Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates

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

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (γc). Because mutations in genes encoding γc or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. Methods. Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n=18) or its vehicle (controls, n=3) and were euthanized at day 90 or earlier if there was allograft rejection. Results. Mean survival time (± standard error of mean) in animals treated with CP-690,550 (53±7 days) was significantly longer than in control animals (7±1 days, P=0.0003) and was positively correlated with exposure to the drug (r=0.79, P<0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46±7 days from transplantation vs. 7±1 days in controls, P=0.0003). Persistent anemia, polyoma virus-like nephritis (n=2), and urinary calcium carbonate accretions (n=3) were seen in animals with high exposure. Natural killer cell and CD4+ and CD8+ T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. Conclusions. 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.

Original languageEnglish (US)
Pages (from-to)791-801
Number of pages11
JournalTransplantation
Volume79
Issue number7
DOIs
StatePublished - Apr 15 2005

Fingerprint

Janus Kinase 3
Immunosuppression
Primates
Allografts
Kidney
Polyomavirus
Mixed Lymphocyte Culture Test
Cytokine Receptors
Macaca fascicularis
tofacitinib
Nephritis
Calcium Carbonate
Blood Group Antigens
Natural Killer Cells
Kidney Transplantation
Blood Glucose
Anemia
Signal Transduction
Arterial Pressure
Reference Values

Keywords

  • CP690,550
  • Immunosuppression
  • JAK/STAT
  • JAK3
  • Primates
  • Transplantation

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

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.; Si, Ming Sing; Paniagua, Ricardo; Higgins, John P.; Holm, Bari; Campbell, Andrew; Lau, Macy; 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.

In: Transplantation, Vol. 79, No. 7, 15.04.2005, p. 791-801.

Research output: Contribution to journalArticle

Borie, DC, Changelian, PS, Larson, MJ, Si, MS, Paniagua, R, Higgins, JP, Holm, B, Campbell, A, Lau, M, Zhang, S, Flores, MG, Rousvoal, G, Hawkins, J, Ball, DA, Kudlacz, EM, Brissette, WH, Elliott, EA, Reitz, BA & Morris, RE 2005, 'Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates', Transplantation, vol. 79, no. 7, pp. 791-801. https://doi.org/10.1097/01.TP.0000157117.30290.6F
Borie, Dominic C. ; Changelian, Paul S. ; Larson, Michael J. ; Si, Ming Sing ; Paniagua, Ricardo ; Higgins, John P. ; Holm, Bari ; Campbell, Andrew ; Lau, Macy ; 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. / Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. In: Transplantation. 2005 ; Vol. 79, No. 7. pp. 791-801.
@article{110c454d0f564f80a2101a795c8cebe2,
title = "Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates",
abstract = "Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (γc). Because mutations in genes encoding γc or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. Methods. Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n=18) or its vehicle (controls, n=3) and were euthanized at day 90 or earlier if there was allograft rejection. Results. Mean survival time (± standard error of mean) in animals treated with CP-690,550 (53±7 days) was significantly longer than in control animals (7±1 days, P=0.0003) and was positively correlated with exposure to the drug (r=0.79, P<0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46±7 days from transplantation vs. 7±1 days in controls, P=0.0003). Persistent anemia, polyoma virus-like nephritis (n=2), and urinary calcium carbonate accretions (n=3) were seen in animals with high exposure. Natural killer cell and CD4+ and CD8+ T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. Conclusions. 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.",
keywords = "CP690,550, Immunosuppression, JAK/STAT, JAK3, Primates, Transplantation",
author = "Borie, {Dominic C.} and Changelian, {Paul S.} and Larson, {Michael J.} and Si, {Ming Sing} and Ricardo Paniagua and Higgins, {John P.} and Bari Holm and Andrew Campbell and Macy Lau and Sally Zhang and Flores, {Mona G.} and Geraldine Rousvoal and Jennifer Hawkins and Ball, {Douglas A.} and Kudlacz, {Elizabeth M.} and Brissette, {William H.} and Elliott, {Eileen A.} and Reitz, {Bruce A.} and Morris, {Randall E.}",
year = "2005",
month = "4",
day = "15",
doi = "10.1097/01.TP.0000157117.30290.6F",
language = "English (US)",
volume = "79",
pages = "791--801",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates

AU - Borie, Dominic C.

AU - Changelian, Paul S.

AU - Larson, Michael J.

AU - Si, Ming Sing

AU - Paniagua, Ricardo

AU - Higgins, John P.

AU - Holm, Bari

AU - Campbell, Andrew

AU - Lau, Macy

AU - Zhang, Sally

AU - Flores, Mona G.

AU - Rousvoal, Geraldine

AU - Hawkins, Jennifer

AU - Ball, Douglas A.

AU - Kudlacz, Elizabeth M.

AU - Brissette, William H.

AU - Elliott, Eileen A.

AU - Reitz, Bruce A.

AU - Morris, Randall E.

PY - 2005/4/15

Y1 - 2005/4/15

N2 - Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (γc). Because mutations in genes encoding γc or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. Methods. Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n=18) or its vehicle (controls, n=3) and were euthanized at day 90 or earlier if there was allograft rejection. Results. Mean survival time (± standard error of mean) in animals treated with CP-690,550 (53±7 days) was significantly longer than in control animals (7±1 days, P=0.0003) and was positively correlated with exposure to the drug (r=0.79, P<0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46±7 days from transplantation vs. 7±1 days in controls, P=0.0003). Persistent anemia, polyoma virus-like nephritis (n=2), and urinary calcium carbonate accretions (n=3) were seen in animals with high exposure. Natural killer cell and CD4+ and CD8+ T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. Conclusions. 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.

AB - Background. Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (γc). Because mutations in genes encoding γc or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. Methods. Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n=18) or its vehicle (controls, n=3) and were euthanized at day 90 or earlier if there was allograft rejection. Results. Mean survival time (± standard error of mean) in animals treated with CP-690,550 (53±7 days) was significantly longer than in control animals (7±1 days, P=0.0003) and was positively correlated with exposure to the drug (r=0.79, P<0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46±7 days from transplantation vs. 7±1 days in controls, P=0.0003). Persistent anemia, polyoma virus-like nephritis (n=2), and urinary calcium carbonate accretions (n=3) were seen in animals with high exposure. Natural killer cell and CD4+ and CD8+ T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. Conclusions. 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.

KW - CP690,550

KW - Immunosuppression

KW - JAK/STAT

KW - JAK3

KW - Primates

KW - Transplantation

UR - http://www.scopus.com/inward/record.url?scp=20244368823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20244368823&partnerID=8YFLogxK

U2 - 10.1097/01.TP.0000157117.30290.6F

DO - 10.1097/01.TP.0000157117.30290.6F

M3 - Article

C2 - 15818321

AN - SCOPUS:20244368823

VL - 79

SP - 791

EP - 801

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 7

ER -