There are currently no clinically approved therapies that specifically target autoimmune diseases, which affect up to 24 million Americans. Present-day treatments compromise efficacy with secondary side effects as a consequence of generalized immunosuppression. A strategy to overcome these problems is to design new immunotherapies that exploit the natural capacity of dendritic cells (DCs) to generate antigen-specific regulatory T cells (Tregs), which in turn can silence undesired immune responses. Recently, I have demonstrated in mice that distinct subsets of skin DCs specialize in the induction of disease-specific Tregs. My findings depart from the long-held paradigm assuming that all DC subsets have similar functions and provide strong evidence that engaging selected DC subsets in vivo has a high probability of success as a safe therapeutic approach for autoimmune disease. However, translating this mouse discovery into human therapeutics is a major challenge. Through unbiased, high-definition molecular profiling of all human skin DC subsets and quantitative comparisons of their Treg-inducing capabilities, I aim to move the field towards a rational design of improved DC-based therapies for autoimmune disorders. As the proposed research unfolds, I will design and generate new tools to target these specialized DC subsets in humans. This proposal is ideally suited for the New Innovator Award. First, it uses innovative state-of-the-art techniques, i.e., CyTOF and RNA- seq, to unravel the DC network in human skin. Second, it is based on an innovative concept, still unexplored in humans, that the generation of disease-protective Tregs can be achieved by a few specialized DC subsets. Finally, the ultimate goal of this proposal is to develop new technology to harness human DC subsets in disease. I anticipate that this study will provide the intellectual framework to enginee improved and much needed clinical treatments against autoimmune diseases.
New therapies for autoimmune diseases are urgently needed to replace current treatments, which are non- specific, short lived, and associated with serious side effects including opportunistic infections and cancer. By translating my knowledge of dendritic cells (DCs) from mice to humans, I aim to develop novel and safe vaccines for autoimmune diseases through the engineering of biologicals that target specific skin DC subsets with immune regulatory function.
| Alcántara-Hernández, Marcela; Leylek, Rebecca; Wagar, Lisa E et al. (2017) High-Dimensional Phenotypic Mapping of Human Dendritic Cells Reveals Interindividual Variation and Tissue Specialization. Immunity 47:1037-1050.e6 |
