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Biomedical subjects

D T Harris

Publications and source records attributed to D T Harris.

87 records · Page 5Linked to original sources
PubMed1980

Elicitation of anti-viral cytotoxic T lymphocytes with purified viral and H-2 antigens.

The minimal molecular requirements for elicitation of secondary anti-Sendai virus CTL were investigated. The hemagglutinin-neuraminidase (HN) glycoprotein of Sendai virus and the H-2Kk glycoprotein of YAC tumor cells were purified and incorporated into phospholipid vesicles. These unilamellar liposomes were then tested for the ability to elicit H-2 restricted secondary anti-Sendai virus CTL. The results indicate that these well-defined vesicles were capable of eliciting secondary anti-Sendai virus CTL which lysed only target cells possessing the H-2Kk haplotype and modified with inactivated Sendai virus.

Animals↗
PubMed1979

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.

Antineoplastic Agents↗
PubMed1979

Phase II study of ICRF-159 in refractory metastatic breast cancer.

ICRF-159, at a dose of 300 mg/m2, was given orally every 8 hours for nine doses every 21 days to 40 patients with metastatic breast cancer refractory to hormonal therapy and cyclophosphamide, methotrexate, 5-fluorouracil, and adriamycin chemotherapy. Two patients with soft tissue disease had short-lived partial responses. The hematologic toxicity was severe. Three patients required rbc transfusions. Four patients became septic at the nadir of leukopenia; two of these patients died while leukopenic. Two patients had platelet counts less than 25,000/mm3. All patients who were nonevaluable or who had life-threatening or lethal toxicity were nonambulatory. Since the 19 nonambulatory patients had a median survival of only 1.25 months as compared to 7 months in ambulatory patients, it is recommended that future phase II trials in chemotherapy-refractory breast cancer be limited to ambulatory patients. Although ICRF-159 has minimal antineoplastic effects, it is not recommended for further investigations in metastatic breast cancer, even at more hematologically tolerable doses of 250 mg/m2 every 8 hours for nine doses.

Blood Cell Count↗
PubMedDate not supplied

Function associated molecules on nonspecific cytotoxic cells: role in calcium signaling, redirected lysis, and modulation of cytotoxicity.

Monoclonal antibodies (mAbs) specific for a putative antigen receptor (function associated molecule, FAM) on fish NCC were tested for their ability to initiate signal transduction responses. Anti-FAM hybridoma target cells were significantly lysed by NCC when tested by redirected lysis (RL). Redirected lysis was enhanced by 1-h pretreatment of the NCC with anti-FAM mAb; however, 18-h pretreatment produced significant inhibition. The effects of the calcium ionophore A23187 on RL were also examined: 10(-4) M but not 10(-5) M A23187 significantly increased RL. Purified NCC were treated with mAb and cellular DNA synthesis was determined. Significant increases in NCC incorporation of tritiated thymidine were measured 72 h after treatment with mAb. Experiments were also conducted to determine levels of free cytosolic calcium in NCC following mAb binding. Anti-FAM mAb binding produced a rapid rise in cytosolic calcium (200-500 nM) determined by Fura-2/AM fluorescence. Calcium ionophore A23187, PHA, and Con-A treatment of NCC also produced significantly increased [Ca2+]i. Target cell binding by NCC caused a three-fold increase in [Ca2+]i. These data suggest that triggering of the FAM may initiate a signal(s) that activates cytotoxicity, increases cytosolic free calcium concentrations, and initiates DNA synthesis.

Animals↗
PubMedDate not supplied

A species-conserved NK cell antigen receptor is a novel vimentin-like molecule.

The role of a novel, evolutionarily conserved function-associated molecule (FAM) in NK cell function has been examined in several species. This molecule has previously been shown to mediate NK and NK-like recognition functions in fish NCC and human NK cells. We now show that this molecule is distributed in those tissues that contain NK cells in mice and rats. Further, we show that this molecule functions as an antigen receptor on NK cells of these species. That is, monoclonal antibodies directed against this FAM inhibit NK cell cytotoxic function and trigger signal transduction pathways in each of the species. Finally, we present evidence that this putative antigen receptor is a vimentin-like molecule which functions to mediate all NK or NK-like recognition functions in a variety of species.

Animals↗
PubMedDate not supplied

Expression of a novel function-associated molecule on cells mediating spontaneous cytolysis in swine.

In the present study, we have analyzed the effects of the anti-FAM mAb 5C6, on endogenous NK cell and lymphokine-activated killer (LAK) cell activity of swine. We report that the anti-FAM mAb 5C6 binds to fresh and cultured lymphocytes with spontaneous cytotoxic activity from swine peripheral blood. In conjunction, the anti-FAM mAb 5C6 inhibits swine cytolysis against K562 target cells. Inhibition was found to be mediated by blocking of conjugate formation. The level of spontaneous killing and mAb inhibition was correlated with the number of swine cells staining positive with the mAb 5C6 as assessed by flow cytometry.

Animals↗
PubMedDate not supplied

An evolutionary conserved target cell antigen along with MHC class I molecules influences susceptibility to murine NK cell lysis.

We have previously characterized a novel monoclonal antibody (mAb), termed 18C2, which binds to and inhibits the lysis of target cells by human natural killer (NK) cells. We now show that the anti-target cell mAb 18C2 also recognizes a similar structure on the murine NK sensitive target cell YAC-1, as well as on NK resistant target cells P815 and EL-4, as observed by flow cytometry. Functional studies demonstrated that the mAb 18C2 inhibited the lysis of both NK sensitive YAC-1 target cells, as well as NK resistant target cell lines P815 and EL-4 by freshly-isolated nylon wool nonadherent (NWNA) NK cells, 5-day lymphokine activated killer (LAK) cells and adherent lymphokine activated killer (ALAK) cells. The inhibitory activity of the mAb 18C2 occurred at the target cell level only. Single cell conjugate assays as demonstrated that the structure recognized by the mAb 18C2 was involved in recognition between NK cells and NK target cells, as the mAb inhibited conjugate formation between a variety of effector cells and various target cell lines tested. Further, the role of major histocompatibility complex (MHC) class I antigens in NK cell cytotoxicity was examined. We observed that target cells expressing low levels of MHC class I antigens in association with the novel target cell antigen were more sensitive to NK cell lysis, as compared to cells that co-express higher levels of MHC class I antigen and the target cell antigen. Further, the presence of this antigen across different species suggests this target cell antigen/structure to be highly evolutionarily conserved.

Animals↗
PubMedDate not supplied

Anti-idiotypic antibody and recombinant antigen vaccines in colorectal cancer patients.

The colorectal carcinoma (CRC)-associated GA733 antigen (also known as CO17-1A, KS1-4, KSA or EpCAM) has been the target of a phase II/III randomized trial of passive immunotherapy with monoclonal antibody CO17-1A and phase I active immunotherapy trials with polyclonal anti-idiotypic antibodies mimicking the CO17-1A or GA733 epitope on the antigen. The CO17-1A antigen was molecularly cloned and the extracellular domain expressed in baculovirus (BV) GA733-2E. Whereas, anti-idiotypic antibody mimics a single epitope on the antigen, BV GA733-2E expresses multiple potentially immunogenic epitopes. In animals, the immunogenicity of BV GA733-2E in aluminum hydroxide was superior to that of anti-idiotype in the same adjuvant. Here, we compared the immunogenicity of anti-idiotypic antibody and GA733-2E antigen in CRC patients. These studies indicate that the antigen is superior to the anti-idiotype antibody in inducing humoral and cellular immunity in CRC patients.

Antibodies, Anti-Idiotypic↗
PubMedDate not supplied

Immunotoxicological effects of JP-8 jet fuel exposure.

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed (3-5). Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.); e.g., the immune system. Significant changes in immune consequences, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long-lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed for 1h/day for 7 days to varying concentrations of aerosolized JP-8 jet fuel to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on their immune systems. It was observed that even at exposure concentrations as low as 100 mg/m3 detrimental effects on the immune system occurred. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in losses of different immune cell subpopulations depending upon the immune organ being examined. Further, JP-8 exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low concentration exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure, as effects were seen at concentrations of jet fuel that did not evidence change in other biological systems. Such changes may have significant effects on the health of the exposed individual.

Administration, Inhalation↗
PubMedDate not supplied

Short-term exposure to JP-8 jet fuel results in long-term immunotoxicity.

Chronic exposure to jet fuel has been shown to have adverse effects on human liver function, to cause emotional dysfunction, to cause abnormal electroencephalograms, to cause shortened attention spans, and to decrease sensorimotor speed. Due to the decision by the United States Air Force to implement the widespread use of JP-8 jet fuel in its operations, a thorough understanding of its potential effects upon exposed personnel is both critical and necessary. Exposure to potential environmental toxicants such as JP-8 may have significant effects on host systems beyond those readily visible (i.e., physiology, cardiology, respiratory, etc.); e.g., the immune system. Previous studies have shown that short-term, low concentration JP-8 exposure had significant effects on the immune system, which should have serious consequences for the exposed host in terms of susceptibility to infectious agents. If these alterations in immune function were long-lasting, it might also result in an increased likelihood of development and/or progression of cancer, as well as autoimmune disease. In the current study, mice were exposed for 1 h/day for 7 days to a moderate (1000 mg/m3) and a high (2500 mg/m3) concentration of aerosolized JP-8 jet fuel to stimulate occupational exposures. One to 28 days after the last exposure the mice were analyzed for effects of the exposure on their immune systems. It was observed that decrease in viable immune cell numbers and immune organ weights found at 24 h after exposure persisted for extended periods of time. Further, JP-8 exposure resulted in significantly decreased immune infection, as analyzed by mitogenesis assays, which persisted for up to 4 weeks post-exposure. Thus, short-term exposure of mice to JP-8 jet fuel caused significant toxicological effects on the immune system, which were long-lasting and persistent. It appears that the immune system may be the most sensitive indicator of toxicological damage due to JP-8 exposure. Such long-term changes in immune status may have significant effects on the health of the exposed individual.

Aircraft↗
PubMedDate not supplied

Protection from JP-8 jet fuel induced immunotoxicity by administration of aerosolized substance P.

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and decreased sensorimotor speed. The United States Air Force has decided to implement the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Exposure to potential environment toxicants such as JP-8 may have significant effects on host physiology. Previous studies in mice have shown that short-term, low concentration JP-8 exposure had significant effects on the immune system; e.g., decreased viable immune cell numbers, decreased immune organ weights, and loss on immune function that persisted for extended periods of time (i.e., up to 4 weeks post-exposure). Previous studies have shown that JP-8 induced pulmonary dysfunction was associated with a decrease in levels of the neuropeptide substance P (SP) in lung lavage fluids. It was found that administration of aerosolized SP was able to protect exposed animals from such JP-8 induced pulmonary changes. In the current study, aerosolized SP was analyzed for its effects on JP-i induced immunotoxicity in exposed mice. It was observed that SP administration could protect JP-8 exposed animals from losses of viable immune cell numbers, but not losses in immune organ weights. Further, exposure of animals to SP inhibitors generally increased the immunotoxicity of JP-8 exposure. SP appeared to act on all immune cell populations equally as analyzed by flow cytometry, as no one immune cell population appeared to be preferentially protected by SP. Also, SP administration was capable of protecting JP-8 exposed animals from loss of immune function at all concentrations of JP-8 utilized (250-2500 mg/m3). Significantly, SP only needed to be administered for 15 minutes after JP-8 exposure, and was active at both 1 microM and 1 nM concentrations. Thus, SP administration appears to be a relatively simple and efficient means to reverse the immunotoxicity due to hydrocarbon exposure.

Aerosols↗
PubMedDate not supplied

Phase II study of maytansine in patients with advanced lymphomas: an Eastern Cooperative Oncology Group pilot study.

During phase I trials with maytansine some activity against lymphoma and lymphocytic leukemia was noted. Therefore, a phase II trial of maytansine in patients with advanced lymphomas refractory to conventional chemotherapy was begun. There were three partial responders (10%) among 31 patients entered in the trial. Toxicity was acceptable; gastrointestinal and neurologic side effects were the most common. Little myelotoxicity and no hepatotoxicity were observed. We conclude that maytansine has very limited activity in heavily pretreated patients with Hodgkin's disease and non-Hodgkin's lymphomas.

Adult↗