Development of therapeutics targeting inflammatory IL-17 producing lymphocytes by
specifically modulating RORgt activity
Dan Littman, MD, PhD
Helen L. and Martin S. Kimmel Professor of Molecular
Immunology, Departments of Pathology and Microbiology
Background and Description of Technology:
Lymphocytes that produce the cytokines IL-17a, IL-17f, and IL-22 are important in
protecting mucosal surfaces from damage inflicted by bacteria and fungi, but also have critical roles in autoimmune diseases and inflammatory processes that impact diseases such as asthma, atherosclerosis and cancer. Most prominent are the Th17 cells; a subset of CD4+ T-helper cells that mediate autoimmunity in mouse models for arthritis, inflammatory bowel disease, and multiple sclerosis. Moreover, other IL-17-producing lymphoid cells also contribute to inflammatory processes. All of these IL-17/IL-22- producing cells express the orphan nuclear receptor RORgt, the aryl hydrocarbon receptor, the chemokine receptor CCR6, and the IL-23 receptor. RORgt, IL-23, and TGFb are required for the differentiation of mouse and human Th17 cells and RORgt is essential for the differentiation of all IL-23R-expressing mouse inflammatory lymphoid cells. Genome-wide association studies in humans have identified the IL-23-dependent inflammatory lymphoid pathway as central in pathogenesis of Crohnʼs disease, rheumatoid arthritis, psoriasis, and other diseases. Moreover, clinical studies with antibodies against IL-12/23 and IL-17 have been highly effective in treatment of psoriasis. Thus, the involvement of the RORgt/IL-23R-dependent pathway is well validated in human inflammatory diseases.
Dr. Littman was first to show that RORgt is essential for Th17 differentiation and innate
lymphoid cells (e.g. intestinal lymphoid tissue inducer cells). His lab has developed a cell based high-throughput RNAi screen to identify genes required for RORgt function and small molecules that can modulate RORgt transcriptional activity. Several classes of small molecules have been identified that interact directly with the ligand-binding domain of RORgt and inhibit IL-17 induction in mouse and human Th17 differentiation cultures. These compounds are highly specific and do not affect differentiation of Th1, Th2, or Treg cells, nor inhibit IL-17 induction upon forced expression of RORa or RORb, and do not inhibit transcriptional activity of several other nuclear receptors. One of the compounds can effectively reduce the onset and severity of experimental autoimmune encephalomyelitis in mice.
To identify other key factors required for the expression of Th17 functional mediators, the
Littman group has initiated a comprehensive study of the Th17 transcriptional regulatory network to uncover new therapeutic targets of biologics and small molecule modulators. New tools have also been developed to study Th17 and other inflammatory lymphoid cells, including different reporter mice and screening systems to identify endogenous ligands for RORgt.
Th17 cells, but not RORgt+ innate lymphoid cells, are absent in germ-free mice, and the
Littman lab has shown that a single commensal bacterial species is sufficient to induce their accumulation in the lamina propria. Colonization with the bacterium imparts protection from enteric pathogens, but also predisposes to autoimmune disease. New approaches are being developed to identify bacterial products and host pathways required for Th17 cell induction in the small intestine. A better understanding of how Th17 cells can be manipulated from the perspective of commensal microbiota will provide further opportunities for therapeutic applications.
Patent applications have been filed around targeting of RORgt in a variety of diseases,
the use of the various classes of compounds identified in the screens, and the use of commensal bacteria and their products to manipulate the balance of pro- and anti-inflammatory lymphocytes. NYU is seeking commercial partners to develop therapeutics targeting RORgt-expressing inflammatory lymphoid cells. Such a partnership would focus on a two-pronged approach towards:
1. For the RORgt program, continue optimization of the current lead compounds and
screen additional proprietary compound libraries with a pharmaceutical partner (the only large-scale screen was performed with the NIHGRI public-access library, which is not considered to be pharmaceutical-grade).
2. Identify new targets in the inflammatory lymphocyte area. This will combine
transcriptional network analysis to characterize the RORgt ligand biosynthetic pathway and designing approaches to modulate it. Finally, some effort can be directed towards the use of microbial products to modulate the Th17 cell pathway in the intestine.
Together, these approaches will complement the RORgt drug development effort
to target other branches of the inflammatory pathways using either small molecules or biological agents.