Interleukin-4 inhibits indoleamine 2,3-dioxygenase expression in human monocytes

Indoleamine 2,3-dioxygenase (IDO), a flavin-dependent enzyme that catalyzes the conversion of tryptophan to kynurenine, is induced in peripheral blood mononuclear cells by interferon-gamma (IFN gamma). Interleukin-4 (IL-4) is a cytokine that modulates the functional properties of monocytes/macrophages, and we investigated the effects of IL-4 on IDO. We showed that IL-4 inhibited the induction of IDO mRNA and IDO activity by IFN gamma in human monocytes. The inhibitory effect was evident with as little as 2 U/mL of IL-4. These results provide the first evidence that a cytokine can provide a negative signal for IDO expression and that IL-4 can influence the catabolism of tryptophan.     

Protein-tyrosine kinase p72syk in Fc gamma RI receptor signaling

In this report we show that gamma-interferon (IFN) induces the expression of the nonreceptor protein tyrosine kinase, p72syk, and that cross-linking the Fc gamma RI receptor in IFN-differentiated U937 cells (U937IF cells) results in the activation of syk kinase. We show that syk is tyrosine phosphorylated (12-fold increase) after Fc gamma RI cross-linking. In vitro kinase assays demonstrate that the specific kinase activity of syk increased eightfold after Fc gamma RI cross- linking. The activation of signal transduction through the Fc gamma RI receptor, as measured by the respiratory burst, is associated with the tyrosine phosphorylation and catalytic activation of the syk kinase. We show that syk coprecipitates with the gamma subunit of the Fc gamma RI, Fc gamma RI gamma. The data suggest that p72syk is involved in signal transduction through the Fc gamma RI receptor, involving the Fc gamma RI gamma subunit.     

Blood transfusion exposure does not influence survival in patients with carcinoma of the breast

There is abundant evidence of immune modulation induced by exposure to blood transfusions. Some studies have demonstrated a detrimental effect of transfusion on the recurrence of malignant disease and survival. We retrospectively studied the impact of blood transfusion exposure on 229 patients with breast cancer who were seen from July 1973 to September 1980, had at least 5 years' follow-up and had been randomized by therapy at the time of diagnosis. The patients were divided into four groups according to transfusion history: Group 1 (111 patients), no transfusion; Group 2 (34 patients), first transfusion after mastectomy; Group 3 (41 patients), first transfusion at mastectomy; and Group 4 (43 patients), first transfusion before mastectomy. All transfused patients received red cells or whole blood or both. At the time of analysis, 124 (54%) of the patients had died. Only Group 2 was statistically associated with decreased survival; recurrence of disease was 85 percent in this group, compared with 53 percent to 61 percent in the other three groups (p = 0.006, log-rank test). In general, Group 2 patients received transfusions because of recurrent disease. We conclude that transfusions before or at mastectomy are not associated with increased recurrence or reduced survival in patients with breast cancer.     

Exogenous lung surfactant: effect on radiographic appearance in premature infants

At birth, premature infants of 25-29 weeks gestation, at high risk for development of neonatal respiratory distress syndrome (RDS), were given a single dose (90 mg) of calf lung surfactant extract (CLSE) by intratracheal instillation. The frequency and severity of RDS were assessed with use of a simple radiographic scoring system in which pulmonary parenchymal densities and the prominence of the air-bronchogram effect were used as indicators of widespread atelectasis. Radiographs were obtained in surfactant-treated and control infants within the first 90 minutes of life as part of an initial evaluation of their pulmonary status. Subsequent examinations were performed at less than 24 hours and less than 48 hours of age. Radiographic assessment of lung disease compared consistently with coordinated data on oxygen and mean airway pressure requirements of the infants. Both indicated a significantly decreased frequency and severity of RDS in the infants treated with surfactant. The results provide supporting evidence of the effectiveness of exogenous lung surfactant replacement in mitigating RDS in very premature infants.     

The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells

Multiple signal transduction cascades, consisting of multiple interacting proteins, are activated following stimulation through most cell surface receptors, including the immunoglobulin receptor of B lymphocytes. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, resulting in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a lipid kinase that consists of an 85-kD regulatory subunit, bound to a 110-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that contains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 120-kD protein that is expressed in early B-lineage cells and in myeloid cells and is phosphorylated on tyrosine following receptor-mediated signaling in T and B lymphocytes. We demonstrate here that phosphorylated c-cbl complexes with CD19 and with PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active PI3K in anti-Ig- stimulated cells. Although we cannot differentiate between a three- component, c-cbl/CD19/p85 complex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct signal transduction pathways.     

Active immunization of murine allogeneic bone marrow transplant donors with B-cell tumor-derived idiotype: a strategy for enhancing the specific antitumor effect of marrow grafts

Persistence of the underlying malignancy remains the major obstacle limiting the success of high-dose chemoradiotherapy with allogeneic bone marrow transplantation (BMT) for lymphomas and multiple myeloma. We used the C3H 38C13 murine B-cell lymphoma, which expresses and secretes clonally derived Ig, the idiotype of which can serve as a tumor-specific antigen, to test the principle of transfer of tumor idiotype-specific immunity with BM. BALB/c marrow donors were twice immunized with 38C13-derived Ig, or with an isotype-matched control Ig, conjugated to keyhole limpet hemocyanin. Lethally irradiated C3H recipients reconstituted with marrow from idiotype immune, but not nonspecifically immune, donors demonstrated protection against subsequent lethal tumor challenge. The immunoprotective effect of immune allogeneic marrow was abrogated by T-cell depletion of the marrow graft before infusion. Low levels of serum anti-idiotypic antibody remained unaltered in recipients of T-cell-depleted immune marrow, consistent with a primary role for T-cell immunity in the cellular mechanism of this phenomenon. A modest therapeutic effect of immune allogeneic marrow was observed against 10 day, 1 cm established subcutaneous tumors, but only in combination with a booster immunization of the recipient post-BMT. These results provide the rationale for a novel strategy for enhancing the specific antitumor effect of allogeneic marrow grafts.     

Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2

Human T-cell lymphotropic virus I (HTLV-I)-induced adult T-cell leukemia (ATL) cells constitutively express interleukin-2 (IL-2) receptors identified by the anti-Tac monoclonal antibody (MoAb), whereas normal resting cells do not. This observation provided the scientific basis for a trial of intravenous anti-Tac in the treatment of nine patients with ATL. The patients did not suffer untoward reactions and did not have a reduction in the normal formed elements of the blood, and only one of the nine produced antibodies to the anti-Tac MoAb. Three patients had transient mixed, partial, or complete remissions lasting from 1 to more than 8 months after anti-Tac therapy, as assessed by routine hematologic tests, immunofluorescence analysis of circulating cells, and molecular genetic analysis of HTLV-I provirus integration and of the T-cell receptor gene rearrangement. The precise mechanism of the antitumor effects is unclear; however, the use of a MoAb that prevents the interaction of IL-2 with its receptor on ATL cells provides a rational approach for the treatment of this malignancy.