Effects of JAK3 Inhibition with CP-690,550 on Immune Cell Populations and Their Functions in Nonhuman Primate Recipients of Kidney Allografts

Paniagua, Ricardo; Sing, Ming; Flores, M; Rousvoal, Geraldine; Zhang, Sally; Aalami, Oliver; Campbell, Andrew; Changelian, Paul S.; Reitz, Bruce A.; Borie, Dominic C.

doi:10.1097/01.tp.0000177643.05739.cd

Cited by 81 publications

(57 citation statements)

References 52 publications

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“…The question then arises: what alternative signals or cytokine (s) might play a role in their homeostasis? Interestingly, treatment of monkeys and human patients with the JAK1,3 inhibitor tofacitinib (CP-690,550) induces a reduction in the number of circulating NK cells (14,15,25). Tofacitinib inhibits JAK3 and thus type 1 and 2 IFNs and multiple common g-chain cytokine signaling, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signaling (26).…”

Section: Discussionmentioning

confidence: 99%

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Homeostasis of Human NK Cells Is Not IL-15 Dependent

Lebrec

Horner

Gorski

et al. 2013

The Journal of Immunology

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IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15–induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti–IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15–mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

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Section: Discussionmentioning

confidence: 99%

“…Similarly, the Jak inhibitor tofacitinib (CP-690,550), which inhibits the signaling of all common g cytokines, has also been shown to induce a profound reduction in the number of circulating NK cells in macaques (14,15).…”

mentioning

confidence: 99%

Homeostasis of Human NK Cells Is Not IL-15 Dependent

Lebrec

Horner

Gorski

et al. 2013

The Journal of Immunology

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“…We also treated cohort 3 RMs with a JAK inhibitor at a similar dose used previously in a NHP model of kidney transplantation [29], approximately 3 months after the second CD3-IT treatment. JAK inhibitor treatment was shown to prolong survival of kidney transplants in cynomolgus monkeys, reduce total peripheral lymphocytes and inhibit the transcription of granzyme B, FasL, RANTES, MIG and IP-10 [97].…”

Section: Discussionmentioning

confidence: 99%

“…Anti-monkey CD3 recombinant immunotoxin (CD3-IT) at 50 lg/kg was administered intravenously by slow bolus injection (NHP resource, material produced by the Massachusetts General Hospital-Dana Farber-Harvard Cancer Center Recombinant Protein Expression and Purification Core Facility) [19,23,24]. JAK inhibitor (tofacitinib citrate, CP-690550 citrate; Selleckchem, Houston, TX, USA) at 15 mg/kg diluted in 0Á5% methylcellulose was given for 5 consecutive days by oral gavage [29]. Each cohort consisted of four animals, which is the minimum number of animals needed to achieve sufficient power to detect a statistically significant difference in various immunological parameters following SVV infection [37,[56][57][58][59].…”

Section: Animals and Sample Collectionmentioning

confidence: 99%

“…JAK inhibitor (tofacitinib citrate, CP-690550 citrate) inhibits mainly JAK3, but also JAK1, JAK2 and, to a lesser degree, tyrosine kinase 2 (TYK2), resulting in the inhibition of cytokine signalling and functionally interfering with T helper type 1 (Th1) and Th2 differentiation as well as suppressing the generation of Th17 cells [26][27][28]. JAK inhibitor has been investigated in a NHP kidney transplant model [29,30] and evaluated further in human kidney transplant settings [31,32]. Furthermore, JAK inhibitors are also being developed for treatment of rheumatoid arthritis [33,34], psoriasis [35] and colitis [36].…”

Section: Introductionmentioning

confidence: 99%

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Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Meyer

Walker

Dewane

et al. 2015

Clinical and Experimental Immunology

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SummaryIn this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease.

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Immunosuppressive Agents for the Prevention of Transplantation Rejection

Pitts

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus), mTOR ( m ammalian t arget o f r apamycin ) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP‐690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab‐CD3, basiliximab, and daclizumab) are discussed elsewhere.

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Effects of JAK3 Inhibition with CP-690,550 on Immune Cell Populations and Their Functions in Nonhuman Primate Recipients of Kidney Allografts

Abstract: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

Cited by 81 publications

References 52 publications

Homeostasis of Human NK Cells Is Not IL-15 Dependent

Homeostasis of Human NK Cells Is Not IL-15 Dependent

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

Immunosuppressive Agents for the Prevention of Transplantation Rejection

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