| First Author | Zwicker KA | Year | 2003 |
| Journal | J Surg Res | Volume | 114 |
| Issue | 2 | Pages | 274 |
| Mgi Jnum | J:86058 | Mgi Id | MGI:2678633 |
| Doi | 10.1016/j.jss.2003.08.012 | Citation | Zwicker KA, et al. (2003) Abstract: Tumor immunity in the context of autoimmunity. J Surg Res 114(2):274 |
| abstractText | As tumors develop, they escape detection by the immune system, perhaps because they differ little from "self". In individuals with autoimmunity, tolerogenic mechanisms have broken down, resulting in activation of immune effectors against autoantigens. We postulate that immune effectors inappropriately activated in autoimmune individuals are capable of protecting against tumor expressing targeted autoantigens. To evaluate this hypothesis, we generated double transgenic mice which spontaneously develop pancreatic insulinomas and in which all CD8+ T cells recognize an autoantigen expressed by normal and transformed beta-islet cells (8.3-NOD-riptag). These mice were generated on a NOD background, which confers a propensity to develop autoimmune diabetes mellitus (DM). In mice with a normal complement of immune effectors (ie: NOD-riptag), the median time of onset of hypoglycemia (a surrogate marker for tumor) was the same as immunodeficient mice (ie: NOD-scid-riptag) (86 vs. 92 days, respectively). This suggests that the baseline immune response is insufficient to affect tumor growth. While all of these mice became hypoglycemic, not all 8.3-NOD-riptags became hypoglycemic. In 8.3-NOD-riptag mice, 13/25 became diabetic. Of diabetic 8.3-NOD-riptags, only 3 became hypoglycemic and these mice had tumor at autopsy. Even in those mice which did not develop overt DM, there was a significant delay in onset of hypoglycemia (ie: median 129 d; P = 0.0008). While these data suggest that 8.3-TCR (transgenic) CD8+ T cells inhibited tumor, the protection was incomplete. Anergy does not appear to be responsible for the failure, for transgenic CD8+ T cells in these individuals respond normally to NRP (the peptide mimotope for the antigen recognized by 8.3-TCR CD8+ T cells). Similarly, clonal deletion does not appear to be responsible for tumor outgrowth, as the number of 8.3-TCR CD8+ T cells does not decline with age or with tumor development. These data demonstrate that, in individuals with tolerogenic defects, primed CD8+ T cells capable of inducing autoimmunity are unable to completely protect against the emergence of tumor expressing the targeted autoantigens. Our initial studies suggest that this failure to confer complete protection is secondary to tumor factors rather than to acquired T cell defects. These factors will be important to define to rationally design tumor vaccines. |
