Cytokines comprise a large family of secreted proteins that regulate cell growth and differentiation of many types of cells. These factors are especially important in regulating immune and inflammatory responses, regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets. We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have received two patents related to targeting Jak3 as the basis for a new class of immunosuppressant/immunomodulatory drugs, and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate the first-generation Jak3 antagonists. One compound, tofacitinib (CP 690,550), was produced by Pfizer and found to be effective in preclinical models. The drug was tested in Phase III studies in rheumatoid arthritis, and has now been approved for this indication. Tofacitinib is also being studied in psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile arthritis and transplant rejection. Several other Jak inhibitors have been developed and are also in clinical trials. The CRADA with Pfizer was renewed this year and was directed at better understanding the mechanisms of action of tofacitinib and related inhibitors. In considering clinical circumstances in which Jakinibs might be useful, we thought a graft-versus-host-disease might be setting in which this agent would be effective. This struck us as an important problem in that the utility of allogeneic hematopoietic stem cell transplantation is often limited by graft-versus-host disease (GVHD), a problem which is a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. We found that administration of tofacitinib prevented an adoptive transfer model of GVHD-like disease mediated by CD8 T cells. Efficacy was manifested by reduction in systemic disease and weight loss, as well as amelioration of mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell-mediated mucocutaneous diseases in patients with GVHD. This year we also investigated the utility of Jakinibs in the setting of cancer therapy. Specifically, we sought to determine whether tofacitinb could limit the host response to immunotoxins, which can limit the efficacy of the latter. We found that monotherapy of mice with tofacitinib (the JAK inhibitor) quells antibody responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. We found that thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced de novo anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics. We have also been studying the effects of tofacitinib on T cell metabolism. T cell activation is associated with a switch to glycolytic metabolism. We have found that tofacitinib inhibits the induction of many key glycolytic enzymes. The interference with cytokine-regulated changes in metabolism may be an important aspect of the mechanism of action of Jak inhibitors. In related studies, we examined the effect of tofacitinib on the evolving enhancer landscapes of activated T cells. We found that tofacitinib has a selective effect on stretch/super enhancers compared to typical enhancers
| Gadina, Massimo; Johnson, Catrina; Schwartz, Daniella et al. (2018) Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol 104:499-514 |
| Schwartz, Daniella M; Kanno, Yuka; Villarino, Alejandro et al. (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78 |
| Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz et al. (2017) Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction. Arthritis Rheumatol 69:148-160 |
| Villarino, Alejandro V; Kanno, Yuka; O'Shea, John J (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18:374-384 |
| Shih, Han-Yu; Sciumè, Giuseppe; Mikami, Yohei et al. (2016) Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality. Cell 165:1120-1133 |
| Hirahara, Kiyoshi; Schwartz, Daniella; Gadina, Massimo et al. (2016) Targeting cytokine signaling in autoimmunity: back to the future and beyond. Curr Opin Immunol 43:89-97 |
| Gadina, Massimo; Schwartz, Daniella M; O'Shea, John J (2016) Decernotinib: A Next-Generation Jakinib. Arthritis Rheumatol 68:31-4 |
| Schwartz, Daniella M; Bonelli, Michael; Gadina, Massimo et al. (2016) Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 12:25-36 |
| O'Shea, John J; Schwartz, Daniella M; Villarino, Alejandro V et al. (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311-28 |
| Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R et al. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21-7 |
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