Immunosuppression by the JAK3 Inhibitor CP-690,550 Delays Rejection and Significantly Prolongs Kidney Allograft Survival in Nonhuman Primates

Borie, Dominic C.; Changelian, Paul S.; Larson, Michael J.; Sing, Ming; Paniagua, Ricardo; Higgins, Julian P T; Holm, Bari; Campbell, Andrew; Lau, M; Zhang, Sally; Flores, Mona G.; Rousvoal, Geraldine; Hawkins, Jennifer; Ball, Douglas A.; Kudlacz, Elizabeth M.; Brissette, William H.; Elliott, Eileen A.; Reitz, Bruce A.; Morris, Randall E.

doi:10.1097/01.tp.0000157117.30290.6f

Cited by 100 publications

(79 citation statements)

References 51 publications

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“…This result, coupled with our findings, may provide an impetus for the reporting of macaque origins in pathogenesis studies and spur research into the functional consequences of these regional differences. Currently, macaque origins are rarely specified in methods sections of immunology and pathogenesis publications (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54), though this data may be profoundly influential.…”

Section: Discussionmentioning

confidence: 99%

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

Krebs

Jin

Rudersdorf

et al. 2005

The Journal of Immunology

106

116

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Acute shortages of Indian origin Rhesus macaques significantly hinder HIV/AIDS research. Cellular immune responses are particularly difficult to study because only a subset of animals possess MHC class I (MHC I) alleles with defined peptide-binding specificities. To expand the pool of nonhuman primates suitable for studies of cellular immunity, we defined 66 MHC I alleles in Cynomolgus macaques (Macaca fascicularis) of Chinese, Vietnamese, and Mauritian origin. Most MHC I alleles were found only in animals from a single geographic origin, suggesting that Cynomolgus macaques from different origins are not interchangeable in studies of cellular immunity. Animals from Mauritius may be particularly valuable because >50% of these Cynomolgus macaques share the MHC class I allele combination Mafa-B*430101, Mafa-B*440101, and Mafa-B*460101. The increased MHC I allele sharing of Mauritian origin Cynomolgus macaques may dramatically reduce the overall number of animals needed to study cellular immune responses in nonhuman primates while simultaneously reducing the confounding effects of genetic heterogeneity in HIV/AIDS research.

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Section: Discussionmentioning

confidence: 99%

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

Krebs

Jin

Rudersdorf

et al. 2005

The Journal of Immunology

106

116

View full text Add to dashboard Cite

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“…99 In animal studies, dosedependent anemia was commonly seen, which is consistent with its known 'off-target' JAK2-inhibitory activity (20-fold less JAK2 inhibition as compared to JAK3) 99 Finterestingly, it was possible to overcome the suppressive effect on erythropoiesis by administering exogenous Epo in cynomolgus monkeys that were exposed to lower levels of the drug. 100 Chronic exposure to CP-690,550 has been reported to cause changes in immune cell subsets in rodent 101 and monkey allotransplant models, 102 an effect that is reflected primarily in reduced numbers of natural killer cells and CD8 þ T lymphocytes; in contrast, B-lymphocyte numbers may be relatively preserved.…”

Section: Clinical Trialsmentioning

confidence: 99%

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

2007

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“…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%

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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Immunosuppression by the JAK3 Inhibitor CP-690,550 Delays Rejection and Significantly Prolongs Kidney Allograft Survival in Nonhuman Primates

Abstract: CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.

Cited by 100 publications

References 51 publications

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials

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

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