Project 461070

A few years ago, we discovered a new class of drugs, based on the use of tiny particles about a billion times smaller than a golf ball (a nanomedicine), that can treat diseases caused by mis-directed attacks of our own organs (e.g., the pancreatic beta cells in type 1 diabetes (T1D)) by the white blood cells of our immune system. These compounds are unique compared to current drugs in that they can specifically treat immunologically complex 'autoimmune' diseases, such as T1D, without impairing the normal function of the immune system, which protects us against infections and cancer. We showed that this new class of drugs function by re-programming an unknown type of white blood cell into autoimmune disease-suppressing counterparts. Recently, we identified the identity of the white blood cell type that gives rise to the autoimmune disease-protecting cells induced by these nanomedicines: the so-called 'T-Follicular Helper (TFH)' cell, normally responsible for orchestrating immune responses to infections, vaccines and cancer. By mapping the status of the genes that are turned off and on along this white blood cell conversion process (in precursor, intermediate and descendant cell types) we have discovered that TFH cells are naturally poised to become anti-inflammatory/anti-autoimmune cells. This suggests that this cell process is meant to occur during normal immune responses. This begs the question of why. This proposal seeks to carefully map the molecular and genetic switches that regulate this cell conversion process, and to use this information to investigate if it contributes to the termination of normal immune responses to vaccines (to return an active immune system into its normal, resting steady state). If our hypothesis is true, these molecular switches could then be pharmacologically mined to either potentiate (against infections, vaccines or cancer) or blunt (in autoimmune disease) immune responses at will.