NKT cells offer an enormous therapeutic potential if we learn how to manipulate them in vivo. As cellular adjuvants of immunity, NKT cells prime and control the maturation of dendritic cells in al infectious contexts. As such, the recruitment of these cells could be critical to vaccine development, immunotherapy of chronic infectious diseases, prevention of infection, and cancer vaccines. However, success will rely heavily on our ability to translate the knowledge of mouse NKT biology to humans. For instance, the pharmacology of compounds capable of activating NKT cells is almost unexplored as are cellular uptake and catabolism. Since, activators of NKT cells are glycolipids, it is most likely that lipoprotein and scavenger receptor polymorphism in human will heavily influence the potency of this new family of immunomodulators. We propose to address some fundamental aspects of the molecular pharmacology of NKT agonists in mice and humans to help a successful use of those molecules in medicine. This goal will be attained through 3 specific aims:
Aim 1 : Proteomic studies of NKT cell agonist transport and metabolism. Based on our previous work, we hypothesize that NKT agonists have a unique biology when compared to other lipids. Original tools need to be designed and used in the context of NKT biology to drive substantial progress in the field and its translation to clinical studies. We will combine novel chemistry and recombinant protein engineering to access the molecular pharmacology of NKT agonists.
Aim 2 : Transport of NKT cell agonists. Using traditional serum biochemistry, we have isolated and characterized the function of the association between FAAH and ?GalCer. Using proteomic approaches we have now profiled serum for all ?GalCer-associated proteins. We hypothesize that many of these proteins will impact positively or negatively the biology of NKT agonists. The study of each of these proteins will be carried out using a robust experimental system combining recombinant protein expression, in vitro biophysical and functional studies, and in vivo model systems of vaccination before being translated to human cells.
Aim 3 : Cellular uptake and catabolism of NKT cell agonists. Uptake, processing and catabolism of NKT agonists have been only superficially examined. We will combine proteomics studies with novel biochemistry and cell biology approaches to understand the delivery and processing of NKT antigens to CD1d loading compartments. As NKT agonists are entering rapidly the clinical field, the knowledge that we will acquire through the current proposal will be critical for successful translational studies.
We will study the molecular pharmacology of a new class of potent adjuvants of immunity called NKT agonists. Unique and novel chemistry will be combined with cutting edge biochemistry and mass spectrometry to understand the behavior of these new drugs. The proof of concept for these studies has already been established and this project will be critical in helping and rationalizing clinical trials that use NKT agonists, a family of new drus that has the potential of having a major impact in medicine.
|Vartabedian, Vincent F; Savage, Paul B; Teyton, Luc (2016) The processing and presentation of lipids and glycolipids to the immune system. Immunol Rev 272:109-19|
|Kain, Lisa; Costanzo, Anne; Webb, Bill et al. (2015) Endogenous ligands of natural killer T cells are alpha-linked glycosylceramides. Mol Immunol 68:94-7|
|Tefit, Josianne Nitcheu; CrabÃ©, Sandrine; Orlandini, Bernard et al. (2014) Efficacy of ABX196, a new NKT agonist, in prophylactic human vaccination. Vaccine 32:6138-45|
|Deng, S; Bai, L; Reboulet, R et al. (2014) A peptide-free, liposome-based oligosaccharide vaccine, adjuvanted with a natural killer T cell antigen, generates robust antibody responses in vivo. Chem Sci 5:1437-1441|
|Kain, Lisa; Webb, Bill; Anderson, Brian L et al. (2014) The identification of the endogenous ligands of natural killer T cells reveals the presence of mammalian Î±-linked glycosylceramides. Immunity 41:543-54|
|Anderson, Brian L; Teyton, Luc; Bendelac, Albert et al. (2013) Stimulation of natural killer T cells by glycolipids. Molecules 18:15662-88|
|Bai, Li; Deng, Shenglou; Reboulet, Rachel et al. (2013) Natural killer T (NKT)-B-cell interactions promote prolonged antibody responses and long-term memory to pneumococcal capsular polysaccharides. Proc Natl Acad Sci U S A 110:16097-102|