title: The effects of 16, 16 dimethyl prostaglandin E2 therapy alone and in combination with low-dose cyclosporine on rat small intestinal transplantation.
abstract: The use of prostaglandin E (PGE) in the setting of allotransplantation both clinically and experimentally has been suggested because PGE has significant immunosuppressive effects and potentially could lessen the toxic effects of cyclosporine. In the present study, we examined the immunosuppressive effects of 16,16 dimethyl prostaglandin E2 (dmPGE2) alone and in combination therapy with low-dose CsA to assess the clinical course, histology and expression of monocyte/macrophage procoagulant activity (PCA) following small intestinal transplantation in a heterotopic model of rat allograft rejection. Therapy with low-dose CsA (1 mg/kg) failed to prevent rejection and all animals reached a terminal state by day 26. In contrast, animals treated with high-dose CsA (10 mg/kg) showed no clinical or histological evidence of rejection and all animals survived. The dmPGE2 (100 micrograms/kg/twice daily) delayed the onset of rejection, but all animals developed severe rejection and subsequently died. Treatment of animals with low-dose CsA (1 mg/kg) in combination with dmPGE2 (100 micrograms/kg twice daily) resulted in a delay in the onset (P = 0.05) and a reduction in the intensity of allograft rejection (P = 0.0001) compared with either agent used alone. Monocyte/macrophage procoagulant activity levels correlated with the degree of rejection in all animals (P = 0.03). There was a statistically significant relationship between PCA levels and the time of onset of rejection and histologic grade of rejection in all groups. The data presented here, therefore, demonstrate a beneficial role for long-term combination therapy with CsA and PGE in small intestinal transplantation and strongly suggest a role for allogeneic induction of PCA in the pathogenesis of rejection.
authors.affiliation: Department of Surgery, University of Toronto, Ontario, Canada.
authors.forename: I H
authors.initials: IH
authors.lastname: Koh
authors.forename: P C
authors.initials: PC
authors.lastname: Kim
authors.forename: S W
authors.initials: SW
authors.lastname: Chung
authors.forename: T
authors.initials: T
authors.lastname: Waddell
authors.forename: P Y
authors.initials: PY
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Gorczynski
authors.forename: G A
authors.initials: GA
authors.lastname: Levy
authors.forename: Z
authors.initials: Z
authors.lastname: Cohen
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000627:therapeutic use*; D000818:Animals; D001779:Blood Coagulation Factors / Q000032:analysis; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000097:blood / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007421:Intestine, Small / Q000637:transplantation*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D001779:Blood Coagulation Factors; D007166:Immunosuppressive Agents; C045071:leukocyte procoagulant activity; C045072:macrophage procoagulant activity; D016572:Cyclosporine; D015064:16,16-Dimethylprostaglandin E2