EXPERIMENTAL BASIS OF A THERAPY-ORIENTED PATHOGENETIC CLASSIFICATION OF APLASTIC-ANEMIA IN CHILDHOOD

Growth and differentiation of hematopoietic progenitor cells is regula ted by a complex network of stimulatory and inhibitory cytokines. Bone marrow failures can be due to a decrease of stimulators or an increas e of inhibitors. T cells produce both. hematopoiesis stimulating and i nhibiting cytokines. Therefore, a role of T cells in regulating hemato poiesis can only be assumed if the gene expression of these antagonist ic acting cytokines can be differentially induced in T cells. To estab lish a model of selective cytokine induction, we investigated the indu ction of IFNgamma as inhibitor and GM-CSF as stimulator of hematopoies is in T cells. Our results showed that IFNgamma mRNA accumulates in T cells which have been pre-activated via the signal transduction unit C D3, but not in unstimulated T cells. This accumulation depends on the expression of the high affinity IL2 receptor which is including the IL 2 receptor alpha-chain (IL2Ralpha, CD25). In a study on children with constitutional (CAA) versus acquired aplastic (EAA) anemia, we investi gated the relevance of this model for the pathogenesis of aplastic ane mia in childhood. We compared the following parameters: 1. Incidence o f hematopoietic progenitor cells and cloning efficiency. 2. activation status and IL2Ralpha expression of bone marrow T cells, 3. T cell cyt okine expression profile. Our results show: 1. The relative incidence of bone marrow progenitor cells is decreased in children with CAA and normal in children with EAA. 2. Clonogenic growth of hematopoietic pro genitor cells is suppressed in children with EAA. 3. Native T cells of children with CAA show an increased induction capacity of IFNgamma pr oduction, however, the induction capacity in children with CAA is norm al. 4. Children with EAA show an increased incidence of activated, IL2 expressing T cells in the bone marrow. Based on these results we woul d like to propose the following therapy-based classification of childh ood aplastic anemias: Aplastic anemias type I (CAA) is due to a reduct ion in the progenitor cell pool. Therefore, bone marrow transplantatio n would be the treatment of choice. In contrast, aplastic anemias type II (EAA) are caused by immunological suppression of the progenitor ce ll growth. In these patients. immunosuppression or -modulation would b e the treatment of choice.