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In the theory, anti-tumor immunity in invertebrates might be based solely on the activity of the innate immune system, relatively poorly developed network of molecular mediators, a small number of effector cells and proportionally poorly developed mechanisms regulating immune response. Therefore, one of the primary tasks of comparative tumor immunology may be the identification of mechanisms of anti-tumor immunity in invertebrates and comparing them with their counterparts in vertebrates. On the other hand, all vertebrates are characterized by both innate and adaptive immunity, displaying great differences related to the advancement stage of the adaptive immunity, its correspondence with innate immunity. In addition, differences in the mechanisms controlling the immune reaction, number of cytokines and their role in the immune response are also important. The identification and comparative analysis of the foregoing mechanisms in invertebrates and vertebrate classes may contribute significantly in clarifying the mechanisms of anti-tumor immunity failure in mammals, as well as tracing the possible link between these and immunoreproductive mechanisms. <p> Furthermore, this could be a way of introducing new, more effective adjuvant and/or immunotherapeutic procedures [4,11]. </p> <p> Based on recent findings, several mechanisms have been identified that participate in the development of the phenomenon of anti-tumor immunity failure in vertebrates: </p> <p> 1. The processes of embryogenesis and mechanisms establishing central immune tolerance to "self" molecules are similar across all vertebrate classes. Therefore, the mechanisms of immunotolerance to embryonic and/or embryonic-like tissues, such as tumor tissues, may be connected with central immunotolerance [11,12]. There is evidence that the mechanisms of central immunotolerance are, more or less, active in adults. This phenomenon could also be involved to some extent in the development of antitumor immunity failure [12,13]; </p> <p> 3. The mechanisms of peripheral maturation of lymphocytes and possible influence of these on the quality of the immune reaction have been also verified in most vertebrate classes [13]; </p> <p> 4. The immune system of vertebrates is closely connected with auto-immunity being a by-product of the adaptive immunity. "Self"-protective immune reaction control mechanisms that could become activated in anti-tumor immune reaction, co-evolved alongside auto-immunity as a "new" evolutionary phenomenon and a new form of selection pressure. Therefore, the activation of anti-tumor immunity as a unique form of auto-immune process was probably followed by a parallel activation of protective mechanisms, i.e. the immune reaction control mechanisms [4]; </p> <p> 5. Unlike non-mammals, the immune system of mammals has "built-in" the mechanisms of tolerance to proliferative tissues like trophoblast. These mechanisms have developed, in the course of evolution, under a very strong selection pressure of alloimmunity and reproductive efficacy. Although very similar to the mechanisms resembling autoimmunity, the mechanisms of immune tolerance to trophoblast can be regarded as more advanced and more effective. On the other hand, there is a great similarity between the mechanisms of immune tolerance to trophoblast and anti-tumor immunity failure mechanisms. These two, apparently diverse mechanisms may be regarded as a protective immune cross-reaction against the proliferative tissues of diametrically different origin [4,11]. </p> <p> All vertebrates are, more or less, susceptible to carcinogenesis, depending on the sensitivity of their DNA to the influence by various carcinogenic factors. The phenomenon of anti-tumor immunity failure is relatively easily verifiable in all vertebrate classes, due to the similarities in organization and functioning of their immune systems. The phenomenon of anti-tumor immunity failure in non-mammals rests largely on the mechanisms of central immune tolerance to embryonic and/or embryonic-like cells and control mechanisms resembling auto-immunity. However, the diversification of the immune reaction control mechanisms in mammals has again produced new possibilities regarding tolerance to proliferative tissues, i.e. trophoblast and tumors. Several observations could be taken as a basis for the future research in the field of comparative tumor genetics, immunology and immunogenetics: </p> <p> 1. The expression of class I and class II molecules, tissue distribution of the molecules and level of polymorphism of class I and class II genes in non-mammals and mammals are substantially different. In most non-mammals, class II genes are more polymorphic in relation to class I, while class I genes are highly polymorphic in mammal genome. Tissue distribution of class II molecules in mammals is restricted on APCs, dendritic cells and B lymphocytes, while non-mammals shows the phenomenon of poor restricted or unrestricted tissue distribution of the class II molecules [14,15]. </p> <p> 2. In all non-mammalian classes of vertebrates class I and class II genes are rambling through genome, but LMP and TAP genes are highly evolutionary conserved within class I region. In mammals, class I and class II genes are clustered on the same chromosome (except equine), but LMP and TAP genes are conserved within class II region [16,17,18]. </p> <p> 3. The transcription of class II/LMP/TAP genes in mammals are controlled from same signals. The absence of class II genes transcription signals lockout antigens processing machinery and class I molecules peptide presentation, as well as the activation of Th1 cells and adaptive immunity effectors actions [19,20]. In non-mammals, antigen processing machinery is under control of class I genes transcription, because class I/LMP/TAP genes are closely connected on the same chromosomal loci [16,17,18]. </p> <p> 4. Anti-tumor immunity in non-mammalian (except birds) vertebrates predominantly depend on the innate immune system, while anti-tumor immunity in mammals depend on the innate and adaptive immune systems and their communication [21]. </p> <p> 5. The specificity in expression and tissue distribution of MHC genes, LMP and TAP genes transcription control, as well as the communication between native and adaptive immunity in nonmammalian vertebrates qualifies a substantially different cytokine network and immune reaction than in mammals. </p> <p> 6. There is a possibility that malignant cells in fishes, amphibians, reptiles and birds are more susceptible to apoptosis than mammalian malignant cells [22]. </p> <p> 7. The high resistance on carcinogens induced genetic changes is evidenced in some experiments with lower vertebrates, leading to a conclusion that DNA from lower vertebrates shows a high level of resistance on carcinogenesis [2,22]. </p> <p> 8. The complex and efficient mechanisms of immune reaction control developed under the evolutionary pressure of high polymorphism of class I genes, auto-immunity and reproductive effectiveness can be included in the mechanisms of anti-tumor immunity failure in mammals. </p> <p> 9. Mammalian extended cytokine network can be activated/deactivated by same or similar factors under different conditions such as pregnancy and malignancy. A small number of cytokines and poor cytokine network are the characteristics of nonmammalian vertebrates. For example, cytokines like IL-10 and IL-4 are unknown in fishes and amphibians, but TGF-β is evidenced in reptiles, birds and probably in other non-mammalian classes [23,24]. 10. Th-like cells are detected in reptiles and amphibians [25], as well as Th and/or Th1-like cells in birds [26], but mammals are single vertebrates which have the advanced system of immune reaction control established on Th1 and Th2 cells, and their balanced activity. The absence or fractional awareness of Th2 model of immune reaction control probably contributes in the strong anti-tumor immunity in nonmammalian vertebrates. </p> <p> 11. Mammalians' immune system may be tolerant to cancer cells because they are very similar to trophoblast cells [11]. </p> <p> 12. Sex hormones, steroids and other factors, which are the attributes of pregnancy and malignant processes, can impair blood-thymus barrier. It can be another mechanism of acquired thymic tolerance to foreign molecules in pregnancy and malignancy [12]. </p> <p> 13. The absence of MHC and costimulatory molecules expression, prostaglandine, Th2 cytokines, sex hormones, steroids and other factors could be promoter of extrathymic lymphocytes maturation in antigen-protective manner in mammalians. It is yet one of the mechanisms that are included in trophoblast and tumor escape [13]. </p> <p> 14. Unlike mammals, the mechanisms of immune reaction control in non-mammalian vertebrates probably are essentially independent from an important role of co-stimulatory molecules. Actually, co-stimulatory molecules like CD40, CD80, CD86 and OX40 were not detected in non-mammalian vertebrates, except CD80 and CD86-like molecules in birds [27]. </p>
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