الفهرس 
Etiology and PathogenesisOnly 14 pages are availabe for public view
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Abstract
Recent advances in tumor immunology have enabled the development of specific biological agents targeted against cancer cells. Even though tumor immunotherapy is one of the most attractive and fascinating fields of modern medicine, clinical applications in humans have shown a limited number of significant responses and revealed many scientific and practical difficulties relating to the translation of apparently flawless in vitro or animal models to the setting of human cancers. Monoclonal antibodies have been used successively in the treatment of B-cell non-Hodgkin’s lymphoma. Radio-immunotherapy (RIT) may be an effective adjunctive modality as most pediatric cancers are radiation sensitive. Cell transfer has shown promise in treating sarcomas in children. Whole or modified T-cell vaccines and antigen-loaded dendretic cells (DC) are under intense clinical and scientific evaluation.
Introduction
The immune system can be broadly divided into two components, the innate immune system and the adaptive immune system. Innate immunity refers to cellular components that serve as the first line of immunological defense but without resulting immunologic memory (Igney and Krammer, 2002 ; Greenberg, 2000). A close interaction exists between the innate immunity and adaptive immunity, both at inception and execution of the response. For instance, the release of inflammatory mediators by cells such as macrophages and dendritic cells (DCs) plays a central role in amplifying and directing specific T-cell responses (Mackall and Helman, 2002). Cooperation between adaptive and innate immune responses also occurs at later stages of the immune response as activated cytolytic T-cells exert some of their antitumor effects through recruitment of innate effectors (monocytes and eosinophils) to the site of the tumor (Reid et al, 2003).
T-lymphocyte response and tumor antigens
Tumor antigens have been shown to be like all other antigens, with few exceptions, they are peptides that are presented to T-lymphocytes in the groove of a major histocompatibility complex (MHC)-encoded protein (Boon et al, 1997). Peptides representing proteins sampled from the extracellular environment are presented in the context of class II MHC, while peptides resulting from intracellular synthesis of proteins are presented in the peptide groove of the class I MHC proteins (Cliff, 2002).
The goal of antigen processing and presentation is the activation of appropriate T-lymphocytes to proliferate, produce cytokines, and promote an immunological reaction
or become cytotoxic cells (Green berg, 2000). The interaction between T-cell receptor (TCR) and antigen -presenting cell (APC) or target cell is initially stabilized by a number of receptor-counterreceptor interactions (Benchetrit et al, 2003; Garrido et al, 2003). Chief among these interactions is the coupling of CD2 on the T-lymphocytes with ligand fusion antigen (LFA-3) on the APCs. A second mechanism is the interaction of the LFA- 1 molecule with the intercellular adhesion molecules (ICAM-1 and ICAM-2), and once the cells have been opposed, the specific interaction of the TCR and the antigen -MHC can occur (Adam et al, 2002).
After antigen-specific triggering, these T-cells secrete lymphokines that activate Tc cells, macrophages, NK cells, and B-cells and can produce other cytokines, such as interleukins (ILs) and TNF, which may be directly lytic to tumor cells (Adam et al, 2002;Greenberg, 2000). In contrast to TH cells, the Tc cell subset is capable of directly recognizing and killing tumor targets by disrupting the target membrane and nucleus (Benchetrit et al, 2003).
Naturally occurring T-cells directed against tumor -associated antigens (TAAs) were frequently detected in various malignancies, including mlanoma, colorectal cancer, leukemia, and breast cancer. T-cell responses against various antigens, such as MDA, CEA, epithelial cell adhesion molecule, Her2/neu, Wilms’ tumor protein, proteinase-3, and NY-ESO-1 have been also reported in a substantial number of cancer patients (Adam et al, 2002; Benchetrit et al, 2003).
B-cells and antibody -dependent tumor killing mechanisms
There are two major mechanisms by which antibodies may mediate tumor cell lysis. Complement -fixing antibodies which bind to tumor cell membrane and promote attachment of complement components that create pores in the membrane, resulting in cell disruption due to loss of osmotic and biochemical integrity (Rolink et al, 2001). An alternative mechanism is the ADCC, in which antibodies, usually of the IgG class, form an intercellular bridge by binding via the variable region to a specific determinant on the target cells, and via the Fc region to effector cells (as macrophages and NK cells) expressing Fc receptors (Pfreundschuh, 2003).
Antibody -dependent cell -mediated cytotoxicity is more efficient in vitro lytic mechanism than the complement -mediated cytotoxicity, requiring fewer antibody molecules per cell to kill (Pfreundschuh, 2003) . Immunotherapy studies with MABs of different idiotype proteins with different capacities to fix complement or mediate ADCC have also suggested that the ADCC may be the chief effector mechanism in cancer patients (Arceci and Cripe, 2002).
Natural killer (NK) cells
NK-cells are distinguished immunologically from T-cells by the absence of TCR gene rearrangement and TCR protein, and lack of surface CD3 and usually CD5 which are T-cell markers., while NK cells usually express one or more “NK-associated” antigens (Greer et al, 2001).
In marked contrast to killing by CTLs, whose ability to recognize targets depends on antigen presentation by MH class I molecules, natural killing is inhibited by MHC class I molecules and is enhanced by their absence, and thus down-regulation or loss of class I molecule expression is commonly observed in virus infected and many transformed cells, which may partially explain the therapeutic activity reported with NK effector cells (Lanier, 2003; Morales and Robert, 2007).
The cytotoxic activity of NK cells can be augmented both in vitro and in vivo with the lymphokines as interleukin-2 (IL-2) and interferon (IFN), and thus, NK activity can be amplified by the imnune T-cell responses (Park et al, 2007).
Macrophages and Dendritic cells
Macrophage activating factors (MAF) are commonly secreted by T-cells following antigen -specific stimulation, and therefore, the participation of macrophage as effector cells may be dependent on T-cell immune response (Benchetrit et al, 2003). T-cell 1ymphokine with MAF activity include IFNs, TNF, IL4 and CM-CSF (Ruscetti and Oppenheim, 2000).
Activated macrophages bind to and lyse transformed cells by an energy -dependent process dependent on trypsin -sensitive membrane structure. Several lytic mechanisms may be operative, depending on the MAF responsible for activating the macrophages, and these include: intercellular transfer of lysosomal products, superoxide production, release of neutral proteinases, and secretion of TNF resulting in tumor cell lysis (Mautner and Haung, 2003).
Dendritic cells are a system of professional APCs that are essential for primary immune responses mediated by T-lymphocytes (Arceci and Cripe, 2002). These cells collect antigens at the peripheral sites and then migrate to the T-cell areas of lymphoid organs to stimulate the immune responses (Saikh et al, 1996).
Key molecular aspects of DCs, which account for their ability to stimulate T-cell response, include the expression of adhesion molecules (ICAM), or the activation of cell surface markers such as CD 80, MHC class II, and T-cell stimulatory cytokines such as IL-I, IL-6 and IL-l2 (Reschner et al, 2008).
Apoptosis and tumorigenesis
The process of apoptosis (programmed cell death) is controlled by numerous pro- and anti-apoptotic factors. Physiologic activator as TNF family (Fas receptor, Fas -ligand and TNF), transforming growth factor (TGF)-β, chemical mediators released during inflammatory process, positive ligand receptor interaction, and DNA injurious agents are involved (Bergmann et al, 2003)(fig 1).
Tumors may develop down-modulation of tumor antigens, secretion of immunosuppressive factors, expression of anti-apoptotic molecules, or proapoptotic factors inducing T-cell death (Bergmann et al, 2003). Recently, FAS -ligand (FASL) expression by tumor cells and inhibition of down stream apoptosis pathways were described as tumor immune escape mechanisms with concomitant decreased sensitivity to chemotherapy (Qudejans et al, 2002; Tantawy, 2002).
Among the tumor immune escape mechanisms described is the alteration or down-modulation in the expression of MHC molecules which play a crucial step in tumor development due to the role of MHC antigens in antigen presentation to T-lymphocytes and regulation of NK cell function (Garrido et al, 2003). Intrinsic functional abnormalities of T-cell or a defect of CD8+ T-cell migration to the tumor may explain their failure to inhibit tumorigenes (Gati et al, 2003).
Recent advances in tumor immunology have enabled the development of specific biological agents targeted against cancer cells. Even though tumor immunotherapy is one of the most attractive and fascinating fields of modern medicine, clinical applications in humans have shown a limited number of significant responses and revealed many scientific and practical difficulties relating to the translation of apparently flawless in vitro or animal models to the setting of human cancers. Monoclonal antibodies have been used successively in the treatment of B-cell non-Hodgkin’s lymphoma. Radio-immunotherapy (RIT) may be an effective adjunctive modality as most pediatric cancers are radiation sensitive. Cell transfer has shown promise in treating sarcomas in children. Whole or modified T-cell vaccines and antigen-loaded dendretic cells (DC) are under intense clinical and scientific evaluation.