ABSTRACT
The immunological environment of leukemic blasts in the bone marrow might play a decisive role in determining an individual's risk for relapse. In order to identify potential predictors of relapse and to elucidate the mechanisms of immune control of leukemic blasts we examined the expression of cytokines, costimulatory molecules and members of the TNF family in leukemic marrow samples in a prospective study. Samples from 49 consecutive pediatric patients with B cell precursor acute lymphocytic leukemia (BCP ALL) were analyzed by semiquantitative RT-PCR. We identified interleukin (IL)-10 expression as a significant adverse prognostic indicator in childhood BCP-ALL. The event free survival (EFS) of patients expressing IL-10 mRNA in high quantity was significantly lower compared with patients expressing low IL-10 mRNA. Taqman RT-PCR of sorted cell populations showed that IL-10 mRNA was synthetized almost exclusively by NK or T cells. In addition, we found an increased expression of IL-1, IL-4, CD86 and VEGF mRNA in patients with late relapses. Possibly, ALL cells mediate a Th2 shift through increased expression of CD86 and thereby influence the individual relapse risk. These findings emphasize the role of the immune system for the outcome of childhood ALL.
Subject(s)
Bone Marrow Cells/immunology , Burkitt Lymphoma/genetics , Burkitt Lymphoma/immunology , Cytokines/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology , Th2 Cells/immunology , Adolescent , B7-2 Antigen/genetics , Base Sequence , Child , Child, Preschool , Cytokines/metabolism , Female , Gene Expression , Humans , Infant , Interleukin-1/genetics , Interleukin-10/genetics , Interleukin-4/genetics , Male , Prognosis , Prospective Studies , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Recurrence , Transcription, GeneticABSTRACT
OBJECTIVE: Soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) might modulate nutritional status in acute leukemia since they are inhibitors of tumor necrosis factor-alpha and interleukin-1 that can induce tissue wasting. On the other hand, tumor load and hypermetabolism may induce malnutrition. We determined whether serum levels of sTNF-RII and IL-1ra are upregulated to prevent overt malnutrition and whether tumor load and hypermetabolism induce overt malnutrition. METHODS: We examined 31 children with newly diagnosed acute leukemia and correlated sTNF-RII, IL-1ra, tumor load and energy expenditure to anthropometric characteristics (weight, weight for height, height, body mass index, fat free mass) and serum protein concentrations (albumin, transferrin, prealbumin). As controls, 68 healthy children were examined for anthropometric characteristics; 33 healthy controls were included for cytokine analysis and biochemical indices. RESULTS: We found no correlations between sTNF-RII, IL-1ra, tumor load and energy expenditure and anthropometric characteristics or protein concentrations. Mean sTNF-RII level was significantly, mean IL-1ra level slightly increased (223% and 113% of the controls). 29% of the children had a high tumor load (> 100.000/microl white blood cells) and 53% had hypermetabolism (resting energy expenditure > 110% of predicted). Anthropometric characteristics were similar to those in controls, however, serum protein concentrations were decreased. CONCLUSION: sTNF-RII and IL-1ra are upregulated in children with leukemia and may therefore prevent overt malnutrition. Tumor load and hypermetabolism do not induce overt malnutrition. The children presented with an early stage of malnutrition as evidenced by low serum protein concentrations but normal anthropometric characteristics.
Subject(s)
Leukemia/blood , Leukemia/metabolism , Malnutrition/metabolism , Receptors, Tumor Necrosis Factor, Type II/blood , Sialoglycoproteins/blood , Acute Disease , Adolescent , Anthropometry , Case-Control Studies , Child , Child, Preschool , Energy Metabolism , Female , Humans , Infant , Interleukin 1 Receptor Antagonist Protein , Leukemia/pathology , Male , Prealbumin/analysis , Serum Albumin/analysis , Solubility , Transferrin/analysis , Tumor BurdenABSTRACT
A 5-month-old male presented with fever, hepatosplenomegaly, leukocytosis with atypical lymphoblasts, anemia and thrombocytopenia. Severe combined imunodeficiency syndrome (T-, B+, NK+), B lymphoproliferative disease and hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus (EBV) were diagnosed. As his clinical situation deteriorated rapidly, BMT was performed with unmanipulated marrow stem cells from his EBV-positive HLA-identical sister after conditioning with dexamethasone (1.75 mg/kg/day), cyclophosphamide (114 mg/kg) and etoposide (10 mg/kg), with no immunosuppression given post transplant. Engraftment occurred on day 6 with explosive proliferation of donor CD8(+) T cells. The patient died 3 days later from acute respiratory distress syndrome. Autopsy revealed full donor engraftment and no signs of hemophagocytic lymphohistiocytosis or B lymphoproliferative disease. Thus, transplanted T cells can expand very rapidly within days after BMT and clear EBV lymphoproliferative disease and hemophagocytic lymphohistiocytosis.
