CHRONIC THROMBOCYTOPENIA IS INDUCED IN DOGS BY DEVELOPMENT OF CROSS-REACTING ANTIBODIES TO THE MPL LIGAND

The MpL ligand (ML) is a potent stimulus for thrombocytopoiesis. To cr eate an in vivo model of ML deficiency, we injected dogs with a recomb inant human ML (rhML) to determine whether cross-reacting antibodies w ould develop and cause thrombocytopenia. RhML was administered subcuta neously for 8 weeks to three normal dogs (mean platelets, 197 +/- 5.5 x 10(3)/mu L), Within 5 days their platelet counts were twice baseline and greater than 4 times baseline by day 21, Then, uniformly, chronic thrombocytopenia developed, At 1 week after terminating rhML, mean pl atelets were 0.5 times baseline and at 2 months 0.25 times baseline. E arly in treatment, marrow biopsies showed increased megakaryocyte numb er and ploidy, which decreased as platelets declined. Paralleling thes e changes, high titer anti-rhML antibodies developed. Autologous Cr-51 -labeled platelet recovery and survival measurements indicated that th e thrombocytopenia was principally due to decreased production. Infusi on of plasma from the thrombocytopenic dogs into two normal dogs and o ne dog previously made thrombocytopenic with rhML caused platelet coun ts to fall gradually. These studies show that dogs with anti-rhML anti bodies develop thrombocytopenia, presumably because the cross-reacting antibodies neutralize endogenous canine ML. The results strongly sugg est that NIL plays an essential role in maintaining normal platelet le vels, (C) 1997 by The American Society of Hematology.