Development and Characterization of a Preclinical Model for the Evaluation of CD205-Mediated Antigen Delivery Therapeutics in Type 1 Diabetes.

Dendritic cells (DCs) are crucial for the production of adaptive immune responses to disease-causing microbes. However, in the steady state (i.e., in the absence of an infection or when Ags are experimentally delivered without a DC-activating adjuvant), DCs present Ags to T cells in a tolerogenic manner and are important for the establishment of peripheral tolerance. Delivery of islet Ags to DCs using Ag-linked Abs to the DC endocytic receptor CD205 has shown promise in the NOD mouse model of type 1 diabetes (T1D). It is important to note, however, that all myeloid DCs express CD205 in humans, whereas in mice, only one of the classical DC subsets does (classical DC1; CD8α+ in spleen). Thus, the evaluation of CD205-targeted treatments in mice will likely not accurately predict the results observed in humans. To overcome this challenge, we have developed and characterized a novel NOD mouse model in which all myeloid DCs transgenically express human CD205 (hCD205). This NOD.hCD205 strain displays a similar T1D incidence profile to standard NOD mice. The presence of the transgene does not alter DC development, phenotype, or function. Importantly, the DCs are able to process and present Ags delivered via hCD205. Because Ags taken up via hCD205 can be presented on both class I and class II MHC, both CD4+ and CD8+ T cells can be modulated. As both T cell subsets are important for T1D pathogenesis, NOD.hCD205 mice represent a unique, patient-relevant tool for the development and optimization of DC-directed T1D therapies.

Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies.

Cancer immunotherapy utilizing vaccines has relied upon the patients' pre-existing immune activation capabilities, augmented by existing adjuvants, to promote tumor-antigen specific immune responses. Generating effective antitumor responses in this way requires overcoming multiple mechanisms of tumor evasion of the immune system. In addition, the generation of tumor immunity must overcome tolerance to tumor antigens, which in most cases are self-antigens. One approach to generate more effective immune responses to tumors is through the manipulation of co-stimulatory molecules that control T-cell reactivity through both positive and negative signaling mechanisms. This review will focus on the T-cell co-stimulatory molecule CTLA4. Engagement of CTLA4 by the ligands B7-1 and B7-2 imparts a negative signal to T-cells and results in alteration of T-cell activity and selection. In murine tumor models, antibodies to CTLA4 can promote tumor rejection and tumor immunity. Antibodies to human CTLA4 have entered clinical trials and demonstrated objective clinical responses, initially for metastatic melanoma. Interestingly, CTLA4 blockade has been associated with organ-specific inflammatory adverse events. These events usually respond readily to short-term anti-inflammatory treatment and cessation of drug treatment, and even when suppressed in this manner appear to correlate with clinically significant and durable antitumor responses.