Therapeutic targeting of Janus kinases

Pesu, Marko; Laurence, Arian; Kishore, Nandini; Zwillich, Samuel H.; Chan, Gary; O’Shea, John J.

doi:10.1111/j.1600-065x.2008.00644.x

Cited by 218 publications

(153 citation statements)

References 95 publications

(109 reference statements)

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, when administrating JAK inhibitors, such as SOCS, active serious infections should have been resolved before the start of treatment. It is considered to be inappropriate to use JAK inhibitors for a person with infectious disease or their possibility with consideration for complication of infection (38)(39)(40). In contrast, the overactive autoimmune responses triggered by microbial pathogens can persist after elimination of infectious pathogens (7).…”

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Tajiri

Imanaka‐Yoshida

Matsubara

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Tajiri

Imanaka‐Yoshida

Matsubara

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…JAK2 is a key component in the signaling pathways elicited by proinflammatory cytokines such as IFN-g, IL-6, IL-12, and IL-23 that play a fundamental role in the inflammatory process and articular destruction in arthritis (5,40). These cytokines in combination with other factors initiate and sustain the T cell and B cell activation leading to production of proteases and other mediators that specifically regulate the inflammatory response, tissue damage, and remodeling processes.…”

Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

show abstract

“…However, given the progressive nature of the disease and its possible evolution to myelofibrosis, patients with the MPL Ser505Asn mutation might benefit from kinase inhibitors designed for patients with MPL W515L/K and JAK2-mutated myeloproliferative diseases. 26 …”

Section: Discussionmentioning

confidence: 99%

Acknowledgments / The Authors

Glasner¹,

Ott²

2013

Wonder Wood

View full text Add to dashboard Cite

The online version of this article has a supplementary appendix. BackgroundThe MPL Ser505Asn mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL Ser505Asn mutation could be underestimated. Design and MethodsWe extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL Ser505Asn mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. ResultsFifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd Chiari syndrome in one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). ConclusionsPatients with familial thrombocytosis caused by a MPL Ser505Asn mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy.Key words: MPL Ser505Asn , hereditary thrombocytosis, splenomegaly, bone marrow fibrosis. Giona F, Torti L, Cenci T, Ricerca BM, Rumi C, Nunes V, Foà R, Leone G, Martini M, and Larocca LM. Hereditary thrombocytosis caused by MPL Ser505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica. 2010; 95:65-70. doi:10.3324/haematol.2009 Hereditary thrombocytosis caused by MPL Ser505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis

show abstract

Therapeutic targeting of Janus kinases

Cited by 218 publications

References 95 publications

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Acknowledgments / The Authors

Contact Info

Product

Resources

About