Previously we reported that TARC-chemotoxin (Report AG000444) can augment cancer vaccine responses. Although this is ongoing study, our preliminary data indicate that CD8+ T cell responses to our cancer vaccines, such as MIP3a-OFA and MIP3a-gp100, can be enhanced by transient depletion of CCR4+ Tregs with TARC-chemotoxin. We also created a new type of Alzheimer's disease vaccine (AD) that is effective in old mice, and it alleviates AD if used at onset of the disease (Report 2012). These results suggest that impaired immune responses in cancer or in aged hosts can be improved by either modulating immune cell subsets or modifying vaccine formulations. Here we report a recent completion of our study on the therapeutic use and mechanism of resveratrol (RSV, a polyphenol originally extracted from red wine). We demonstrate that despite the aggressive nature of 4T1 breast cancer in mice, RSV can efficiently block its escape and metastasis. The mechanism of this process was that RSV inhibited the generation and activity of tBregs. As a result, RSV-treated mice elicited cancer-neutralizing effector CD8+ T cells due to the loss of suppressive activity of tBregs and their inability to induce conversion of Tregs. The manuscript describing these findings has been recently submitted for publication (Lee-Chang et al., 2013). To elucidate the mechanism of old age-associated immune impairments we also conducted a two-part study: (A) To link skewed immune responses in elderly to a functional imbalance of B cells;and (B) to design strategies to combat and restore immunological impairments. By analyzing B cells from old humans, macaques and mice we discovered an evolutionary conserved new subset of B cells. The clinical importance of these cells, designated 4BL cells, is that they induce autoimmune CD8+ T cells. However, this process is reversible, as we could successfully restore immune responses, as well as to eliminate 4BL cells and concurrently autoimmune CD8 T cells, via induction of de novo B-cell lymphopoiesis in old mice. Overall, our study provides a mechanistic insight in the role of these pathogenic B cells in age-associated immunological dysfunctions. Moreover, utilizing our recently developed 4BL-tareging strategy, we demonstrate that age-associated immunological impairments can be repaired in old mice. The discovery of 4BL cells is being applied for patenting, and data were submitted for publication (Lee Chang ety al.2013).
|Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2014) Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood 124:1450-9|
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