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Origin of Anti-tumor Immunity Failure in Mammals
Translated by Marija Rusimovic
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“… sciences long ago recognized that observations are not superior to hypotheses in generating scientific progress nor are hypotheses superior to observations. Both are necessary.”
David F. Horrobin
(1939-2003)
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INTRODUCTION
The history of science has shown the majority of hypotheses to be wrong. Sharp scientific criticism and strictly controlled experimental studies reject most of the hypotheses, leaving behind only a small number of assumptions and ideas. Nevertheless, each logical assumption should have its rightful place on the scientific “battlefield” supposed to assess its validity and determine its final fate. Even when a hypothesis is wrong, it still finds its place in the entire efforts of the humankind towards attaining the scientific truth. Namely, the wrong hypotheses serve largely to illuminate the way towards the correct ones or, at least, to show which way not to follow. Correct or not, ideas and hypotheses are necessary for the progress of science. They epitomize the efforts of human thought to elucidate nature without experimental verification and in the circumstances of scant data availability. Finally, hypotheses and ideas represent a symbiotic creation of our knowledge and imagination, the two most impressive appearances in the evolution of humans.
It is thoroughly unknown whether Charles Darwin was indeed familiar with the phenomenon of similarity between microcosm and macrocosm claimed by many philosophers and physicists to be convincing and fascinating. Whatever his knowledge might have been in this regard, the possibility that Darwin’s approach to defining the phenomena in biology is applicable to both planetary and cellular levels is fairly real. Namely, many physiological and pathological phenomena like those found in immunology and oncology, such as various forms of immune tolerance and immunomodulation, clonal selection of immune and tumor cells, modification of subset relationships between immune cells in tissues and organs, rest on the basic postulates of Darwinism, i.e. randomness of change, negative and positive selection, set-up of ecological niches, and the like.
The body of any animal can be viewed as a society or “ecosystem” whose individual members are cells, reproducing by cell division and organized into collaborative assemblies or tissues. In this “ecosystem”, the cells are born, live and die under various forms of selection pressure like territorial limitation, population size, source of nutrients provided, infectious agents, etc. The body is a highly organized society of cells whose main task is the maintenance of homeostasis of the whole organism. The failure of control mechanisms which make the cell the unit of society, marking the beginning of its “asocial” behaviour, is most frequently a malignant alteration. This process is not abrupt, nor is it based on the single event. It is, rather, a long-term process characterized mainly by mutation, competition and natural selection operating within the population of cells. The basic mechanisms controlling the cell sociability represent the first defence line against the altered cells, while the second line of defence is supposed to be made up of the immune system cells. Speaking in Darwinian terms, within the “ecosystem” of organism, cells of the immune system operate as “predators” of the altered and mutated cells or cells infected by the intracellular parasites.
The biological phenomena whose mechanisms are, at present, explored and largely understood, certainly had their own evolution. Searching for the origin and details of the evolution of “advanced solutions” as well as selection pressures that might justify their emergence and existence, we often fail to see that many such phenomena are, in fact, co-evolutionary by-products of “evolutionary innovations”. In other words, the evolutionary emergence of “advanced solutions” is sometimes, if not always, accompanied by certain by-products and by the co-evolution of compensatory mechanisms acting as a counterbalance to these.
An example of the evolution of “advanced solutions” is the evolution of adaptive immunity, and co-evolution of auto-immunity and alloimmunity. Alongside with the diversification of the mechanisms of adaptive immunity, auto-immunity and alloimmunity gain attribute of the evolutionary by-products and become sources of selection pressure. To that effect, alloimmunity could be a source of very strong selection pressure in mammals, simply because it is directly connected with the reproductive efficacy. At the same time, new forms of selection pressure that are connected with adaptive immunity gave rise to new mechanisms controlling killer machinery of the immune system. Finally, the last in a line of by-products in the processes of evolutionary “modelling” and “re-modelling” of vertebrate immune system can be called the failure of anti-tumor immunity.
There is now much evidence that tumors can be immunogenic. Tumor cells very often express antigens in a form recognizable by the host immune system, but most frequently without consequences on tumor progression. This has been shown in many experimental models and different experimental conditions. Immediate mechanisms for the escape of tumors from the immune response are very similar to mechanisms for the escape of the fetoplacental unit (as allograft) from the maternal immune response. The similarity between these two mechanisms is so significant that any randomness must be banished. Mechanisms of anti-tumor immunity in mammals are probably substantially different from mechanisms of anti-tumor immunity in other classes of vertebrates. Moreover, the type of most frequent tumors in non-mammalian vertebrates is also significantly different. Finally, the incidence of malignant tumors in non-mammalian vertebrates is significantly lower than the incidence of malignant tumors in mammals. These facts indicate that the mammalian immune system during the anti-tumor immune response is tricked by the similarity between tumor cells and trophoblast or other placental cells. From this aspect, anti-tumor immunity failure in mammals can be defined as an immunoreproductive phenomenon, which is developed under the evolutionary pressure of auto-immunity and alloimmunity/reproductive effectiveness. It may be a specific evolutionary approach in the rendering of anti-tumor immunity failure in mammals, and a new possibility for anti- tumor immunotherapy.
As my intention has been to include only those critical points related to the origin as well as parallelism between immunoregulatory/suppressive mechanisms in pregnancy and tumor sufferers, I set out to write this publication presuming that the majority of readers are already familiar with the fundamentals of medicine, biology, immunology, immunopathology, oncology, mammalian reproduction and vertebrate evolution. To that effect, this publication is free of descriptions otherwise found in most textbooks. Naturally, the book is intended for all readers showing interest. If, upon reading this subject matter, the interest of readers grows into practical work in the fields of reproductive or tumor immunology, or something even greater, the author’s satisfaction would be complete, and the objective of the entire publication fulfilled.
Finally, I recommend the articles cited throughout the text to all those readers who would like to expand their knowledge regarding the evolution of the immune system, alloreactivity, immune recognition, various forms of immune tolerance, reproductive and tumor immunology, as well as comparative immunology and oncology.
Author, 2004
Kluwer Academic/Plenum
Publishers/Springer
Hardbound, ISBN 0-306-486-296
July 2004, 270 pp.
EUR 115.00 / USD 145.00 / GBP 80.00
eBook, ISBN 0-306-48630-X
July 2004,
EUR 120.00 / USD 145.00 / GBP 85.00
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Contents
INTRODUCTION
Chapter 1.
The Vertebrate Immune System
1.1 THE VERTEBRATE IMMUNE SYSTEM EVOLUTION 1
1.1.1 Macrophages
1.1.2 Lymphocytes and Lymphoid Organs
1.1.2.1 Origin of TCR(s)
1.1.3 Cytokines throughout Vertebrate Evolution
1.2 MHC MOLECULES – NATURE, FUNCTION AND EVOLUTION
1.2.1 MHC System in Mammals
1.2.1.1 The Structure
1.2.1.2 The Function
1.2.1.3 Non-Classical MHC Molecules (class Ib)
1.2.2 The MHC System in Non-mammals
1.2.3 Ontogeny of MHC Molecules Expression
1.2.4 The Evolution of MHC Molecules
1.2.5 Mechanisms of MHC Molecules Variability
1.2.5.1 Viruses like Inductors of MHC Variability
1.2.5.2 The Heterozygote Advantage Hypothesis
1.2.5.3 The Moving Target Hypothesis
1.2.5.4 Shifting MHC Presentation Holes
1.2.5.5 Shifting T-Cell Recognition Holes
1.2.6 Variability of TAP, LMP and Other Immunological Genes
1.2.7 Regulation of MHC Genes Transcription
1.2.7.1 Cytokines which modulate expression of MHC class I molecules
1.2.7.2 Cytokines which modulate expression of MHC class II molecules
1.3 AUTO-IMMUNITY - A BY PRODUCT OF ADAPTIVE IMMUNITY
1.3.1 Sex Hormones and Auto-immunity
1.3.2 Evolutionary Pressure of Auto-immunity
REFERENCES
Chapter 2.
Alloimmunity and Pregnancy
2.1 ALLOIMMUNITY
2.1.1 Allorecognition
2.1.1.1 Dichotomy of Direct and Indirect Allorecognition
2.1.1.2 Secondary (auto-immune-like) Alloimmune Response
2.1.2 Xenoreactivity
2.1.3 Alloimmunity in Vertebrates
2.2 ALLOIMMUNITY AND VIVIPARITY
2.2.1 Evolution of Viviparity
2.2.1.1 Viviparity in Cartilaginous fish
2.2.1.2 Viviparity in Reptiles
2.2.1.3 Viviparity in Mammals
2.2.1.4 Expression of MHC molecules on Different Types of Placenta in
Mammals
2.2.2 Evolutionary Pressure of Alloimmunity
REFERENCES
Chapter 3.
Anti-tumor Immunity Failure in Mammals
3.1 MECHANISMS OF ANTI-TUMOR IMMUNITY
3.1.1 Antigen Processing/Presenting Machinery
3.1.2 Antigen Recognition by TCR
3.1.3 DSs Maturation/Activation
3.1.3.1 Heat Shock Proteins (HSP)
3.1.3.2 Role and Expression of Co-Stimulatory Molecules
3.1.3.3 DCs and Th1/Th2 Dichotomy
3.1.4 Th1 Type and Th2 Type of Anti-tumor Immune Response
3.2 ARE TUMORS IMMUNOGENIC?
3.2.1 Tumor-Associated/Specific Antigens
3.2.1.1 Carcinoembryonic Antigen (CEA) and Alpha-fetoprotein (AFP)
3.2.1.2 Differentiation Antigens (DA)
3.2.1.3 Viral Antigens (VA)
3.2.1.4 Oncogenic Fusion Proteins (OFP)
3.3 BASIC MECHANISMS OF ANTI-TUMOR IMMUNITY FAILURE IN MAMMALS
3.3.1 Altered Expression of MHC Molecules and Tumor Antigens by Tumor Cells
3.3.1.1 Expression of HLA-G on Tumor Cells as a Mechanism of
Immunosurveillance
3.3.2 Altered Expression of Co-stimulatory and Adhesion Molecules by Tumor
Cells and APCs
3.3.3 Downregulation of Anti-tumor Immune Response by Cytokines
3.3.4 Th1/Th2 Immunity and Tumor Escape
3.3.5 Downregulation of Immune Response by Molecules Other than Cytokines
3.3.6 Anti-tumor Immunity Failure by Apoptosis and/or Anergy Induction
3.3.6.1 Extrathymic Lymphocyte Maturation and Selection
3.3.6.2 Failure of Blood-thymus Barrier
3.3.7 Immunomodulatory Role of Prostaglandine
REFERENCES
Chapter 4.
Immunosurveillance Mechanisms of the Fetoplacental Unit
4.1 “SEMINAL PRIMING” AND SUCCESSFUL PREGNANCY
4.1.1 Role of TGF-b in “Seminal Priming”
4.2. DECIDUA AND TROPHOBLAST
4.2.1 Decidual Immunocompetent Cells
4.2.1.1 Decidual NK Cells
4.2.1.2 Class Ib MHC Molecules and Activity of Decidual Immune Cells
4.2.1.3 Decidual T Cells
4.2.1.4 Decidual Macrophages
4.2.1.5 Cytokine Network of the Decidua
4.2.2 The Trophoblast
4.2.2.1 Trophoblast Expression of MHC Molecules
4.2.3 Pregnancy and Cytokines
4.2.3.1 IL-10
4.2.3.2 TGF-beta
4.2.3.3 IL-4
4.2.3.4 IL-6
4.2.3.5 IL-2
4.2.3.6 IL-12
4.2.3.7 IL-15
4.2.3.8 IL-18
4.2.3.9 IFN-gamma
4.2.3.10 TNF- alpha and beta
4.2.4 Activity of Trophoblast TAP Machinery
4.3. PROSTAGLANDINE
4.3.1 Immunomodulatory Role of Prostaglandine
4.4. SEX HORMONES AND IMMUNITY IN PREGNANCY
4.4.1 Progesterone
4.4.1.1 Progesterone Induced Blocking Factor (PIBF)
4.4.2 Estrogens
4.5. IMMUNOMODULATORY PROTEINS
4.6 ANTI-TROPHOBLAST IMMUNITY FAILURE BY APOPTOSIS AND/OR ANERGY INDUCTION
4.6.1 Extrathymic Lymphocyte Maturation (eTLM) and Selection
4.6.2 Failure of Blood-thymus Barrier
4.7 EVOLUTIONARY SOLUTIONS OF VIVIPARITY IN MAMMALS
REFERENCES
Chapter 5
Tumors in Mammals and Non-mammalian Classes of Vertebrates
5.1. COMPARATIVE ONCOLOGY
5.1.1 Genetic Properties of Tumors in Vertebrates
5.1.1.1 Oncogenes
5.1.2 Phenomenon of Cell Socialization in Embryogenesis vs. Oncogenesis
5.1.3 Selection of Tumor Cells as Micro-evolutionary Process of Tumor
Development
5.1.4 Factors Influencing Oncogenesis in Vertebrates
5.1.4.1 Age
5.1.4.2 Temperature
5.1.4.3 Gender
5.1.4.4 Chemical Carcinogens
5.1.4.5 Radiation
5.1.4.6 Viruses
5.2. TUMORS IN NON-MAMMALIAN CLASSES OF VERTEBRATES
5.2.1 Tumors in Cartilaginous fish
5.2.2 Tumors in Bony fish
5.2.3 Tumors in Amphibians
5.2.4 Tumors in Reptiles
5.2.5 Tumors in Birds
5.2.6 Some Important Conclusions
5.3. ANTI-TUMOR IMMUNITY AS AUTO-IMMUNITY
5.4. PREGNANCY AS A “SUCCESSFUL” TUMOR
5.4.1 Immunological Properties in Successful vs. Unsuccessful Pregnancy
5.4.2 Immunological Properties in Pregnancy and Tumor Microenvironment
5.5. EVOLUTION OF THE HYPOTHESIS
5.5.1 Origin of Anti-tumor Immunity Failure in Vertebrates
REFERENCES
INDEX
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