PubMed · 5676958
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S R Mawson. 1968-08-31. Myringotomy.. https://doi.org/10.1136/bmj.3.5617.539
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BACKGROUND: Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the alpha chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation. METHODS: We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation. RESULTS: Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the 134 patients (35 percent) who received placebo (P=0.03). Graft survival at 12 months was 95 percent in the daclizumab-treated patients, as compared with 90 percent in the patients given placebo (P=0.08). The patients given daclizumab did not have any adverse reactions to the drug, and at six months, there were no significant differences between the two groups with respect to infectious complications or cancers. The serum half-life of daclizumab was 20 days, and its administration resulted in prolonged saturation of interleukin-2alpha receptors on circulating lymphocytes. CONCLUSIONS: Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.
In recent pediatric trials of acute myeloid leukemia (AML), children with Down syndrome (DS) have had significantly more megakaryoblastic leukemia and have experienced better outcome than other children. To further characterize AML in DS, Children's Cancer Group Studies 2861 and 2891 prospectively studied demography, biology, and response in AML and myelodysplastic syndrome (MDS) of children with and without DS. These studies evaluated timing of induction therapy and compared postremission chemotherapy with marrow transplantation in 1,206 children. One-hundred eighteen (9.8%) had DS, a fourfold increase in 20 years. DS patients were younger, had lower white blood cell and platelet counts, more antecedent MDS, acute megakaryoblastic leukemia or undifferentiated AML, and an under-representation of chromosomal translocations (P < .001 for each variable). Four-year event-free survival in DS was 69% versus 35% in others (P < .001). Intensively timed induction conferred significantly higher mortality in DS patients; bone marrow transplantation offered no advantage. Conventional induction followed by chemotherapy achieved an 88%, 4-year, disease-free survival in DS patients versus 42% in others (P < .001). Megakaryoblastic leukemia was unfavorable in others but prognostically neutral in DS. AML in DS is demographically and biologically distinct from AML in other children. It is singularly responsive to conventional chemotherapy and may warrant even less therapy. The increasing proportion of DS patients with AML most likely reflects changes in attitudes about entering DS patients on AML trials and possibly increasing ability to distinguish megakaryoblastic leukemia from lymphoid leukemia.
We report here a naturally occurring isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 (GMRbetaC) with a truncated intracytoplasmic tail caused by deletion of a 104-bp exon in the membrane-proximal region of the chain. This beta intracytoplasmic truncated chain (betaIT) has a predicted tail of 46 amino acids, instead of 432 for betaC, with 23 amino acids in common with betaC and then a new sequence of 23 amino acids. In primary myeloid cells, betaIT comprised approximately 20% of the total beta chain message, but was increased up to 90% of total in blast cells from a significant proportion of patients with acute leukemia. Specific anti-betaIT antibodies demonstrated its presence in primary myeloid cells and cell lines. Coexpression of betaIT converted low-affinity GMRalpha chains (KD 2.5 nmol/L) to higher-affinity alphabeta complexes (KD 200 pmol/L). These could bind JAK2 that was tyrosine-phosphorylated by stimulation with GM-CSF. betaIT did not support GM-CSF-induced proliferation when cotransfected with GMRalpha into CTLL-2 cells. Therefore, it may interfere with the signal-transducing properties of the betaC chain and play a role in the pathogenesis of leukemia.