Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates

Dominic C. Borie, Michael J. Larson, Mona G. Flores, Andrew Campbell, Geraldine Rousvoal, Sally Zhang, John P. Higgins, Douglas J. Ball, Elizabeth M. Kudlacz, William H. Brissette, Eileen A. Elliott, Bruce A. Reitz, Paul S. Changelian

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background. Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). Methods. Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. Results. Mean survival time (±SEM) in animals treated with MMF alone (23±1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5±9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2±8.7 days) than animals that received less CP-690,550 (33.3±12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. Conclusions. Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

Original languageEnglish (US)
Pages (from-to)1756-1764
Number of pages9
JournalTransplantation
Volume80
Issue number12
DOIs
StatePublished - Dec 2005
Externally publishedYes

Fingerprint

Mycophenolic Acid
Primates
Allografts
Kidney
Janus Kinase 3
tofacitinib
Pyelonephritis
Graft Rejection
Virus Diseases
Immunosuppressive Agents
Bacterial Infections
Kidney Transplantation
Non-Hodgkin's Lymphoma
Immunosuppression
Anemia
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Borie, D. C., Larson, M. J., Flores, M. G., Campbell, A., Rousvoal, G., Zhang, S., ... Changelian, P. S. (2005). Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation, 80(12), 1756-1764. https://doi.org/10.1097/01.tp.0000184634.25042.ea

Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. / Borie, Dominic C.; Larson, Michael J.; Flores, Mona G.; Campbell, Andrew; Rousvoal, Geraldine; Zhang, Sally; Higgins, John P.; Ball, Douglas J.; Kudlacz, Elizabeth M.; Brissette, William H.; Elliott, Eileen A.; Reitz, Bruce A.; Changelian, Paul S.

In: Transplantation, Vol. 80, No. 12, 12.2005, p. 1756-1764.

Research output: Contribution to journalArticle

Borie, DC, Larson, MJ, Flores, MG, Campbell, A, Rousvoal, G, Zhang, S, Higgins, JP, Ball, DJ, Kudlacz, EM, Brissette, WH, Elliott, EA, Reitz, BA & Changelian, PS 2005, 'Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates', Transplantation, vol. 80, no. 12, pp. 1756-1764. https://doi.org/10.1097/01.tp.0000184634.25042.ea
Borie, Dominic C. ; Larson, Michael J. ; Flores, Mona G. ; Campbell, Andrew ; Rousvoal, Geraldine ; Zhang, Sally ; Higgins, John P. ; Ball, Douglas J. ; Kudlacz, Elizabeth M. ; Brissette, William H. ; Elliott, Eileen A. ; Reitz, Bruce A. ; Changelian, Paul S. / Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. In: Transplantation. 2005 ; Vol. 80, No. 12. pp. 1756-1764.
@article{b19da0c1e759417c8abd2c6fcc38a15e,
title = "Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates",
abstract = "Background. Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). Methods. Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. Results. Mean survival time (±SEM) in animals treated with MMF alone (23±1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5±9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2±8.7 days) than animals that received less CP-690,550 (33.3±12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. Conclusions. Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.",
keywords = "CP690,550, Immunosuppression, JAK/STAT, JAK3, Mycophenolate mofetil, Primates, Transplantation",
author = "Borie, {Dominic C.} and Larson, {Michael J.} and Flores, {Mona G.} and Andrew Campbell and Geraldine Rousvoal and Sally Zhang and Higgins, {John P.} and Ball, {Douglas J.} and Kudlacz, {Elizabeth M.} and Brissette, {William H.} and Elliott, {Eileen A.} and Reitz, {Bruce A.} and Changelian, {Paul S.}",
year = "2005",
month = "12",
doi = "10.1097/01.tp.0000184634.25042.ea",
language = "English (US)",
volume = "80",
pages = "1756--1764",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates

AU - Borie, Dominic C.

AU - Larson, Michael J.

AU - Flores, Mona G.

AU - Campbell, Andrew

AU - Rousvoal, Geraldine

AU - Zhang, Sally

AU - Higgins, John P.

AU - Ball, Douglas J.

AU - Kudlacz, Elizabeth M.

AU - Brissette, William H.

AU - Elliott, Eileen A.

AU - Reitz, Bruce A.

AU - Changelian, Paul S.

PY - 2005/12

Y1 - 2005/12

N2 - Background. Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). Methods. Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. Results. Mean survival time (±SEM) in animals treated with MMF alone (23±1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5±9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2±8.7 days) than animals that received less CP-690,550 (33.3±12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. Conclusions. Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

AB - Background. Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). Methods. Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. Results. Mean survival time (±SEM) in animals treated with MMF alone (23±1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5±9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2±8.7 days) than animals that received less CP-690,550 (33.3±12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. Conclusions. Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

KW - CP690,550

KW - Immunosuppression

KW - JAK/STAT

KW - JAK3

KW - Mycophenolate mofetil

KW - Primates

KW - Transplantation

UR - http://www.scopus.com/inward/record.url?scp=30144434833&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=30144434833&partnerID=8YFLogxK

U2 - 10.1097/01.tp.0000184634.25042.ea

DO - 10.1097/01.tp.0000184634.25042.ea

M3 - Article

C2 - 16378072

AN - SCOPUS:30144434833

VL - 80

SP - 1756

EP - 1764

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 12

ER -