Innate Immune Therapy For Cancer
Tumor cells usually express antigens which are distinguishable from normal “self” antigens and are thereby recognized by the host immune system. However, the host immune system barely responds to tumors in patients. Supplementation with adjuvant (such as
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INNATE IMMUNE THERAPY FOR CANCER Screen for Molecules Capable of Activating the Innate Immune System Tsukasa Seya1,3, Nasim A. Begum1, Midori Nomura1,3, Shoutaro Tsuji1,3 , Misako Matsumoto1,3 , Akira Hayashi3, Ichiro Azuma2, and Kumao Toyoshima1 1
Department of Immunology Osaka Medical Center for Cancer and Cardiovascular Diseases Higashinari-ku, Osaka 537 2 Institute of Immunological Science Hokkaido University Kita-ku, Sapporo 060, and 3 Organization for Pharmaceutical Safety and Research (OPSR) Tokyo 113 Japan
I. SUMMARY Tumor cells usually express antigens which are distinguishable from normal “self ” antigens and are thereby recognized by the host immune system. However, the host immune system barely responds to tumors in patients. Supplementation with adjuvant
(such as BCG-CWS) in patients with cancer contributes to regression of intrinsically growing cancer. The adjuvant targets antigen-presenting cells, i.e. innate immunity, but not lymphocytes, and promotes up-regulation of MHC, co-stimulators and initial cytokines in antigen-presenting cells. We hypothesized that the role of the adjuvant is to provide conditions suitable for antigen-presentation where antigens are available and the lack of adjuvant-induced priming of antigen-presenting cells results in unresponsiveness to tumor antigens. Here, we report innate immune therapy applicable to cancer patients by supplementation with adjuvants for induction of potent immune responses against tumors.
Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib et al. Kluwer Academic/Plenum Publishers, New York, 2000.
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II. INTRODUCTION In the human immune system, lymphocytes are major effectors involved in destruction of foreign material. Each of the lymphocytes exresses a specific antigen receptor
which is generated by somatic gene rearrangement and is clonally distributed on T and B cells. A tremendous number of clones each expressing unique antigen receptors can cover a huge variety of nonself antigens. To eliminate foreign cells, CD8-positive T lymphocytes mature into CTL equipped with perform, granzymes and Fas ligand, and B
lymphocytes mature into plasma cells to produce antibodies (Abs). Antigen (Ag) is absolutely required to trigger activation of the lymphocyte immune system, a system designated as acquired immunity (Janeway and Travers, 1997). However, in vitro animal experiments, minimal or ineffective Ab production or CTL induction has been induced by stimulation of pure Ag without adjuvant (Janeway, 1989). Animals effectively produce Ab against foreign material when they are co-sensitized with adjuvant plus purified Ag. Adjuvants consisting of mineral oil and bacterial contituents do not directly activate lymphocytes, but potentially induce immune responses involving lymphocytes. Recent findings have indicated that the targets of the adjuvant are not lymphocytes but antigen-presenting cells (APC), and it has been proposed that the immune system involving APC, namely innate immunity, must be elicited p
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