blankenstein, showed that ifnγ production was necessary for cd4+ t cell-mediated antitumor immunity. a series of experiments showed that it was essential for nonhematopoietic cells at the site of challenge, to express functional ifnγ receptors. further experiments showed that ifn-γ was responsible for inhibition of tumor induced angiogenesis and could prevent tumor growth through this method. (qin and blankenstein, 2000) mhc class ii and immunotherapy many of the aforementioned mechanisms by which cd4+ cells play a role in tumor immunity are dependent on phagocytosis of tumors by apcs and subsequent presentation on mhc class ii. it is rare that tumor cells will express sufficient mhc class ii to directly activate a cd4+ t cell. as such, at least two approaches have been investigated to enhance the activation of cd4+ t cells. the simplest approach involves upregulation of adhesion molecules, thus extending the presentation of antigens by apc. (chamuleau et al., 2006) a second approach involves increasing the expression of mhc class ii in tumor cells. this technique has not been used in vivo, but rather involves injection of tumor cells which have been transfected to express mhc class ii molecules, in addition to suppression of the invariant chain (ii, see below) through antisense technology. (qiu, 1999) mice vaccinated with irradiated strains of these cells show a greater immune response to subsequent challenge by the same tumor, without the upregulation of mhc class ii, then do mice vaccinated with irradiated, but otherwise unaltered tumor cells. these findings signify a promising area of future research in the development of cancer vaccines. mhc class i and class ii pathways the down regulation of the invariant chain (ii) becomes important when considering the two pathways by which antigens are presented by cells. most recognized tumor antigens are endogenously produced, altered gene products of mutated cells. these antigens, however, are normally only presented by mhc class i molecules, to cd8+ t cells, and not expressed on the cell surface bound to mhc class ii molecules, which is required for presentation to cd4+ t cells. research has shown that the two pathways by which antigens are presented cross over in the endoplasmic reticulum of the cell, in which mhc class i, mhc class ii and endogenously synthesized antigenic proteins are all present. these antigen proteins are prevented from binding to mhc class ii molecules by a protein known as the invariant chain or ii, which, in a normal cell, remains bound to the mhc class ii molecule until leaving the er. down regulation of this ii, using antisense technology, has yielded promising results in allowing mhc class i tumor antigens to be expressed on mhc class ii molecules at the cell surface (qui, 1999). upregulation of mhc class ii due to the extremely polymorphic nature of mhc class ii molecules, simple transfection of these proteins does not provide a practical method for use as a cancer vaccine. (chamuleau et al., 2006) alternately, two other methods have been examined to upregulate the expression of these proteins on mhc class ii− cells. the first is treatment with ifnγ, which can lead to increased mhc class ii expression. (trincheiri and perussia, 1985, fransen l, 1986) a second, more effective approach involves targeting the genes responsible for the synthesis of these proteins, the ciita or class ii transcription activator. selective gene targeting of ciita has been used ex vivo to allow mhc class ii− cells to become mhc class ii+ (xu, et al. 2000). upregulation of ciita also causes an increased expression of ii, and as such, must be used in conjunction with the antisense techniques referred to earlier (qui, 1999). in some forms of cancer, such as acute myeloid leukemia (aml) the cells may already be mhc class ii+, but because of mutation, express low levels on their surface. it is believed that low levels are seen as a direct result of methylation of the ciita promoter genes (morimoto et al., 2004, chamuleau et al., 2006) and that demethylation of these promoters may restore mhc class ii expression (chamuleau et al., 2006).