Novel Immunosuppression: R348, a JAK3- and Syk-Inhibitor Attenuates Acute Cardiac Allograft Rejection

Deuse, T.; Velotta, Jeffrey B.; Hoyt, Grant; Govaert, Johannes A.; Taylor, Vanessa; Masuda, Esteban S.; Herlaar, Ellen; Park, Gary; Carroll, D. C.; Pelletier, Marc; Robbins, Robert C.; Schrepfer, Sonja

doi:10.1097/tp.0b013e318166acc4

Cited by 32 publications

(25 citation statements)

References 42 publications

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“…R348 is a prodrug of R333 demonstrating enhanced bioavailability and absorption of compound in vivo. R348 was found to prevent acute rejection in a rat heart heterotopic allograft model and synergized with tacrolimus to prolong cardiac allograft survival (16).…”

Section: Jak3 Inhibition Significantly Attenuates Psoriasiform Skin Imentioning

confidence: 99%

“…Previous studies have shown that treatment of rodents with specific JAK3 inhibitors can prevent graft rejection and decrease the severity of arthritis, although the efficacy of these compounds in restricting inflammatory responses in other diseases has not been explored (15,16). To determine whether inhibition of JAK3-dependent cytokine signaling could suppress chronic skin inflammation, such as occurs in psoriasis, we treated CD18 mutant PL/J mice with R348, a prodrug of R333.…”

Section: Reversal Of Psoriasiform Lesions In Cd18 Mutant Pl/j Micementioning

confidence: 99%

“…The cell-based selectivity of R333 was described previously (16). We further evaluated R333 potency and selectivity for inhibition of various tyrosine kinases in cells by measuring phosphorylation of the kinase itself or signaling proteins downstream to the kinase of interest.…”

Section: R333 Selectively Inhibits Jak3 Activity In Human Primary Celmentioning

confidence: 99%

“…We identified a novel small molecule kinase inhibitor, R333, showing potent inhibition of JAK1/3-dependent signaling pathways. The cell-based selectivity of R333 was described previously (16). R333 inhibits IL-2 signaling in T cells and IL-4 signaling in B cells with EC 50 s of 0.18 and 0.07 M, respectively, and is a potent inhibitor of T cell proliferation in the MLR with an EC 50 of 0.12 M. R333 was less potent against Epo/JAK2-dependent signaling pathways in primary erythroblasts (EC 50 of 0.84 M) and was selective for JAK1/ JAK3 when tested in various receptor tyrosine kinase signaling and proliferation assays (16).…”

Section: Jak3 Inhibition Significantly Attenuates Psoriasiform Skin Imentioning

confidence: 99%

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JAK3 Inhibition Significantly Attenuates Psoriasiform Skin Inflammation in CD18 Mutant PL/J Mice

Chang

Zhao

et al. 2009

The Journal of Immunology

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JAK3, a member of the Janus kinase family, is predominantly expressed in hemopoietic cells and binds specifically to the common γ chain of a subfamily of cytokine receptors that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Previous studies suggest that this tyrosine kinase plays key roles in mediating T cell functions, and inhibition of JAK3 has been shown to prevent graft rejection and decrease the severity of arthritis in rodent models. However, the functions of JAK3 in the development of skin immune responses and diseases such as psoriasis have not been determined. CD18 mutant PL/J mice develop spontaneous T cell-dependent psoriasiform skin disease with several similarities to human psoriasis. In this study, we treated mice with established skin disease with R348, a small molecule inhibitor of JAK3, and observed a marked attenuation of skin lesions following 6 wk of treatment. Histological analyses revealed major reductions of both epidermal and dermal lesion severity scores in R348-treated CD18-deficient PL/J mice compared with vehicle controls, which was associated with decreased CD4+ T cell infiltration. In addition, systemic levels of IL-17, IL-22, IL-23, and TNF-α were significantly lower in mice receiving the compound, and T cells isolated from R348-treated mice also showed reduced phosphorylation of Stat5 after stimulation with IL-2. These findings suggest that small-molecule inhibitors of JAK3 may be useful in the treatment of inflammatory skin diseases such as psoriasis and strongly implicate JAK signaling events as important in the pathogenesis of this disease.

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Section: Jak3 Inhibition Significantly Attenuates Psoriasiform Skin Imentioning

confidence: 99%

Section: Reversal Of Psoriasiform Lesions In Cd18 Mutant Pl/j Micementioning

confidence: 99%

Section: R333 Selectively Inhibits Jak3 Activity In Human Primary Celmentioning

confidence: 99%

Section: Jak3 Inhibition Significantly Attenuates Psoriasiform Skin Imentioning

confidence: 99%

See 2 more Smart Citations

JAK3 Inhibition Significantly Attenuates Psoriasiform Skin Inflammation in CD18 Mutant PL/J Mice

Chang

Zhao

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our group has recently shown that R348 prevents acute allograft rejection in a heterotopic heart transplant model and synergistically interacts with tacrolimus (24). In this study, we demonstrate that the efficacy of this JAK3 inhibitor also prevents the development of chronic rejection in an OAD model.…”

Section: Discussionmentioning

confidence: 78%