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D L Longo

Publications and source records attributed to D L Longo.

At least 235 records · Page 13Linked to original sources
PubMed1992

Immunoregulation in cancer-bearing hosts. Down-regulation of gene expression and cytotoxic function in CD8+ T cells.

The causes of the decreased immune responsiveness in tumor-bearing hosts are incompletely understood. The impact of a decreased immune response in cancer patients on the clinical response in immunotherapy trials has not been evaluated. The present report demonstrates a marked decrease in the therapeutic efficacy of adoptively transferred T lymphocytes obtained from murine hosts bearing tumor for greater than 30 days [late tumor-bearing mice (TBM)] as compared with normal mice and mice bearing tumor for less than 21 days (early TBM). In vitro analysis of the functions of the T lymphocytes from late TBM showed an apparently normal proliferative response to anti-CD3 and IL-2 with adequate lymphokine production from CD4+ cells, but a significant decrease in the cytotoxic function of CD8+ cells. The decreased cytotoxicity was not because of cell-mediated suppression. The expression of granzyme B mRNA was significantly delayed and decreased in magnitude in CD8+ cells from late TBM. Culture supernatants from two unrelated tumor cell lines were able to inhibit the cytotoxic activity of normal CD8+ cells in vitro. The tumor-derived suppressive factor is not transforming growth factor-beta (TGF-beta), but it has not been further characterized. The data suggest that one potential mechanism responsible for immunologic defects in patients with large tumor burdens is a tumor-induced defect that compromises the function of CD8+ effector T cells.

Animals↗
PubMed1992

Interleukin-2-activated natural killer cells can support hematopoiesis in vitro and promote marrow engraftment in vivo.

Purified natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID) to ascertain their effect on hematopoiesis. When activated and propagated with recombinant human interleukin-2 (rhIL-2) in vitro, SCID spleen cells maintained a phenotypic and lytic spectrum consistent with a pure population of activated NK cells. When added with syngeneic bone marrow cells (BMC) in soft agar, the activated NK cells could support hematopoietic growth in vitro without the addition of exogenous hematopoietic growth factors. However, when syngeneic BMC were added along with cytokines to produce optimal growth conditions, the addition of NK cells was then inhibitory for hematopoietic colony formation. Antibodies to interferon-gamma (IFN-gamma) partially reversed the inhibitory effects. Supernatants from the NK-cell cultures could also exert these effects on hematopoiesis, although to a lesser extent. Analysis of the NK cell RNA demonstrated that activated NK cells express genes for hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and IL-1 beta. The NK cells were also found to express IFN-gamma, transforming growth factor-beta 1 (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) mRNA. Analysis of the NK-cell supernatants using factor-dependent myeloid progenitor cell lines showed that the NK cells were producing G-CSF and growth-promoting activity that could not be attributed to IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF, G-CSF, macrophage CSF (M-CSF), or stem cell factor. The transfer of activated NK cells with BMC into lethally irradiated syngeneic mice resulted in greater BMC engraftment in the recipients. Thus, these results using a pure population of activated NK cells indicate that when activated, these cells can produce a variety of growth factors for hematopoiesis and exert significant hematopoietic growth-promoting effects in vivo.

Animals↗
PubMed1992

MYC rearrangements in histologically progressed follicular lymphomas.

Histologic transformation of low-grade follicular lymphoma to an aggressive-grade lymphoma occurs in 60% to 80% of patients during their clinical course. The events that drive the transformation process are poorly understood. Deregulation of the MYC gene has been implicated in a small number of cases. This observation led us to examine the molecular organization of the MYC oncogene in 38 cases of histologically transformed lymphomas that arose from follicular lymphomas, and in 18 of the initial pretransformation follicular lymphomas. In addition, we examined 58 "control" low-grade follicular lymphomas that had not yet shown evidence of histologic progression. Immunoglobulin heavy chain and light chain gene rearrangements were detected in all biopsies and rearrangements of the BCL-2 locus were seen in 36 of 38 of the transformed lymphomas (consistent with their origin from follicular lymphomas), in 18 of 18 of the pretransformation follicular lymphomas, and in 51 of 58 of the control follicular lymphomas. All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma. MYC rearrangements were detected in 3 of 38 (8%) transformed lymphomas and in 1 of 58 (2%) control follicular lymphomas. The latter MYC rearranged follicular lymphoma was clinically aggressive and transformed to a high-grade lymphoma that led to the death of the patient within 20 months. None of the 18 pretransformation follicular lymphomas showed MYC rearrangement, including two from patients who later demonstrated MYC rearrangement in the progressed aggressive lymphoma. PvuII mutational analysis failed to identify additional MYC gene abnormalities in the progressed lymphomas. Because the Epstein-Barr virus (EBV) is associated with a fraction of high-grade lymphomas and is known to upregulate BCL-2, we looked for a potential role for this agent in our progressed lymphomas. We did not detect viral sequences in any case indicating that EBV does not play a major role in progression. The presence of MYC rearrangements in a small fraction of progressed aggressive lymphomas, and not in the corresponding antecedent follicular lymphomas, suggests that acquisition of a MYC rearrangement is in some cases associated with the transformation event.

Chromosome Aberrations↗
PubMed1992

Prevention of acute chemotherapy-induced death in mice by recombinant human interleukin 1: protection from hematological and nonhematological toxicities.

Previous studies have demonstrated that interleukin 1 (IL-1) can protect most mice from the acute lethal toxicity mediated by high doses of radiation and/or some chemotherapeutic drugs. The results presented herein demonstrate that the pretreatment of mice with recombinant human interleukin 1 alpha (rhIL-1 alpha) protects mice from the lethal effects of several myelotoxic chemotherapeutic drugs, including 5-fluorouracil (5FUra), cyclophosphamide, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), and 1,3-bis-(2-chloroethyl)-1-nitrosourea. However, pretreatment with rhIL-1 alpha was not effective against the acute lethal toxicity generated by doxorubicin and cisplatin. The chemoprotective effects appear to be at least partially due to myeloprotection/restoration, since the recovery of myeloid colony-forming units and the total cellularity in the bone marrow and spleen were accelerated in the rhIL-1 alpha-pretreated mice. However, the chemoprotective effects of rhIL-1 alpha are apparently not limited to myeloprotection, since pretreatment with rhIL-1 alpha protects mice against the lethal toxicity of both 5FUra and cyclophosphamide, yet bone marrow transplants rescue mice treated with 5FUra but not those treated with cyclophosphamide. The chemoprotective effects of rhIL-1 alpha may be at least partially indirect, since the efficacy of chemoprotection by rhIL-1 alpha is reduced in athymic mice, and interleukin 6, but not tumor necrosis factor alpha, can substitute for rhIL-1 alpha in chemoprotection from 5FUra.

Animals↗
PubMed1992

Intensive therapy with cisplatin, interleukin-2 and interferon-alpha-2a in patients with metastatic melanoma. A phase II Study.

OBJECTIVE: Based upon their individual clinical activity and combined effects in animal models or in vitro, we wished to evaluate a regimen of cisplatin, interferon-alpha, and IL-2 in patients with metastatic melanoma. DESIGN: Phase II pilot study. SETTING: Referral-based US Government clinical research unit. PATIENTS: Nine patients with metastatic malignant melanoma. INTERVENTION: Cisplatin 75-100 mg/m2 was administered intravenously over 30 minutes on days 1 and 8. Interferon-alpha 2a 5 Mu/m2 body surface area (BSA) was given subcutaneously for 4 days beginning 1 day before each dose of cisplatin. Beginning on day 15 and day 22, IL-2 was administered by intravenous continuous infusion at 3 Mu/m2 BSA/d for 96 hours and by daily intravenous bolus concurrent with daily subcutaneous doses of interferon-alpha 2a. MAIN OUTCOME MEASURES: Antitumor response and toxicities. RESULTS: The study was stopped due to renal and hematopoietic toxicity and severe, delayed nausea and vomiting associated with the cisplatin-interferon treatment. Three of 9 patients achieved a partial response (duration 2.5, 4, 14+ months), and an additional patient had a 50% reduction in measurable tumor volume before undergoing resection of residual disease. Overall response rate was 45%. CONCLUSION: This regimen was associated with excessive toxicity, and the lack of complete responses in a patient cohort with favorable characteristics for response (good performance status, predominance of skin and lymph node metastatic sites) suggests that it had no advantage over less toxic treatment regimens. REGISTRATION: National Cancer Institute/Cancer Therapy Evaluation Program T89-0137.

Adult↗
PubMed1992

Hematopoietic stem cell depletion by restorative growth factor regimens during repeated high-dose cyclophosphamide therapy.

We studied the effects of six cycles of repeated cyclophosphamide (CTX) therapy followed by restorative therapy with either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF on the hematopoietic stem cell compartment. Stem cell function was assessed by serially transferring bone marrow cells from CTX-CSF-treated mice into lethally irradiated recipient mice. Bone marrow cells from mice that initially received either G-CSF or GM-CSF after CTX therapy more rapidly lost the ability to repopulate the recipient lymphoid organs, showed a dramatic loss of hematopoietic progenitors, a more rapid loss of CFU-S capacity, and a 40% to 50% reduction in marrow repopulating ability (MRA). Interleukin-1 (IL-1) appeared to have little effect on the CTX-treated mice when used alone. However, when administered before the CTX-CSF regimen, IL-1 prevented the stem cell depletion as determined by CFU-C, CFU-S, and MRA through the serial transplantation procedures. These results support the hypothesis that repeated treatments with myelosuppressive drugs followed by stimulation with the CSFs may induce damage to the host stem cell compartment, and further suggest that pretreatment with IL-1 before CTX therapy may prevent this stem cell damage.

Animals↗
PubMed1992

Immunologic and hematologic effects of neuroendocrine hormones. Studies on DW/J dwarf mice.

DW/J dwarf mice lack acidophilic anterior pituitary cells and are deficient in growth hormone and other neuroendocrine mediators. These mice were examined to determine the effects of these deficiencies on hematopoietic and immune system development. Previous studies have suggested that these mice had immunologic defects primarily involving T cell development. However, we have found that these mice exhibit decreased peripheral blood cell counts affecting all lineages (erythrocytic, leukocytic, and platelets). Examination of lymphoid tissues of dwarf mice indicated that their spleens were hypoplastic. Treatment of these mice with recombinant human growth hormone resulted in a significant improvement of peripheral blood counts and spleen cell number. Analysis of the bone marrow indicated a profound deficiency of B cell progenitors in the dwarf mice. However, in untreated dwarf mice, mature B cells and T cells were observed in the spleens. Although treatment with recombinant human growth hormone could correct the hematopoietic deficiencies in these mice, it did not restore the B cell progenitor populations, suggesting that an absence of growth hormone is not solely responsible for this deficiency. Thus, these mice display significant myeloid and lymphoid deficiencies that have been previously undetected.

Animals↗
PubMed1992

Increased circulating nitrogen oxides after human tumor immunotherapy: correlation with toxic hemodynamic changes.

BACKGROUND: Toxicity to interleukin-2 (IL-2) tumor immunotherapy is manifested principally by the vascular leak syndrome, hypotension, and a hyperdynamic response with low systemic vascular resistance. Nitric oxide (.N = O), a recently discovered biological mediator of vascular smooth muscle relaxation, is produced in increased amounts by numerous cell types exposed to a number of inflammatory cytokines. PURPOSE: Our purpose was to determine if there is an increased production of .N = O in patients receiving IL-2 tumor immunotherapy, and, if so, whether increases in .N = O production correlate with hemodynamic instability. METHODS: Twelve patients undergoing immunotherapy trials with IL-2 and anti-CD3 monoclonal antibody-activated lymphocytes (T-AK cells) were studied. Plasma levels of nitrate (NO3-), the stable end metabolic product of .N = O synthesis, were measured before and at the end of IL-2 treatment cycles. RESULTS: We observed a ninefold increase in plasma levels of NO3- in patients after 7 days of treatment (P less than .0001). A significant decrease in both systolic and diastolic blood pressures was observed in all patients (P less than .001). CONCLUSIONS: We propose that mediated induction of .N = O synthase enzyme leads to progressive increases in .N = O production which, in turn, produces clinically significant hypotension. IMPLICATIONS: Since .N = O synthesis can be competitively inhibited by L-arginine analogues, a possible pharmacologic modulation of .N = O production could potentially contribute to better management of toxic side effects seen in IL-2 cancer therapies.

Amino Acid Oxidoreductases↗
PubMed1992

Polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose in combination with interleukin 2 in patients with cancer: clinical and immunological effects.

We have performed a phase IB study of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose (poly-ICLC) in combination with interleukin 2 (IL-2) in 25 patients with a variety of cancers. Patients received weekly or biweekly poly-ICLC by i.m. injection, at doses ranging from 0.01 to 1.0 mg/m2, for 1 month. This was followed by 2 months of outpatient therapy with biweekly i.m. poly-ICLC in combination with IL-2 (3 x 10(6) units/m2) given i.v. by 24-h continuous infusion twice weekly, using a portable infusion pump. No objective tumor responses were observed. Toxicity was moderate at all poly-ICLC doses tested and increased only slightly following the addition of IL-2. No increases in peripheral blood natural killer (NK) activity were observed after treatment with poly-ICLC alone. However, high dose poly-ICLC (greater than or equal to 0.3 mg/m2) in combination with IL-2 resulted in NK activity greater than that seen using the same dose of IL-2 in combination with lower poly-ICLC doses. Increases in the number and percentage of CD56+ cells were evident only after initiation of IL-2 therapy and were unaffected by the poly-ICLC dose. In the majority of patients, these increases were preferentially associated with the subset of CD56+ cells coexpressing CD8, while the CD56+/CD16+ population was elevated to a lesser extent. Moderate increases in serum neopterin levels and 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells were noted at 72 h following initial treatment with 1.0 mg/m2 poly-ICLC. No induction of alpha or gamma interferon was detected. This study shows that the addition of poly-ICLC to a well tolerated IL-2 regimen can significantly enhance NK activity. Poly-ICLC can be used to enhance IL-2-induced NK lytic activity without increases in the dose and, therefore, the toxicity of IL-2 treatment.

Antigens, CD↗
PubMed1992

Human growth hormone promotes engraftment of murine or human T cells in severe combined immunodeficient mice.

Growth hormone (GH) has previously been implicated in T-cell development, and here we test its efficacy in promoting T-lymphocyte engraftment in mice with severe combined immune deficiency (SCID). SCID mice receiving syngeneic thymocytes and treated with recombinant human GH (rhGH) had significantly better T-cell engraftment in their lymph nodes. Human T-cell engraftment was also strongly promoted by rhGH in SCID recipients receiving human peripheral blood lymphocytes. Additionally, although mature human cells have not been thought to enter the murine thymus, human T cells were detected in the SCID thymus after rhGH treatment. Thus, rhGH can be used to optimize long-term peripheral T-cell engraftment in these human-mouse chimeras and may also be useful clinically in treating T-cell deficiencies.

Animals↗
PubMed1992

Donor-type activated natural killer cells promote marrow engraftment and B cell development during allogeneic bone marrow transplantation.

Purified NK cells were obtained from mice with severe combined immune deficiency and were activated with human IL-2 (hrIL-2) in vitro to determine if, once activated, these cells could be transferred with compatible bone marrow cells (BMC) and promote marrow engraftment in irradiated allogeneic recipients. After culture with hrIL-2, these cells maintained a phenotypic and lytic spectrum consistent with a pure population of activated NK cells. These activated NK cells were then adoptively transferred with the donor BMC and rhIL-2 into lethally irradiated allogeneic hosts. The addition of NK cells with the BMC allowed for more rapid hematopoietic engraftment as determined through short term studies, and greater donor-derived chimerism with accelerated reconstitution of the B cell population as determined with long term analysis. No evidence of graft-vs-host disease was detected in the recipients receiving the activated NK cells with allogeneic T cell replete BMC and hrIL-2. The mechanism by which the transferred NK cells improved BMC engraftment was at least partly through the abrogation of the host effector cell's ability to mediate resistance to the marrow graft. Thus, the administration of donor-type activated NK cells with BMC and hrIL-2 may significantly augment hematopoietic engraftment and immune reconstitution in the clinical setting of allogeneic BMT without giving rise to graft-vs-host disease.

Animals↗
PubMed1992

Hodgkin's disease.

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Combined Modality Therapy↗
PubMed1992

Histogenetic correlations between subcategories of small noncleaved cell lymphomas.

To assess the biologic relevance of the morphologic distinctions between subtypes of small noncleaved cell lymphomas (SNCL), ie, the sporadic Burkitt's type (sBT) and the non-Burkitt's type (nBT), we have examined the molecular organization of several lymphomagenic oncogenes (c-myc, bcl-1, bcl-2) and the potential pathogenetic contribution of the Epstein-Barr virus (EBV). Twenty-nine cases of SNCL, not associated with immunodeficiency syndromes, were reviewed and classified as sBT (18 cases) or nBT (11 cases) without knowledge of the clinical or molecular data. Southern blot analysis of 18 sBTs found 17 to contain c-myc rearrangements. Fifteen of these comigrated with an Ig heavy-chain gene segment, indicating t(8;14) translocation. Chromosome 8 breakpoints were clustered in the first exon and the first intron of the c-myc gene. Chromosome 14 breakpoints mapped to the JH locus in three tumors, the S mu locus in nine tumors, and the S alpha locus in the remaining three tumors. Cases involving the S alpha locus appeared to have a more rapid clinical course. All sBTs possessed germline bcl-2 and bcl-1 gene fragments. In contrast, Southern blot analysis of 11 nBTs found none with c-myc rearrangements. Rather, three of 10 evaluable nBTs had bcl-2 rearrangements. The remaining seven showed no evidence of involvement by any of the lymphoma-associated oncogene/breakpoint regions studied. EBV genome was detected in two sBTs and in one nBT, and thus was not a distinguishing feature. These results indicate that the subtle histologic differences that distinguish subcategories of SNCL are significant biologically and reflect distinct molecular mechanisms of lymphomagenesis. Furthermore, the data suggest that the nBTs comprise a heterogeneous group with respect to their molecular genetic composition and confirm the remarkable molecular genetic homogeneity of the sBT group.

Adolescent↗
PubMed1992

IL-2 induces IL-6 production in human monocytes.

IL-2 is a potent activator of effector and secretory activities of human monocytes. Since monocytes are an important source of IL-6, we investigated whether IL-2 can induce IL-6 production and whether regulatory circuits can modulate this process. We found that stimulation of monocytes with IL-2 induced expression of IL-6 mRNA and bioactivity in a dose-dependent manner. Production of IL-6 in monocytes can be induced by other cytokines such as IL-1 beta. By using mAb alpha-IL-1 beta we showed that IL-2-induced IL-6 production is not mediated by the autocrine stimulation of IL-1 beta elicited by IL-2. IL-6 induction by monocytes is not a common response to activating signals because IFN-gamma did not induce IL-6 expression under conditions in which it elicits tumoricidal activity. In contrast, IFN-gamma could completely abrogate the induction of IL-6 expression by IL-1 beta but did not affect the levels of mRNA and the secretion of IL-2-elicited IL-6. We have previously reported that transforming growth factor-beta inhibits IL-6 production in response to IL-1 beta. Studies on the inhibitory activity of transforming growth factor-beta demonstrated that this cytokine differs from IFN-gamma because it inhibited both IL-1- and IL-2-induced IL-6 expression. These data demonstrate that, in human monocytes, both IL-1 and IL-2 stimulate IL-6 expression by independent mechanisms that can be dissociated by the susceptibility to the inhibitory effect of IFN-gamma. IL-6 production is also down-regulated by TGF-beta, whose inhibitory activity is stimulus-unrelated.

Cells, Cultured↗
PubMed1992

Preclinical evaluation of bryostatin as an anticancer agent against several murine tumor cell lines: in vitro versus in vivo activity.

We have examined the ability of bryostatin 1 to inhibit the in vitro growth and in vivo development of a panel of four murine tumors of diverse tissue origins. A wide range of antiproliferative responses was observed for the four tumors. At 100 ng/ml the in vitro growth of the Renca renal adenocarcinoma, the B16 melanoma, the M5076 reticulum cell sarcoma, and the L10A B-cell lymphoma were inhibited by 0, 40, 40, and 94% respectively. All three cell lines sensitive to bryostatin in vitro responded to multiple dose, 1 microgram/injection/day in vivo i.p., bryostatin therapy. Only the in vitro resistant Renca tumor failed to respond to bryostatin in vivo. The correlation between in vitro and in vivo antitumor efficacy suggests a direct mechanism of antitumor activity for bryostatin. Both local regional therapy (M5076 i.p.) and systemic therapy (B16 lung metastases and L10A s.c. tumors) with bryostatin were successful at prolonging survival time. Multiple i.p. doses of bryostatin at a minimum level of 0.5-1.0 microgram/injection were required to observe significant in vivo antitumor effects. The success of in vivo administration of bryostatin in mice bearing 8-10-mm s.c. masses of L10A lymphoma (5-10 x 10(9)) and our further observation that five of a panel of six human B-cell lymphoma cell lines were sensitive to the growth inhibitory effects of bryostatin in vitro suggest that bryostatin may be effective in treating lymphoid malignancies in humans.

Adenocarcinoma↗
PubMed1992

Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions.

Human peripheral blood lymphocytes (huPBL) were injected into mice with severe combined immune deficiency (SCID). It was ascertained that murine natural killer (NK) cells were capable of affecting engraftment of human lymphocytes in SCID mice. The presence of host NK cells resulted in the clearance of the human lymphocytes. Human T lymphocytes were the primary cell to engraft in the SCID recipients, with human T cells being detected in the spleen, lymph nodes, bone marrow and peritoneal cavity of the mice up to several months after transfer. No human T cells were detected in the murine thymus and the level of engraftment in the periphery could be highly variable. Additionally, there appeared to be significant reactions between the human lymphocytes and the murine host resulting in a xenogeneic graft-vs.-host reaction (XGVHR). The predominant manifestation involved splenomegaly resulting from an expansion of murine hematopoietic cells in the spleens of these xenogeneic chimeras. The severity of the XGVHR could be correlated with the extent of human T cell engraftment and the recovered human T cells were found to be in a proliferative state. Thus, there appear to be significant host-vs.-graft and graft-vs.-host interactions occurring in human/mouse lymphocyte chimeras.

Animals↗