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Biomedical subjects

D L Longo

Publications and source records attributed to D L Longo.

At least 343 records · Page 19Linked to original sources
PubMed1989

Cytokine gene expression during the generation of human lymphokine-activated killer cells: early induction of interleukin 1 beta by interleukin 2.

Culture of human peripheral blood leukocytes with interleukin 2 (IL-2) stimulates their differentiation into lymphokine-activated killer (LAK) cells, with a broad range of cytotoxicity against fresh tumor cells and tumor cell lines (Grimm et al., J. Exp. Med., 155: 1823-1841, 1982). We chose to utilize a molecular approach to determine whether IL-2 stimulates the expression of cytokine genes by the mixed cell population which may be involved in the generation or regulation of lytic activity. Northern blot analysis performed with total cellular RNA from LAK cells cultured for varying periods of time with IL-2 revealed that the genes which code for cytokines [interleukin 1 (IL-1)alpha and beta, gamma-interferon, tumor necrosis factor alpha, and lymphotoxin] were not spontaneously expressed. As soon as 2 h after IL-2 treatment, IL-1 alpha and IL-1 beta mRNAs were expressed. Both nonadherent and adherent populations of LAK cells express IL-1 beta mRNA; however, the adherent population produced more IL-1 beta mRNA and maintained its expression for a prolonged period of time. Other cytokine mRNAs (gamma-interferon, tumor necrosis factor alpha, and lymphotoxin) were expressed later than the IL-1 mRNAs with maximal levels between Days 2 through 7. Our results indicate that LAK cell populations can generate a variety of cytokines which may be involved in the generation of lytic activity.

Cell Separation↗
PubMed1989

Appearance of neuropeptides in ascitic fluid after peritoneal therapy with interleukin-2 and lymphokine-activated killer cells for intraabdominal malignancy.

Administration of intravenous interleukin-2 (IL-2), followed by intraperitoneal IL-2 and autologous lymphokine-activated killer (LAK) cells to six patients with colonic, ovarian, or endometrial carcinoma restricted to peritoneal spread increased significantly the ascitic fluid concentrations of the neuropeptides substance P (SP) and calcitonin-gene related peptide (CGRP). After intravenous IL-2 alone, the level of SP rose 10- to 140-fold, without a change in that of CGRP. Intraperitoneal IL-2 and LAK cells led to elevations in the concentrations of SP and CGRP to respective maximal means of 319 and 175 pM after 8 hr, which were maintained for 24-48 hr without alterations in the levels of vasoactive intestinal peptide or somatostatin. SP and CGRP from peritoneal fluid were chromatographically indistinguishable from synthetic neuropeptides. The increases in concentrations of SP and CGRP after IL-2 and LAK-cell therapy are the first demonstration of a neural response to a human cellular immunological reaction. The time course and magnitude of the neuropeptide response suggest a role in the vascular side effects of this form of treatment.

Ascitic Fluid↗
PubMed1989

Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy.

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.

Adult↗
PubMed1989

Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia.

Immune function in patients with hairy cell leukemia (HCL) was examined serially during treatment with alternating monthly cycles of recombinant interferon alpha-2a and 2'-deoxycoformycin (dCF). At presentation, most patients had normal numbers of T lymphocytes and their cells had normal proliferative responses to mitogens [phytohemagglutinin (PHA) and concanavalin A (Con A)] and alloantigens. Patients had severe monocytopenia, decreased delayed-type hypersensitivity (DTH) reactions, and decreased peripheral blood natural killer (NK) activity. Treatment caused a profound decrease in all lymphocyte subpopulations. T cells were more affected than B cells or NK cells. Numbers of CD4+ and CD8+ lymphocytes decreased to levels less than 200 cells/microliters in all patients during treatment. This decrease in T cell number was associated with a marked decrease in proliferative responsiveness to PHA, Con A, and alloantigens. These abnormalities persisted throughout the 14 months of treatment and have continued for up to 6 months beyond discontinuation of treatment. NK cell activity increased during treatment, but cycled depending on the phase of treatment; highest activities were observed after interferon (IFN)-alpha and lower levels of activity were observed after dCF. DTH responses generally did not improve during therapy. Levels of IgM, IgG, IgA, and IgD did not change during treatment, but IgE levels rose in most patients. All immunosuppressive effects were attributable to dCF since patients receiving IFN-alpha 2a alone did not exhibit these same immunosuppressive effects, and patients receiving dCF alone after IFN failure exhibited similar abnormalities. Despite this severe immunosuppression from dCF, life-threatening opportunistic infections have not been observed in our patient population. Six patients developed localized Herpes zoster infection among 21 patients who had received dCF. Pending the results of long-term follow-up, we recommend that dCF be reserved for patients who have failed splenectomy and IFN therapy.

Coformycin↗
PubMed1988

Augmentation of natural killer activity, induction of IFN and development tumor immunity during the successful treatment of established murine renal cancer using flavone acetic acid and IL-2.

The investigational drug flavone acetic acid (FAA) has been previously shown to systemically augment NK activity in vivo in normal mice within 24 h of i.p. or i.v. administration. The current study investigates the ability of FAA, and/or rIL-2, to augment NK activity and antitumor responses in mice bearing murine renal cancer (Renca). The results demonstrate that FAA potently augments NK activity in the blood, spleen, and liver of Renca-bearing mice and that the administration of rIL-2 in addition to FAA results in a further augmentation of NK activity over that observed with FAA alone. Renca-bearing mice treated with FAA (200 to 250 mg/kg) plus rIL-2 exhibited a significantly increased incidence of long term survivors (59%) over that observed following treatment with FAA (0%) or rIL-2 (5%) alone. Therapeutic synergy between FAA and rIL-2 was observed against primary tumors, minimal residual disease, and experimental-induced pulmonary metastases. Mice cured of Renca by FAA plus rIL-2 treatment were largely resistant to rechallenge with Renca suggesting a role for T lymphocytes. The augmentation of NK activity and the therapeutic effects of FAA coincided with the rapid induction of high titers of serum IFN of the alpha/beta type within 4 h of FAA administration. Subsequent studies demonstrated that the contribution of FAA could be partially replaced by the administration of several doses of human rIFN-alpha A/D Bg1 before the initiation of rIL-2 administration. The observed synergistic antitumor effects of FAA plus rIL-2 coincided with the augmentation of NK activity, induction of IFN-alpha/beta, and induction of long lasting tumor immunity. Overall, these results suggest that this approach may obviate the need for adoptive immunotherapy in association with rIL-2 administration for at least some tumor types.

Adjuvants, Immunologic↗
PubMed1988

Essential role of the interleukin 2-interleukin 2 receptor pathway in thymocyte maturation in vivo.

The role of the IL-2-IL-2-R pathway in thymocyte differentiation in vivo is unknown. We have examined fetal thymocyte development in vivo, under conditions where all IL-2-R were saturated from day 13 of gestation with anti-IL-2-R mAbs that were previously shown to render mature T cells unable to respond to IL-2. This produced a dramatic change in the composition of developing T cells: thymocytes from day 1 neonatal mice born to anti-IL-2-R-treated mothers did not contain CD4+ or CD8+ single-positive cell populations. In addition, no generation of surface TCR beta chain-expressing T cells or antigen-reactive functional T cells occurred in treated mice. These data suggest that IL-2-IL-2-R interactions provide signals crucial to in vivo intrathymic development of mature T cells.

Animals↗
PubMed1988

Eosinophilia associated with adult T-cell leukemia/lymphoma.

Eosinophilia is associated with a number of disorders including malignancies. A patient is described who had eosinophilia associated with adult T-cell leukemia/lymphoma (ATL) induced by human T-lymphotropic virus type I (HTLV-I). Both tissue and peripheral blood eosinophilia and high titers of HTLV-I antibody were present. The eosinophilia was most likely caused by the malignant cells producing one or more lymphokines. The patient has achieved a durable complete remission from combination chemotherapy. Because durable remissions in ATL are rare with any known therapy and eosinophilia has not previously been associated with ATL, it is possible that the tumor in this patient was derived from a T-cell subset not usually transformed by HTLV-I. ATL is another malignancy now known to cause eosinophilia.

Adult↗
PubMed1988

Deletion of 3(p14p23) in secondary erythroleukemia arising in long-term survivors of small cell lung cancer.

Cytogenetic studies were done on the leukemia cells of two patients with small cell lung cancer (SCLC) who developed erythroleukemia (acute nonlymphocytic leukemia, French-American-British M6) after combined modality chemotherapy and radiotherapy for their lung cancer. Surprisingly, both erythroleukemias exhibited the del(3)(p14p23) predominantly found in SCLC. In four other patients who had secondary erythroleukemias associated with other cancers, no deletions of 3p were found. These findings could be accounted for by one of three possible mechanisms: (a) an inherited recessive gene (anti-oncogene or tumor suppressor gene) in this region of 3p was uncovered by the combined modality therapy, (b) an inherited predisposition to damage of both chromosomes at 3p14 leads to SCLC and erythroleukemia after exposure to carcinogens and/or chemotherapy-radiotherapy, or (c) the finding of lineage specificity for the 3p deletion with the presence of the 3p deletion in SCLC and erythroleukemia suggests a common bone marrow precursor.

Aged↗
PubMed1988

Human natural lymphocyte effector cells: definition, analysis of activity, and clinical effectiveness.

Lymphokine-activated killing has enormous potential in the treatment of cancer. Lymphoid effectors have the potential to recognize and lyse a wide array of tumor cells, a phenomenon which has been seen in vitro and to some extent in vivo. However, studies have indicated that complexity exists not only in the nature of the lymphocyte that can be activated ex vivo for therapeutic use, but also in the delivery of such therapy in a clinical setting. This review attempts to deal with both issues. The nature of the cells mediating lymphokine-activated killer activity, their heterogeneous phenotype, their activation requirements, and a hypothetical mechanism of action are discussed. In addition, previous clinical studies are reviewed and key issues are raised that need to be addressed in upcoming clinical trials.

Humans↗
PubMed1988

Elevated serum levels of soluble Tac peptide in adult T-cell leukemia: correlation with clinical status during chemotherapy.

Adult T-cell leukemia associated with human T-cell leukemia virus type I (HTLV-I) is characterized by a clonal expansion of a CD4-positive subset of T lymphocytes that constitutively express high numbers of interleukin-2 receptors and that frequently infiltrate the skin; osteolytic bone lesions, and hypercalcemia. Using an enzyme-linked immunosorbent assay (ELISA) test, we measured the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, in the serum of 50 patients with adult T-cell leukemia (38 Japanese and 12 American patients), 8 patients with other hematologic malignancies, 8 asymptomatic HTLV-I-antibody-positive carriers, and 17 normal controls. The serum level of soluble Tac peptide (geometric mean U/mL, 95% CI) was elevated at presentation in all patients with adult T-cell leukemia (16,461; 819 to 330,896) when compared with normal controls (238; 112 to 502), patients with other hematologic malignancies (1302; 475 to 3569), and healthy HTLV-I antibody-positive carriers (490; 115 to 2086). The highest levels were seen in patients (n = 33) with acute (32,154; 2587 to 399,598) compared with chronic (5464; 661 to 45,156) disease (n = 14). Serum levels of Tac peptide also tended to be more elevated in patients with adult T-cell leukemia with hypercalcemia (32,072; 2461 to 417,908) compared with normocalcemic patients (13,885; 496 to 388,436). Serial measurements of soluble Tac peptide levels in serum were done in four patients with adult T-cell leukemia during chemotherapy and the levels reflected disease activity. These observations suggest that the measurement of soluble Tac peptide levels in patients with adult T-cell leukemia is useful as a noninvasive measure of tumor burden and will help in the diagnosis of the disease and management of these patients.

Acute Disease↗
PubMed1988

Resistance to recombinant interferon alfa-2a in hairy-cell leukemia associated with neutralizing anti-interferon antibodies.

To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a.

Antibodies↗