| zjhxiaohui |
2006-06-05 01:37 |
Tumor immunology（肿瘤免疫）
大二时候做的课件，有兴趣的同学，下了慢慢研究一下。
Tumor immunology
￥The introduction of Tumor immunology
￥Common properties of tumor cells
￥The history of Tumor immunology research
￥Development of Tumors
￥Tumor antigen
￥Immunological effect
￥Immunotherapy
1、The introduction of Tumor immunology
Tumor immunology is the study of :
(1)the antigenic properties of transformed cells;
(2)the host immune responses to these tumor cells;
(3)the immunologic consequences to the host of growth of malignant cells;
(4)the means by which the immune system can be modulated(调节) to recognize tumor cells and promote tumor eradication(消退).
2、Common properties of tumor cells
1. Failure to respond to the regulatory signals responsible for maintaining normal growth and controlling tissue repair.
2.Autonomous growth without an absolute requirement for exogenous growth signals.
3.Invasive growth through normal tissue boundaries.
4.Metastatic growth in distant organs following entry into blood and lymph channels.
5.Monoclonal origin, although genotypic and phenotypic heterogeneity may develop as tumor mass increases .
6.Differences in appearance and membrane antigenic display from nontransformed differentiated cells of the same tissue origen.
3、The history of Tumor immunology research
The research of tumor immunology started from the beginning of the last century, when people tried various of ways to proved the existence of tumor specific antigen. Researchers didn’t proved the existence of specific antigen expressed by tumor induced by MCA (metnylcholanthrene,甲基胆蒽), until 1950s on the base of successful in animal culture of purified lineage.
1959 Thomas “immunologic surveillance”
1970 Burnet theory of immunologic surveillance
1975 Kohler & Milstein hybridoma technique , mAb
1970s~ Boon the existence of specific antigen in the molecule level
1980s
4、Development of Tumors
The transformation of normal cell to malignancy can result from variety of different causes, the particular nature of which helps determine if the immune system will effectively control the outgrowth of the tumor cell. These transforming events may occur spontaneously(自发地) during cell division as random mutation or gene rearrangements; alternatively, they may be induced by a chemical, physical, or viral carcinogen.
Natural development ( Immunodeficiency )
Induced
1.Chemical
2.Physical
**chemical carcinogens
Tumor induced by chemical carcinogens were initially described in the 18th century, when chimney sweeps were observed to have an unusually high incidence of carcinoma of scrotum(阴囊）.
Painting tar on epithelial cells became a useful experimental technique for inducing tumors in the lab.
Classification:
1.initiator: initiate transformation of normal cells to tumor cells.
2. promoter: promote initiated cells to proliferate
3. malignant agent : cause initiated cells to transform to malignant cells.
**physical carcinogens
Evidence of tumor induction by physical carcinogens accrued (产生)rapidly following the discovery of X-rays and radioactivity in the late 19th century when many of the early radiologists developed skin cancer.
Ionization radiation (电离辐射)
Ultraviolet ray(紫外线)
Electromagnetic wave(电磁波)
5、Tumor antigen
The field of tumor immunology is based in large part on the supposition that tumors express antigens that permit immunologic separation of malignant from normal cells.
The relevant tumor antigens fall into two major categories.
UTA (Unique tumor antigen): found only in tumor cells and therefore represent ideal targets for an immunologic attack.
TAA (Tumor associated antigen): found in tumor cells and also in some normal cells, but qualitative and quantitative differences in antigen expression permit the use of these antigens to distinguish tumor cells from normal cells.
**UTA (Unique tumor antigen)
These antigens can be detected only in tumor cells not in other host cells.
Many tumors linked epidemiologically(流行) with viruses, viral genomes present in tumor cells have been isolated, viral proteins expressed in human tumors identified ,and the resulting unique viral antigens demonstrated to be potentially immunogenic.
**TAA (Tumor associated antigen)
Although it may be possible to detect unique tumor antigens in all tumors, many tumors display antigens that distinguish them from normal cells. These tumor-associated antigens may be expressed by some normal cells at particular stages of differentiation, but the quantitative expression or the composite expression in association with other lineage or differentiation markers can be useful for identifying transformed cells.
6、Immunological effect
Virtually all of the effector components of the immune system have the potential to contribute to the eradication(根除) of tumor cells. It is likely that each of these effector mechanism can play a role in the control of tumor growth ,but particular mechanism may be more or less important ,depending on the tumor and setting.
1.Innate immunity
NK , Macrophage , DC etc.
2.Adaptive immunity
CMI --T cell,
HI --B cell
**T cells
The T—cell response is unquestionably the most important host response for the control of growth of antigenic tumor cells. It is responsible for both the direct killing of tumor cells and the activation of other components of the immune system.
& CD4+T cell : Ag→ APC (MHC-Ⅱ molecule)→ Th cell→ secretion of cytokines→ effect ( activate other effector cells and induce inflammatory response )
& Tc cell : Ag→ APC (MHC-Ⅰ molecule) → Tc cell→ effect ( secretion of cytokines and lysis of tumor cells)
**B cells
A potential role for host antibody responses in human tumor immunity was previously suggested by the occasional detection of tumor-reactive antibodies in the serum of patients.
Two major mechanisms by which antibodies may mediate tumor cell lysis.
1. Complement-fixing antibodies bind to the tumor cell membrane and promote attachment of complement components that create pores in the membrane, resulting in cell disruption due to the loss of osmotic and biochemical integrity.
2. ADCC: Many potential effector cells ,including NK cells ,Macrophages ,granulocytes ,can mediate the lytic event . ADCC is more efficient in vitro lytic mechanism than complement-mediated cytotoxicity, requiring fewer antibody molecules per cell to kill.
**Natural killer cells
NK cells can kill a wide range of tumor targets in vitro .
The cytolytic potential of NK cells is large contained by off signals delivered via families of inhibitory receptors that bind to class 1 molecules on potential target cells.
**Macrophages
Macrophages are important in tumor immunity as antigen presenting cells to stimulate the immune response and as potential effector cells to mediate tumor lysis .
Resting macrophages are not cytolytic to tumor cells in vitro ,but can become cytolytic if activated with macrophage-activating factors.
7、Immunotherapy
Although the host immune system may often be inadequate for controlling tumor growth, the presence of identifiable tumor antigens in most tumor cells, the identification of a detectable but ineffective host response to many tumors, and an improved understanding of the mechanisms by which tumor cells evade immunity suggest that it may be possible to control and amplify the immune system to promote tumor eradication.
The recent technologic advances that permit isolation of lymphocyte subpopulations, identification and purification of tumor antigens, growth of selected antigen-specific T cells, amplification of immune responses with cytokines, and production of antibodies that can target surface tumor antigens have created a new potential and enthusiasm for the immunotherapy of tumors. Several distinct approaches to immunotherapy are being studied, and it seems likely that at least some of these approaches will soon become important modalities for the treatment of selected tumors.
1.Operation
2.Radiacal therapy
3.Chemical therapy
4.Biological therapy
**Immunization to tumor antigen
DC precursors can be readily isolated from the peripheral blood and expanded in vitro to large numbers with the appropriate cytokines. Such DC have been loaded with tumor antigens by a variety of means, including transfection, infection with recombinant viruses, incubation with the tumor protein or peptide, or phagocytosis of apoptotic tumor cells, and then inoculated（接种） into the patient to induce responses. The optimal way to deliver DC remains to be clarified, but immune responses and clinical antitumor responses have already been observed.
An alternative approach has been to isolate tumor cells from a biopsy specimen（活检标本） ,introduce cytokine genes and gene encoding costimulatory molecules expressed by professional APC , and then use these gene-modified tumor cells to immunize the host .
Another option being explored is to deliver tumor antigens in vivo in forms that will direct them to DC for presentation .
**Adoptive (过继性) T-cell therapy
Animal models have been developed in which hosts bearing advanced tumors can be treated by the transfer of tumor –specific syngeneic T cell.
Complete tumor elimination following adoptive therapy requires an extended period ,and the cells transferred must therefore be capable of persisting in the host to be effective.
There is now substantial experience with adoptive T-cell transfer in humans. The most completely analyzed studies have been for the treatment of virus-related diseases .
**Administration of Monoclonal Antibodies
There are multiple mechanisms by which monoclonal antibodies can mediate anti-tumor activity ,and enhancing these activities can increase the efficacy of mAb therapy . Initial efforts focused on improving ADCC activity because this appears to be a much more significant in vivo effector mechanism than complement-mediated lysis or opsonization .
Although each antibody will need to be carefully evaluated for toxicity and efficacy(效力) ,mAb therapy is certain to become an increasingly important part of treatment regimens for cancer .
8、Tumor Immunity
There is a growing sense that cancer immunology is entering a mature phase in its development and that the long cherished hopes for the field - effective immunotherapies for cancer - will become a reality in the coming decades. |
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