Immunomodulation In An Infant With Familial Hemophagocytic Lymphohistiocytosis (FHLH) Following Chemotherapy

Abstract • 29

FHLH is an autosomal recessive disorder associated with hepatosplenomegaly, cytopenias lymphohistiocytic accumulation in the reticuloendothelial system and hemaphagocytosis. Immunologic dysregulation with defective T cell, NK activity, macrophage activation and cytokine production can occur. Elevated transforming growth factor beta TGF_b produced by activated T cells and monocytes can be anti-inflammatory, whereas interleukin-6 (IL-6) induces T cell proliferation and activation. We have reported IL-6 and nitric oxide (NO) to increase in monocyte cultures after antigen stimulation (Ann Allergy 73:493-6, 1994; J. Allergy Clin. Immunol. 101:243a, 1998). We clinically and immunologically evaluated a 5-month-old Hispanic infant with FHLH for TGF_b, IL-6, (NO) and extended lymphocyte phenotypes, CD3⁺, CD4⁺, CD8⁺, CD28⁺, CD95⁺, (fas rc), CD54RA⁺, CD62L⁺, DR⁺, CD38⁺, CD69⁺ using ELISA, Greiss reagent and 4′ color flow cytometry pre and post chemotherapy with VP 16 @ 65 mg/m² and dexamethasone over 10 courses of treatment. TGF_b (924.4 pg/ml-4286.8 pg/ml), IL-6 (215.4 pg/ml-4225 pg/ml) in PHA-stimulated supernatant mononuclear cells and serum NO (4.267 µM-11.660 µM) dramatically increased post treatment along with CD8⁺ T cells (22-30%) and NK⁺ cells (2-14%). Resting naïve cells (CD54RA⁺ CD62L⁺) decreased in CD4⁺ (75-52%) and CD8⁺ (64-47%). T cell activation was suggested by increases in CD95⁺ cells on CD4⁺ cells (1-19%) and CD38⁺ CD69⁺ cells (1-23%) and HLADR⁺ CD69⁺ cells (1-25%) on CD8⁺ cells. Immunoregulatory cytokine changes along with T cell and NK phenotypes may indicate a direct or indirect effect of chemotherapy on the pathogenesis of FHLH. A markedly improved clinical response was noted following treatment. Thus, both a favorable clinical and immunologic effect was noted following chemotherapy for FHLH.