Translational Immunology research: a support for clinical immunological research

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications, trials & patents

Abstract

A major project that involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. The positive results observed with tofacitinib in the animal model of SLE, served as a springboard for a phase 1b/2a, randomized, double blind, placebo-controlled clinical trial. Undertaken in collaboration with Drs. Sarfaraz Hasni and Mariana Kaplan, this study aimed to determine the safety and tolerability of tofacitinib in patients with SLE and mild to moderate disease activity. A manuscript reporting the findings of the trial Was published in Nature Communications. The TIS is also currently collaborating with Drs. Robert Colbert and Hanna Kim on a natural history study of juvenile dermatomyositis (JDM) paired with a compassionate use of the JAK1/JAK2 inhibitor baricitinib. JDM is the most common form of idiopathic inflammatory myopathy in children and its pathogenesis is thought to be due in part to innate immune dysregulation as well as autoimmunity. It is associated with a high expression of interferon or IFN-regulated genes (IFN signature) in peripheral blood, muscle, and skin. Treatment is empiric with a mainstay of high-dose steroids combined with other immunosuppressive medications often requiring prolonged therapy with significant side effects. Case reports in adults have anecdotally noted some clinic benefit with JAK inhibitor therapy (tofacitinib, ruxolitinib) with suggesting that this may target the IFN-driven pathology in dermatomyositis. In this project our group helps with translational studies to characterize the JDM patients. We collected PAXgene tubes for RNA and gene expression, particularly interferon-regulated gene expression, serum, and urine for cytokine analysis and PBMCs for assessment of detailed immunophenotyping. As in some of the studies highlighted above, we have begun to assess the drug target engagement and pharmacodynamic effects by measuring STAT phosphorylation in different immune cell types at multiple timepoints during the day, which can be correlated with the level of JAK inhibitor in the blood. Some of these results have been published in Annals of Rheumatic Disease. We are also collaborating with Drs. Peter Grayson and Marcela Ferrada who are investigating the molecular mechanisms driving Relapsing polychondritis (RP), an immune-mediated, inflammatory, systemic disorder characterized by recurrent episodes of inflammation in tissues such as the ear and nose and peripheral joints as well as the tracheobronchial tree. The inflammatory status eventually results in tissue damage and functional loss. Moreover, the disease is frequently associated with RA. To better understand the immunological alterations occurring in RP patients, we have extensively immunophenotyped the patients that enrolled in their natural history study. Preliminary results have shown some interesting alterations in the number of CD19+ B cells, which appeared to be significantly decreased in the patients when compared to healthy donors. Moreover, we have been involved in the collaboration which has defined a novel disorder, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Patients with somatic mutations at methionine 41 in UBA1, an X-linked gene, encoding the major E1 enzyme that initiates ubiquitylation. Patients developed an often-fatal, treatment-refractory inflammatory syndrome in late adulthood, with fevers, cytopenia, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Patients fulfilled clinical criteria for inflammatory (relapsing polychondritis, Sweets syndrome, polyarteritis nodosa, giant cell arteritis) and hematologic (myelodysplastic syndrome or multiple myeloma) conditions. A manuscript describing VEXAS was published in the New England Journal of Medicine whereas the manuscript describing how somatic mutations in UBA1 define a subset of RP patients with VEXAS was published in Arthritis and Rheumatology. In collaboration with Dr. Giuseppe Scium at Sapienza Unversity in Rome, Italy, we have recently shown that iver ILC1 are heterogeneous for the expression of distinct effector molecules and surface receptors, including granzyme A (GzmA) and CD160, in mice. ILC1 expressing high levels of GzmA are enriched in the liver of adult mice and represent the main hepatic ILC1 population at birth. We also showed that ILC1 defined by the expression of GzmA and CD160 are characterized by graded cytotoxic potential and ability to produce IFN-. A manuscript descrbing these results was recently published in the European Journal of Immunology. Another fruitful collaboration has been established with Professor Laura Santambrogio at Weill Cornell School of Medicine. In one collaborative study we e identified oxidative alterations in key components of the major histocompatibility complex (MHC) class II molecule antigen processing and presentation machinery in vivo under conditions of hyperglycemia-induced metabolic stress. Moreover, we observed some quantitative and qualitative changes in the MHC class II immunopeptidome of Ob/Ob mice on a high-fat diet compared with controls. These results highlight a link between glycation reactions and altered MHC class II antigen presentation that may contribute to T2D complications. The results of this work were published in the journal Immunity. In another study in collaboration with the same group, we reported that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN- mediated STAT1/NF- pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. Moreover, 3-HKA has protective effects in an experimental mouse model of psoriasis and similar findings were observed in in a mouse model of nephrotoxic nephritis. The TIS has also been investigating novel approaches for the treatment of autoimmune diseases. In collaboration with the O'Shea group, the Kaplan group, and Pfizer (via a CRADA), we are currently evaluating the effects of tofacitinib and second-generation JAK-selective inhibitors on T cells and innate lymphoid cells. Since a major limitation of JAK/STAT gene knockout studies in mice is the complete loss of ILC populations (including NK cells), pharmacological of this signaling cascade with JAK inhibitors is an attractive alternative strategy to study the role of cytokine signaling in ILC biology. We have been investigating the effects of pan- as well as JAK-selective inhibitors on the development and functions of iNKT cells and the studies are still currently ongoing.