whereas untransfected cells were killed only if peptide was added to the culture. In addition, the level of mutant pS3 expressed by the transfected cells was at the low end of what is found in natural human and murine tumors.
|
From page 417... ...
To test the ability of the mutant peptide vaccine to treat a mouse with an established tumor, researchers injected tumor cells, waited 8 days until they could see or palpate tumor nodules that were 2 to 4 millimeters in diameter, and then immunized with peptidepulsed dendritic cells either (1) a single time or (2)
|
From page 418... ...
Autopsy showed no difference in the number of number of nodules in the lungs of groups A and C, which received wild-type tumor cells. However, there was statistically significant protection in group D immunized mice had substantially fewer nodules than unimmunized mice in group B
|
From page 419... ...
5. Tumor cells may be tolerogenic.
|
From page 420... ...
Using mixed lymphocyte-tumor cell culture, they obtained CTL clones that lyse autologous /tumor cells. Most of this work has been done with melanoma, which proved to be easier to work with that other tumor types that are now under investigation (e.g., sarcoma, lung, blood, renal, and head and neck carcinoma)
|
From page 421... ...
, a previously unknown gene whose sequence is the same in DNA from melanoma cells and blood lymphocytes of the same patient. MAGE-1 belongs to a family of genes that are expressed in melanoma and other tumors; the coding regions in a terminal segment include about 300 amino acids for the putative proteins.
|
From page 422... ...
In fact, most melanoma patients have CTL precursors that can be readily restimulated in vitro by autologous tumor cells. This implies that immunization should be possible, and should increase the levels of such CTLs.
|
From page 423... ...
Results were similar when IL-2 was used in place of B7.1. Otherwise, however, results were less impressive: there was a CTL response, but never enough to protect against challenge with living p8 15 tumor cells, and prior infection with MD adenovirus prevented CTL responses to p8 15.
|
From page 424... ...
Human patients show tumor response but no CTL response, either spleen or peripheral blood; experimental mice show CTL responses but no regression of tumors.
|
From page 425... ...
The structure of HER-2/neu includes a very large extracellular domain, so large that there are potentially epitopes for every individual. Initial experiments revealed that 15 percent or 16 percent of breast cancer patients have existent antibody responses to HER-2/neu, including 42 percent of patients with documented overexpression of the protein.
|
From page 426... ...
In several of these patients, the IgG antibody binds to the same tumor cells that overexpress HER-2/neu. Using epitope mapping, they have discovered a segment of the extracellular domain that is rich in cystine and thus a potential binding site.
|
From page 427... ...
In addition, most autoimmune disease is relapsing and often resolves spontaneously, while this strategy requires a rapid and aggressive autoimmunity that can eradicate the organ. (Parenthetically, there is a general lack of attention to CTLs in the field of autoimmunity, possibly because autoimmunity isn't mediated by CTLs, or possibly because CTLs are too difficult to deal with.)
|
From page 428... ...
But rat peptides failed to induce any response in male rats. Trying another approach, researchers first immunized male rats to homologous human PAP peptides, then immunized with rat peptides, and this sequential immunization did induce helper T-cell and antibody responses to rat PAP.
|
From page 429... ...
For many cancers these target antigens still aren't known, although it is assumed that tumor cells themselves are important the 26 Based on a presentation by Drew Pardoll, M.D.
|
From page 430... ...
This was a surprise at the time, but other groups soon reported that GMCSF has the unique and interesting function of inducing hematopoietic progenitors to differentiate not only into granulocytes and macrophages, but also into dendritic cells. It may be that these high-potency APCs, differentiating locally in the presence of GM-CSF, have something to do with the enhanced systemic immune response to GM-CSF-transduced tumor cells.
|
From page 431... ...
In order to determine whether paracrine elaboration of GM-CSF generated human immune responses, patients were randomized in a double-blind fashion to receive either irradiated tumor cells or irradiated tumor cells transduced with the GM-CSF gene. DTH was chosen as the simplest and most reproducible assay for in vivo immune response.
|
From page 432... ...
Researchers also hope to use activated T-cells to identify the relevant antigens for antigen-specific vaccines. One group has been pursuing this concept in the mouse model using CT26, an NMUinduced colon cancer, in order to identify the repertoire of antigens that are being recognized by the CD8 arm of the immune response following vaccination with GM-CSF-transduced tumor cells.
|
From page 433... ...
. A single vaccination with B7-transduced tumor cells does not evoke a measurable response that maps to the tumor's MHC type.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.