title: Inhibition of the enzyme purine nucleoside phosphorylase (PNP) reduces refractoriness to transfused platelets in a dog model.
abstract: To better define the role of T-cells in alloimmunization, we induced purine nucleoside phosphorylase (PNP) deficiency in a dog platelet transfusion model. Short-term administration of eight different drug schedules using several combinations of the PNP inhibitor 8-aminoguanosine and/or deoxyguanosine did not induce significant toxicity in four treated animals as demonstrated by blood chemistries, cell counts, and autologous platelet recovery and survival measurements. However, continuous long-term daily administration of these agents produced significant renal and/or hepatic toxicity leading to death in five of six animals. Modification of the drug schedule to early short-term administration of both deoxyguanosine and 8-aminoguanosine, followed by long-term intermittent doses of only 8-aminoguanosine, was not only well tolerated by all the animals but also resulted in significant immunosuppression. Overall, six of nine evaluable dogs (67%) treated with some combination of PNP inhibitors did not become refractory to eight weekly transfusions of platelets from a single random donor dog, P less than 0.005, compared to untreated controls, only 3/21 (14%) not immunized. Furthermore, in four evaluable recipients, discontinuation of the 8-aminoguanosine while continuing platelet transfusions from their original donors did not result in refractoriness. In addition, these four recipients were also unable to recognize platelets from two other random donors. This suggests that both specific and non-specific tolerance to foreign platelet antigens had been induced by PNP-inhibitor therapy. Other evidence for the efficacy of this immunosuppressive treatment was the almost normal post-transfusion recovery and survival of donor platelets, both during and after treatment. This suggests failure to form even low levels of platelet alloantibodies in the immunosuppressed recipients. In contrast, B-cell immunity to soluble antigens was intact as demonstrated by a normal antibody response to keyhole limpet haemocyanin (KLH) antigen.
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle.
authors.forename: S J
authors.initials: SJ
authors.lastname: Slichter
authors.forename: H J
authors.initials: HJ
authors.lastname: Deeg
authors.forename: W R
authors.initials: WR
authors.lastname: Osborne
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology; D001803:Blood Transfusion; D003849:Deoxyguanosine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D007114:Immunization; D007288:Inosine / Q000097:blood; D007519:Isoantigens; D008297:Male; D017713:Platelet Transfusion; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*
chemical_list: D007519:Isoantigens; D006151:Guanosine; C032533:8-aminoguanosine; D007288:Inosine; D011683:Purine-Nucleoside Phosphorylase; D003849:Deoxyguanosine