Janus kinase 3 inhibition with CP-690,550 prevents allograft vasculopathy.
Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common gamma chain. The rationally designed inhibitor of JAK3, CP-690,550, prevents acute allograft rejection in rodents and in nonhuman primates. Here we investigated the ability of CP-690,550, to prevent allograft vasculopathy in a rodent model of aorta transplantation. Aortas from AxC Irish (RT1(a)) or Lewis (RT1(l)) rats were heterotopically transplanted into the infra-renal aorta of Lewis recipients and harvested at 28 or 56 days. Treated recipients received CP-690,550 by osmotic pumps (mean drug exposure of 110 +/- 38 ng/ml). Significant intimal hyperplasia was demonstrated in untreated allografts when compared with isografts at 28 days (2.08 +/- 0.85% vs. 0.43 +/- 0.2% luminal obliteration, respectively, P = 0.001) and 56 days (5.3 +/- 2.4% vs. 0.38 +/- 0.3%, P = 0.002). Treatment caused a 51% reduction in intimal hyperplasia at day 56. CP-690,550-treated animals also had a significant reduction of donor-specific IgG production and of the gene expression for suppressor of cytokine signaling-3 and with unchanged levels of expression of RANTES, IP-10 and transforming growth factor-beta1. These results are the first to show that JAK3 blockade by CP-690,550 effectively prevents allograft vasculopathy in this rat model of aorta transplantation.
Rousvoal
Geraldine
G
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5407, USA.
Si
Ming-Sing
MS
Lau
Macy
M
Zhang
Sally
S
Berry
Gerald J
GJ
Flores
Mona G
MG
Changelian
Paul S
PS
Reitz
Bruce A
BA
Borie
Dominic C
DC
D000818:Animals; D001011:Aorta / Q000637:transplantation*; D001161:Arteriosclerosis / Q000517:prevention & control*; D018946:Chemokine CCL5 / Q000235:genetics; D006965:Hyperplasia; D007371:Interferon-gamma / Q000096:biosynthesis; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000473:pathology
D018946:Chemokine CCL5; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; C479163:tofacitinib; D053616:Janus Kinase 3