Dendritic cells: friend or foe in autoimmunity?

The large amount of information that has been acquired from human and animal models substantiates that the DC lineage system represents a double-edged sword in the immune system. Presumably, in normal physiology, tolerizing DCs guard against autoimmunity and control established immune reactions, whereas immunogenic DCs provide active host defenses. In autoimmune diseases, there is strong evidence to support the idea that tolerance is overridden by the development of immunogenic DCs that favor cross-priming. Based on the wide range of possible clinical applications, it is not surprising that manipulation of DCs for clinical benefit is rampant. Indeed, multiple clinical strategies are currently underway, including the development of DC immunotherapy for cancer vaccines and graft survival. In cancer, DC-based vaccines for solid tumors, such as melanoma, were well-tolerated and produced beneficial antitumor responses, even in patients who had advanced disease. Although initial trials such as these are highly promising, the ultimate goal is to develop DC-based strategies that will lead to highly specific, long-lasting immunity against the cancer cells. In autoimmune diseases and transplant settings, the goal is to devise strategies that will block the initiation and maintenance of autoreactive and antigraft responses, respectively. Specific strategies for autoimmune diseases might include interference with cross-priming events that activate autoreactive T cells and genetic engineering to introduce molecules that have immunosuppressive functions, such as IL-10, TGF3, Fas ligand, ILT3, and ILT4. Successful application to these diseases will necessitate high specificity. In this regard, recent preliminary studies that described antigen-specific suppression of a primed immune response by tolerogenic DCs are especially informative.