DEFUNCT HEMATOPOIETIC PROGENITOR GROWTH AND HETEROGENEOUS IMMUNOLOGICAL PHENOTYPES IN ACQUIRED APLASTIC-ANEMIA OF CHILDHOOD - IDENTIFICATION OF SUBSETS WITH DECREASED HEMATOPOIETIC PROGENITORS AND INCREASED IL15 OR IL10 PRODUCTION

Acquired aplastic anemia (AAA) is a disorder with multiple causes. The pathogenetic mechanisms leading to marrow failure are diverse. The cl inical finding, that most patients respond to immunosuppressive therap y implicates an immune pathophysiology of AAA. On the other hand succe ssful and long lasting reconstitution after allogeneic stem cell trans plantation implicates, that a stem cell defect is a major pathogenetic factor. We analyzed immunological and hematological parameters on 91 pediatric patients with AAA at time of diagnosis. We defined three dis tinct pathogenetic subgroups by analyzing the frequency of hematopoiet ic progenitors and the frequency of activated T-cells in patients bone marrow: type I: decreased percentage of hematopoietic progenitors; ty pe II: increased percentage of activated T-cells; type III: increased percentage of pluripotent progenitors. In 51% of the AAA patients we f ound a relative decreased frequency of hematopoietic progenitors and 2 9% of the patients demonstrated an increased percentage of activated T -cells, 25% patients showed an increased percentage of pluripotent hem atopoietic progenitors. In order to characterize these distinct immuno logical subgroups, we investigated the plasma levels of IFN-gamma and IL15 as inhibitors and ILIO as stimulator of hematopoiesis. IL15 plasm a levels were significantly elevated in AAA patients when compared to controls. In contrast we could not demonstrate a difference between IF N-gamma or IL10 plasma levels in AAA patients when compared to control s. However for IL10 and IL15 we were able to define subgroups of patie nts with highly elevated plasma levels of the cytokines. These data in dicate that the immunopathogenesis of AAA can be heterogeneous. This h eterogeneity might reflect exposure to different exogenous agents or h eterogeneity in intrinsic susceptibility. The clinical impact of our f indings needs to be assessed in long-term follow up of the patients.