Lymphocyt tumor-specific

CpG ODNs are also effective as vaccine adjuvants to enhance adaptive TH1 cellular immune responses.104 In mice, CpG ODNs can trigger strong TH1 responses,105 enhancing the number and function of tumor-specific Cytotoxic T lymphocytes (CTLs) and IFN-y secreting T cells.106 This has resulted in therapeutic vaccines in mouse tumor models where no other approach has shown comparable efficacy, even with large (1 cm) established tumors.107 108 Even without a vaccine, CpG ODNs can induce CD8+ T cell-mediated regression of established tumors with durable memory responses.109... 

Immune dysfunction and poor tumor-specific immune responses are observed in cancer patients with enhanced Treg cell activity. Furthermore, many different types of tumors possess high frequency of Treg cells that inhibit various immune functions including T-cell proliferation, cytokine production and cytotoxic activity. Trl cells also participate in a poor anticancer response. The infiltrating lymphocytes in Hodgkin s lymphoma contain both Treg and Trl cells that suppress various immune functions. 

The problem is that if an individual antibody-producing cell is isolated and grown in culture, its descendants have a limited lifespan that severely limits their use for the routine preparation of monoclonal antibodies. In 1975, Milstein and Kohler discovered how monoclonal antibodies of almost any desired antigen specificity can be produced indefinitely and in large quantities. Their method was to fuse a B lymphocyte producing antibody of the desired specificity with a cell derived from a cancerous lymphocyte tumor, called a myeloma cell, which is immortal. The cell fusion is called a hybridoma, which is both immortal and secretes the same specific antibody originally encoded by the B lymphocyte. 

The production in vitro of mAbs with a predetermined specificity has only been possible since the advent of the technology of hybridomas, which was introduced by Kohler and Milstein in 1975. These hybridomas are the products of in vitro fusion of myelomas with normal B lymphocytes. The fusion products preserve the capacity for self-propagation in a culture, as well as the secretion of the antibodies of interest, characteristics inherited from the parent myeloma and the normal B lymphocyte, respectively. The myelomas used in such fusions generally involve cell lines from B-lymphocyte tumors developed in mice or rats (Cotton and Milstein, 1973 Kohler and Milstein, 1975b Shulman et al., 1978), while... 

Activation and differentiation of cytotoxic T lymphocytes (CD8+ T cells) (CTLs) require interplay of various cytokines and cells. During the presentation of tumor-specific antigens by antigen-presenting cells (APCs) to helper T cells (CD4+ T cells), cytokines present in the microenvironment control the helper immune response to develop into either a cellular or a humoral response. CD4+ T cells have been classified into Thl and Th2 subsets according to the pattern of cytokines they produce. Thl clones secrete IL-12 and IFN-y, whereas Th2 clones secrete IL-4, IL-5, IL-6 and IL-10. Thl immune response is beneficial for the development of the cellular cytotoxic (CD8) immune response, whereas Th2 immune response is inhibitory to cytotoxic response. IFN-y is a type 1 interferon that also promotes Thl-type anti-tumor immunity, reduces tumor cell growth, and inhibits angiogenesis. 

Cytokines in most cases modulate tumor-specific inhibition dependent on direct lytic activity of cytotoxic CDS T cells or on polarization of CD4 T cells. But tumor eradication also depends on noncytotoxic CD4 and CDS lymphocytes releasing high amounts of proinflammatory cytokines that recruit distinct effector leukocytes at the tumor site. This series of events emphasizes the cytokine action in the tumor site upon several distinct cell types and immunoinflammatory mechanisms. However eradication of established tumors involves distinct mechanisms, each endowed with a different curative potential and not only cytokines. ... 

In recent years, interest has focused on the role of cell-mediated immune response in melanoma. Specific cell-mediated responses may play a role in tumor regression, but the role of specific cells such as cytotoxic T lymphocytes (CTLs) is not fully understood. Tumor-infiltrating lymphocytes (TILs) have been shown in vivo and in vitro to possess antitumor reactivity. TILs contain a large number of mature tumor-specific lymphocytes and have been a target for manipulation in immunotherapeutic approaches for melanoma. 

Interest in using tumor-specific cytotoxic lymphocytes grew out of evidence of the immunological deficiencies present in studies using TIL and the belief that enhancing specificity for tumor would increase efficacy. Although TIL... 

Induction of Tumor Specific Cytotoxic T Lymphocytes In Vivo... 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

---