Biomedical subjects

J M Reuben

Publications and source records attributed to J M Reuben.

At least 37 records · Page 2Linked to original sources

PubMed1992

B-cell activation and differentiation by HIV-1 antigens among volunteers vaccinated with VaxSyn HIV-1.

The generation of memory B cells in response to vaccination with a baculovirus-derived recombinant gp160 candidate AIDS vaccine, VaxSyn HIV-1, was investigated in 12 healthy human volunteers who were immunized with VaxSyn HIV-1, hepatitis B vaccine, or alum adjuvant alone on days 1, 28, 180, and 540. Peripheral blood mononuclear cells were collected pre- and post-immunization and cultured unstimulated or with pokeweed mitogen (PWM), VaxSyn HIV-1 (rgp160), or HIV-1 lysate (iHIV-1) for 7 days before polyclonal and HIV-1-specific IgG production in culture supernatants (SNs) were measured. No differences were seen in the spontaneous or PWM-induced IgG production in SN from vaccinees and controls. Only vaccinee SN contained higher-than-normal levels of polyclonal IgG after stimulation with either rgp160 or iHIV-1, especially after the second and third booster immunizations on days 180 and 540, respectively. There were also contemporaneous increases in HIV-1-specific antibody in SN of all vaccinees, albeit at different time points throughout the study. We conclude that VaxSyn HIV-1 induces antigen-specific B-cell responses with the generation of memory B cells in vivo that can be reactivated in vitro to deliver an anamnestic response.

AIDS Vaccines↗

PubMed1991

Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia.

In DAB486IL-2 the receptor-binding domain of native diphtheria toxin is replaced by human IL-2 sequences. This recombinant fusion protein is selectively cytotoxic for cells bearing high-affinity IL-2 receptors--eg, leukaemic cells. A patient with chronic lymphocytic leukaemia who did not respond to gamma interferon and conventional antileukaemic drugs has responded to DAB486IL-2.

Diphtheria Toxin↗

PubMed1991

Induction of cytokines in normal placental cells by the human immunodeficiency virus.

Placental cotyledon mononuclear cells (CMC) resemble peripheral blood monocytes/marcophages (MM) with respect to their expression of surface antigens and cellular function. CMC also express the CD4 antigen receptor and are thus susceptible to infection with the human immunodeficiency virus (HIV). When vertical transmission of HIV from mother to fetus occurs, the infection often remains latent until appropriate factors initiate the transcription of virus-specific mRNA. Cytokines, such as interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) which are produced by MM, up-regulate HIV expression in infected cells. The induction of cytokines in MM does not require active infection with HIV since heat-inactivated HIV (iHIV) and envelope gp120 caused cytokine secretion. We studied the ability of CMC from normal placentas to secrete these cytokines following stimulation with endotoxin, iHIV, recombinant GP160 and GAG55, and synthetic p17, HGP-30. Whereas CMC spontaneously secreted low levels of IL-1 beta and TNF-alpha, they constitutively secreted high levels of IL-6. All cytokine levels could be boosted by endotoxin. GP160, iHIV, and HGP-30 failed to augment cytokine levels above baseline. In contrast, GAG55 significantly boosted only TNF-alpha. The relevance of these findings is discussed with respect to the putative roles of cytokines in the immunoregulation of HIV in utero.

Cell Transformation, Viral↗

PubMed1990

Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma.

Fifty patients with locally advanced or metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) at 100 mg orally daily starting on day 1 and cimetidine 300 mg orally four times a day starting on day 15. When disease progressed, coumarin was escalated to 100 mg orally four times a day. Three patients (6%; 95% confidence interval [Cl], 2% to 17%) achieved a partial response, one of those after dose escalation. In addition, one patient had a minor response, then progressing disease, and again had a minor response after dose escalation. All four responders had nonassessable primary tumors (three had had prior nephrectomy and one a renal angioinfarction). The only major toxicity was renal (37 patients had minor to moderate elevations in serum creatinine level). Immunologic studies (hypersensitivity skin testing, lymphocyte blastogenesis response, number of lymphocytes, T lymphocytes, T helper and T suppressor subsets, and T helper: suppressor ratio), performed before and after therapy, showed a relative lymphopenia and decreased hypersensitivity skin-testing results at baseline, and a general decline over time in the number of T cells and T helper and T suppressor subsets. There was no enhancement in any of the immunologic parameters tested. The response rate was 6%, lower than previously reported; a general immunodeficiency was noted at baseline, and the lymphopenia worsened with progressing disease, unaffected by therapy.

Adult↗

PubMed1989

Phase I study of cancer therapy with recombinant interleukin-2 administered by intravenous bolus injection.

Sixty-six patients with disseminated malignancy were treated with recombinant interleukin-2 (IL-2) on a three times a week (M, W, F) IV-bolus injection schedule. Doses ranged from 0.001 to 14.0 x 10(6) units/M2 body surface area. Consecutive groups of 3-5 patients were placed on each dose level and were maintained on that level except for dosage de-escalation for toxicity. Toxicity to all major organ systems were noted with major toxicity including fever and chills, anorexia, fatigue and malaise, arthralgias and arthritis as well as hepatic and renal toxicity. All toxicity reversed within one week of drug cessation. Renal toxicity manifested by azotemia, arthritis and fatigue were the common dose limiting toxicities and the maximally tolerated dose was 12 x 10(6) units/M2. Pharmacokinetic studies indicated a short half-life (T1/2 alpha = 7-23 minutes). At doses over 0.5 x 10(6) units/M2 increases in absolute lymphocytes and eosinophil counts were noted. All T lymphocyte subsets increased. Maximal increases were seen at 4-8 x 10(6) units/M2 with a lesser increase at 10-14 x 10(6) units/M2 dosage level. Circulating NK cells also increased while circulating LAK cells were detected during therapy. Partial responses were noted in 3 patients with melanoma. These lasted 4, 6 and 16 months and involved pulmonary, pulmonary plus mesenteric and retro-orbital plus hepatic metastases respectively in these patients.

Drug Evaluation↗

PubMed1989

A pilot study of diethyldithiocarbamate in patients with acquired immune deficiency syndrome (AIDS) and the AIDS-related complex.

We investigated the use of diethyldithiocarbamate (DTC, or Imuthiolr, Merieux Institute) as a therapeutic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and AIDS-Related Complex (ARC). Patients were prospectively stratified and randomized to receive DTC 200 mg/m2 intravenously weekly for 16 weeks or no therapy, followed by crossover to the opposite arm for an equal period. Forty-four patients were entered and forty were evaluable. There was a statistically significant decrease in symptoms in the DTC treated patients compared to the controls (p = .002). There was a significant improvement in lymphadenopathy in the treated patients compared to the controls (p = .005). One patient showed disappearance of splenomegaly, one clearing of antifungal agent-resistant perianal moniliasis, and one clearing of hairy leukoplakia. No significant differences in progression were noted. No changes were seen in any of the immunological parameters measured. There was no significant toxicity. Because of the changes in symptoms and in lymphadenopathy, we suggest that further study of DTC, both alone and in combination with other agents, may be indicated.

AIDS-Related Complex↗

PubMed1988

Association of levels of circulating C1q binding macromolecules with induction chemotherapy response in head and neck cancer patients.

Ninety-five untreated patients with squamous cell carcinoma of the upper aerodigestive tract expressed significantly higher levels of C1q-binding macromolecules as compared to 45 noncancer-bearing controls. No relationship between C1q-binding macromolecules and levels of circulating IgG-immune complexes as determined by the solid-phase C1q-binding assay or the C3d-solid-phase assay could be defined suggesting that C1q-binding macromolecules were distinct from IgG-circulating immune complexes. An elevated level of C1q-binding macromolecules within these patients was predictive of subsequent response to induction chemotherapy; those with elevated levels characteristically showed no response. Using multivariate logistic regression analysis including the covariates of American Joint Committee staging parameters as well as C1q assay results, levels of the isolated macromolecules added significant prognostic information as to the probability of chemotherapeutic response. The quantitation of C1q macromolecules has clinical implication as to choice of therapeutic regimens against head and neck cancer. The nature of these substances remains to be defined.

Adult↗

PubMed1987

Decreased 5'-nucleotidase activity in suppressor (OKT8) T lymphocytes from homosexuals with AIDS-related complex: nonassociation with enhanced deoxynucleoside toxicity.

The purine metabolic enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'nucleotidase (5NT) have been shown to be important for normal lymphocyte maturation. Abnormalities of these enzymes have been associated with hereditary as well as acquired immunodeficiency states. Enzyme activity was measured in helper (OKT4) and suppressor (OKT8) lymphocyte subsets from 10 homosexuals with AIDS-related complex (ARC) and in 10 healthy controls. There were no significant differences in either mean ADA activity or mean PNP activity between ARC OKT4 cells and control OKT4 cells and between ARC OKT8 cells and control OKT8 cells. By contrast, mean 5NT activity was slightly decreased in OKT4 cells from ARC patients compared with that of controls and more significantly diminished in ARC OKT8 cells compared with that of controls. Both deoxyadenosine and deoxyguanosine, when incubated separately with OKT4 and OKT8 cells in the presence of EHNA, an ADA inhibitor, did not significantly inhibit lymphocyte blastogenesis to a greater extent in ARC patients than in controls. Hence, the decreases in 5NT activity most likely reflect lymphocyte immaturity and are not associated with biochemical abnormalities leading to increased deoxynucleoside toxicity.

5'-Nucleotidase↗

PubMed1987

A pilot clinical trial of the toxicity and immunorestorative effects of T cell reconstituting factor (SR 270258) in immunosuppressed cancer patients.

The in vivo immunorestorative effects of a highly purified protein fraction from human serum--designated SR 270258, prealbumin, or T cell reconstituting factor--was examined in cancer patients following radiation therapy. Sixteen patients with either Stage III head and neck cancer, nonoat cell lung cancer, or esophageal cancer were randomized to either receive (11 patients) or not receive (five patients) subcutaneous injections or SR 270258 at a dose of 2 mg/m2 three times per week for a total duration of 1 month. Treated patients were observed frequently for signs of toxicity. Blood was drawn initially and at weekly intervals for measurement of immunologic tests, which included percentage and absolute number of T cells, B cells, and other lymphocyte subpopulations; lymphocyte blastogenic responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed; and one-way mixed lymphocyte responses. Delayed type hypersensitivity responses to seven recall antigens were also tested. Mean lymphocyte blastogenic responses were significantly suppressed in patients relative to normal (p less than 0.05). There were no consistent changes in lymphocyte blastogenic responses, the percentage of lymphocyte subpopulations, or skin test responses in patients receiving SR 270258 versus untreated patients. However, the absolute number of OKT11 positive (E rosette receptor positive) T lymphocytes increased a mean of 52% (406 +/- 356 to 617 +/- 344/mm3; p = 0.03) in treated patients whereas no change was observed in untreated patients (366 +/- 226 to 446 +/- 327). Significant increases in the absolute number of OKT4 positive helper cells (158 +/- 109 to 221 +/- 112; p less than 0.05), OKT8 positive suppressor cells (179 +/- 186 to 279 +/- 184; p less than 0.05), and surface immunoglobulin-bearing B cells (49 +/- 47 to 155 +/- 268; p less than 0.05) also occurred. Prealbumin can induce a significant lymphocytosis in heavily irradiated, lymphopenic cancer patients. Lymphocyte blastogenesis and skin tests, however, were not improved at this dose and schedule.

Antigens, Surface↗

PubMed1986

Phase I clinical study of nafazatrom.

Nafazatrom, a synthetic pyrazolinone derivative, has been shown to have substantial antitumor activity in vitro and antitumor and antimetastatic activity in experimental animal systems. The drug has produced no substantial toxicity in preclinical studies and during limited human trials. A phase I clinical trial with this substance was performed at this institution. Nafazatrom was administered orally in a single daily dose. The initial starting dose was 30 mg/m2 and, in the absence of toxicity, subsequent dose levels were reached after 100% escalation. Six patients were treated at each dose level. Forty-eight patients with various metastatic malignant tumors (mostly with melanoma, breast carcinoma, soft tissue sarcoma, renal cell carcinoma and colorectal carcinoma) were entered on this program. No objective remissions were observed. Twelve patients remained stable for periods in excess of 8 weeks. No consistent, substantial or dose-limiting toxicity was detected. The maximum tolerated dose was not reached, and dose escalation was stopped at 4,000 mg/m2/day as initially planned. With the oral preparation, within this dose range and at this schedule, nafazatrom has no antitumor or other biologic activity.

Adult↗

PubMed1986

Relationship of exposure to human T lymphotropic virus and T helper cells in homosexual men.

The detection of serum antibodies (Ab) against HTLV-III in individuals with AIDS and related symptoms (ARC) has unambiguously defined the association of the virus infection to AIDS. This study was done to determine the extent of exposure to HTLV-III in homosexual men by measuring (Ab) and relating it to the stage of disease and T cell subsets. We found Ab in 89.5% of the 492 men with the median titers by stage of disease being 1600 for symptom-free, 6400 for ARC or Kaposi's sarcoma, and 4800 for opportunistic infection (OI), respectively. There was no correlation between Ab titers and either absolute or relative T helper cells (T4+), even though these cells decreased with disease severity. More specifically, however, symptom free patients had a normal distribution of the helpers of suppression (T4+/Leu8+), whereas, in symptomatic men, there was a significant decrease suggesting that the target cell for the virus is a subpopulation of the T helper cell.

Acquired Immunodeficiency Syndrome↗

PubMed1986

Effect of azimexon therapy on host defense parameters and disease-associated symptoms in the acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC).

Azimexon, a 2-cyan-aziridinyl immune modulator, was given at a dose of 250 mg/m2/day for 10 days IV to 12 patients with AIDS and 16 with AIDS related complex (ARC). A decrease in total number of AIDS related symptoms from 43 to 24 and in mean number from 2.6 to 1.5 was observed among ARC patients (p less than .01). The most commonly improved symptoms were diarrhea, fatigue, and weight loss with the least frequently improved being lymphadenopathy. The following improvements in immune parameters were observed among ARC patients. DTH to recall antigens improved with an increase in number of positive tests from 35 to 47 and in mean number of positive skin tests from 2.2 on day 0 to 2.9 on day 14 (P less than .05). The geometric mean of the absolute lymphocyte count was 1.395 X 10(3)/microliter on day 0 with a significant increase of 18.0 percent on day 5 (P less than .01) and a 7.7 percent increase on day 21. The geometric mean of the OKT4+ cells on day 0 was 0.250 X 10(3)/microliter with a 33.3 percent increase on day 5 (P less than .07) and a 14.1 percent increase on day 21. T4/T8 ratio increased by 32.7 percent on day 5 (P less than .05) and by 19.4 percent on day 21 from an initial geometric mean of 0.339 X 10(3)/microliter on day 0. The geometric mean of GVH responses increased by 18.2 percent on day 5 (P less than .05) and by 24.0 percent on day 21 (P less than .07) from an initial value of 41.04 mm3. No symptomatic or immunologic improvements were observed among AIDS patients, but rather a significant decrease in mitogenic responses. PHA responses decreased by 70.3 percent on day 5 (P less than .05) and 42.2 percent on day 21 from an initial geometric mean of 4.02 X 10(3) cpm/10(3). Con-A responses decreased by 75.1 percent on day 5 (P less than .05) and increased by 20.3 percent on day 21 from an initial value of 1.14 X 10(3)/10(5) cells. Pretreatment number of absolute OKT4+ cells was the most significant prognostic survival variable. Thus, 8/9 patients with less than 0.10 X 10(3) OKT4+ blood cell/microliter subsequently died as compared to only 1/17 with greater than or equal to 0.10 X 10(3) OKT4+ cells (p less than .001). The only toxic effect of this treatment was mild hemolysis which disappeared upon cessation of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS-Related Complex↗

PubMed1986

Enhanced serological and virological findings of Epstein-Barr virus in patients with AIDS and AIDS-related complex.

The potential involvement of Epstein-Barr virus (EBV) in AIDS was examined by determining the type of EBV-specific antibody responses and the EBV content or lymphoproliferative ability present in selected body fluids of patients with AIDS or AIDS-related complex. The results were compared with two control groups. An enhanced antibody response to a broad spectrum of EBV antigens was found in patients with AIDS or AIDS-related complex. The pattern of virus-specific antibody responses resembled that associated with a persistent or reactivated infection. The content of EBV in oropharyngeal secretions and the lymphoproliferative ability in peripheral blood from patients with AIDS or AIDS-related complex was significantly greater than that from healthy controls and approached levels detected in the control group with infectious mononucleosis. These findings, together with recent reports of cellular-level interaction between EBV and human T lymphotropic virus type III, suggest that EBV may have a contributory role in these disorders.

AIDS-Related Complex↗

PubMed1986

Phase I study of multiple dose intramuscularly administered recombinant gamma interferon.

We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.

Agranulocytosis↗

PubMed1986

Initial clinical studies with copovithane.

Copovithane is a new copolymer of low molecular weight and with a significant in vivo antitumor activity in preclinical trials. The mechanism of action is unknown. Ninety-one patients with various metastatic neoplasms beyond the curable stage were treated with copovithane by weekly intravenous administration. Dose levels ranged from 1 to 33 g/m2/week. No dose-limiting toxicity was reached. Tolerance was excellent, with minor fatigue, occasional nausea, and intermittent proteinuria as the only significant side effects in less than 25% of patients. Two patients achieved a partial remission, and five patients reached minor responses during therapy. Antitumor effects were noted only in cutaneous and subcutaneous metastases. Extensive immunologic evaluation revealed some improvement in helper:suppressor T cell ratio, in vitro cytotoxicity tests, and lymphocyte blastogenic responses in patients treated at intermediate levels. The immunologic testing also suggested that the higher dose levels (22-33 g/m2 weekly) might adversely affect the immune response. The clinical relevance of these changes is uncertain. Phase II clinical trials are recommended utilizing weekly doses between 10 and 15 g/m2.

Adult↗

PubMed1986

Terminal transferase in leukemias by flow cytometry.

The object of this study was to develop a flow-cytometric procedure for measuring terminal transferase (TdT) in leukemic cells by indirect immunofluorescence. We demonstrated the presence of TdT in an average of approximately 80% of the cells from 12 patients with ALL, one with CML in lymphoid blast crisis, and one with T-lymphoblastic leukemia. These results compared favorably to a separate slide test for TdT using an immunofluorescent or immunoperoxidase method. In the 21 patients with nonlymphocytic leukemias and in six normal donors we studied, less than a mean of 3% of the cells were TdT+. In 11 of 12 patients with ALL, the TdT+ cells also carried the HLA-DR antigen and in 8 of 12 cases of ALL the TdT+ cells also expressed the CALLA antigen. We concluded that the flow-cytometric method facilitates the measurement of TdT and may significantly increase the ability to diagnose residual and recurrent ALL leukemias.

Cell Line↗

PubMed1985

Volatile nitrites. Use and adverse effects related to the current epidemic of the acquired immune deficiency syndrome.

Early reports of the acquired immune deficiency syndrome (AIDS) in homosexual men suggested that the cause might be related to homosexual life-style practices, including use of recreational drugs. Inhalation of volatile nitrites is a possible contributing factor in AIDS because their pharmacologic properties lead to toxicity. Metabolism of N-nitroso compounds produces mutagens, teratogens, and potent carcinogens in 39 different animal species, and volatile nitrites have deleterious effects on human lymphocytes in vitro and in vivo. In relation to the current AIDS epidemic, the timing of production and sales of volatile nitrites for recreational use is the only new life-style factor that might answer the question "why AIDS now?" Prevalence of nitrite use among male homosexuals is very high, and almost every reported case of Kaposi's sarcoma during the past three years includes a history of prior nitrite use. The age of the group of patients in whom Kaposi's sarcoma and AIDS are developing is consistent with a cohort initially exposed seven to 10 years ago. Cessation of nitrite use could reduce the epidemic.

Acquired Immunodeficiency Syndrome↗

PubMed1985

Cytoplasmic IgM in leukemic B cells by flow cytometry.

The presence of intracellular cytoplasmic immunoglobulin M (IgM) in leukemic cells from patients with acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL) was investigated by flow cytometry. The objective of the study was to develop a reproducible flow cytometric method. A Burkitt's lymphoma-derived B-cell line, Daudi, and a pre-B ALL, Nalm-6, served as prototypes. Normal B cells and cells from patients with chronic myelogenous leukemia (CML) were used as negative controls. Cytoplasmic mu was expressed in 77.3 +/- 7.5% (n = 10) of Nalm-6 cells. CALLA+ ALL and CML cells lacked cytoplasmic mu. The surface-membrane immunoglobulin on the viable B cells was blocked with purified goat anti-human IgM. Subsequently, the B cells were fixed in cold absolute methanol and stained with a fluorescein-conjugated goat anti-human IgM to demonstrate cytoplasmic IgM. After the surface-membrane IgM was blocked, normal B cells had no cytoplasmic IgM (0.3-0.5% positive cells) detectable by flow cytometry. However, the peripheral blood lymphocytes from five patients with CLL and the Daudi cells contained cytoplasmic IgM, ranging from 7.8 to 76.7% and 45.7 to 89.3%, respectively. We conclude that cytoplasmic mu in Nalm-6, CLL, and Daudi cells can be easily and rapidly demonstrated by flow cytometry.

Animals↗