Douglas J Ball

Publications (2)35.2 Total impact

• Article: 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
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  ABSTRACT: 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). 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. 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. 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.
  Transplantation 01/2006; 80(12):1756-64. · 4.00 Impact Factor
• Article: Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.

  Paul S Changelian, Mark E Flanagan, Douglas J Ball, Craig R Kent, Kelly S Magnuson, William H Martin, Bonnie J Rizzuti, Perry S Sawyer, Bret D Perry, William H Brissette, [......], Michael Larson, Ming-Sing Si, Ricardo Paniagua, John Higgins, Bari Holm, Bruce Reitz, Yong-Jie Zhou, Randall E Morris, John J O'Shea, Dominic C Borie
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  ABSTRACT: Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
  Science 11/2003; 302(5646):875-8. · 31.20 Impact Factor