Translational Immunology research: a support for clinical immunological research

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A major project that involves the TIS is the definition of molecular biomarkers for autoimmune and autoinflammatory diseases. 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, 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 Rheumatoid Arthritis. To better understand the immunological alterations occurring in RP patients, we have extensively immunophenotyped the patients that enrolled in their natural history study. In collaboration with Drs. Sarfaraz Hasni and Mariana Kaplan we have been involved in a study that assessed the peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ) in Lupus patients. Patients with mild to severe disease activity were randomized to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Parameters of endothelial function and arterial inflammation were measured as well as neutrophil dysregulation, metabolic disturbances, and gene expression studies (performed by the TIS). The study that is currently in press in Annals of Rheumatic Disease showed that PGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE. In a collaborative study with Dr. Dan Kastner and Dr. Christina Kozycki we participated in the characterization of an autoinflammatory disease caused by dominant gain-of-function mutations in the ALPK1 gene which resulted in a syndrome named ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache). Nearly all patients (significant phenotypic variation) exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralization. The TIS was involved in signaling studies which showed that patients exhibited increased STAT1 phosphorylation leading to augmented interferon gene expression. Anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life; anti-IL-6 (tocilizumab) was the only anti-cytokine therapy that improved intraocular inflammation. A manuscript reporting these results has just been published in Annals of Rheumatic Diseases. In collaboration with Dr. Giuseppe Sciume at Sapienza University in Rome, Italy, we have shown that the transcription factor STAT4 played an unexpectedly divergent role in regulating effector differentiation of ILC1 and NK cells during intestinal inflammation in mice. A manuscript describing these results is currently under review. Another fruitful collaboration has been established with Professor Laura Santambrogio at Weill Cornell School of Medicine. In one collaborative study we demonstrated that metabolic insults promoted the presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death) on MHC Class II, ultimately supporting pathogenic autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies exacerbated hepatocytes cell death, as determined by increased liver-specific transaminases, detected in the sera of high fat but not control mice. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions including autoimmune hepatitis, primary biliary cholangitis, and type 2 diabetes. The study showed that metabolic insults caused by high-fat-high-fructose diet elicited liver damage, which promotes pathogenic immune autoreactivity by supplying PDIA3 T cell and B cell epitopes. A manuscript describing these results in currently in press in the journal Science Immunology. The TIS has also been investigating novel approaches for the treatment of autoimmune diseases. In collaboration with the O'Shea and Kaplan groups 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 Innate Lymphoid Cell (ILC) populations (including natural killer cells), pharmacological alternation 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 and JAK-selective inhibitors on the development and functions of invariant natural killer T cells and the studies are still currently ongoing.