Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A.
In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.
Pai
S Y
SY
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Fruman
D A
DA
Leong
T
T
Neuberg
D
D
Rosano
T G
TG
McGarigle
C
C
Antin
J H
JH
Bierer
B E
BE
D000208:Acute Disease; D000328:Adult; D001853:Bone Marrow / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006086:Graft vs Host Disease / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors
D002148:Calmodulin-Binding Proteins; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases