It is often said that the mechanism of action of BCG is unknown, but without an effective cellular immune response BCG does not inhibit tumor growth. In fact, a great deal is known about the immune response to BCG. As a complex living organism, the responses induced to BCG infection are broad and highly varied. BCG attaches to bladder tumor cells and urothelial cells by means of specific receptors, fibronectin and integrin [45,46]. Internalization of BCG is correlated with immune response and sensitivity to BCG. In vitro studies suggest that poorly differentiated cell lines, unlike well-differentiated lines, internalize BCG and are sensitive to BCG . Clinical studies similarly suggest that low-grade tumors are relatively less sensitive to BCG . BCG antigens are expressed on the surface of tumor cells, and MHC class II antigen expression is upregulated [49-51]. BCG is a nonspecific stimulant to the reticuloendothelial system and induces a local inflammatory response with the infiltration of granulocytes followed by macrophages and lymphocytes, particularly helper T cells. Phagocytosis and the ratio of helper/suppressor cells are increased . BCG induces a wide range of cytokines, including interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 12 (IL-12), tumor necrosis factor alpha (TNFa), interferon gamma (IFNy), granulocyte/macrophage colony stimulating factor (GM-CSR) and soluble intercellular adhesion molecule I (ICAM-I) . The cellular immune or Th1 response predominates and is correlated with tumor destruction. More recent studies show that BCG, like other mycobacteria, contains high amounts of CpG oligodeoxynucleotide motifs that induce TNF-related apoptosis-inducing ligand (TRAIL). Following BCG administration urinary TRAIL and TRAIL-expressing neutrophils are found in the urine, and expression is correlated with response to BCG therapy . Using ELISA, urine IFNy, and TRAIL levels were initially undetectable in BCG therapy patients but were high after later induction treatments. More recent studies have shown CpG oligodeoxynucleotide induce TRAIL expression via IFN production.
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