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PubMed1998

Wool production in transgenic sheep: results from first-generation adults and second-generation lambs.

In sheep transgenic for a sheep insulin-like growth factor 1 (IGF-1) cDNA driven by a mouse keratin promoter, we assessed wool production and properties in 51 adults of the first generation (G1) and in 56 lambs of the second generation (G2). Transgenic G1 sheep had an increased rate of wool production during spring and summer of year 2 compared with nontransgenic half-sibs, with a maximum increase of 17% in December, but during the winter nadir rates were similar. At second- and third-year shearing, however, fleece weights were not significantly different. There was a trend for transgenic animals to have coarser wool of lower staple strength. A controlled feeding trial revealed no significant differences in feed intake. The transgene was expressed not only in skin but also in a wide range of other tissues. Circulating IGF-1 concentrations were not significantly different between transgenic and nontransgenic animals, suggesting that local mechanisms were more important than systemic mechanisms for wool production, but were significantly higher in males than in females. In the G2 sheep, transgenic fleece weight did not differ significantly from nontransgenic either as lambs or at the end of the lamb year. Although the transgene was inherited in Mendelian fashion and was widely expressed, the production advantage seen in animals of the first generation did not persist in the second generation.

Animal Husbandry↗

PubMedDate not supplied

Oral (gavage) two-generation (one litter per generation) reproduction study of pentachlorophenol (penta) in rats.

The potential for pentachlorophenol (penta) to induce general and reproductive/developmental toxicity was evaluated in Crl Sprague-Dawley rats, employing a two-generation reproduction toxicity study. Penta was administered by gavage at doses of 0, 10, 30, and 60 mg/kg/day. In both generations, the parental animals (30/sex/group) were intubated daily for 10 weeks before cohabitation and continuing through cohabitation, gestation, and lactation periods. Intubation of the F1 generation was begun 28 days postpartum. Animals were evaluated daily for mortality and general toxicity (clinical observations, body weights and gains, feed consumption). Organ weights were recorded and histopathological evaluations were made. Specific indices of reproductive function evaluated included estrous cycles, mating and fertility, parturition, lactation, viability, and growth and development of offspring, including sexual maturation, sperm parameters, and numbers of ovarian primordial follicles. All deaths in the parental rats were unrelated to penta. Expected metabolic effects of penta, sporadic increased liver weights associated with hepatocellular centrilobular hypertrophy and vacuolation and lipofuscin pigmentation, were evident in the 10-, 30-, and 60-mg/kg/day dose group P1 and F1 animals. Toxicity, in the form of liver pathology (single cell necrosis), reduced body weights and associated reductions in organ weights, and reduced feed consumption were noted in both generations at the 30- and 60-mg/kg/day doses. Developmental toxicity associated with these doses included reduced pup weights and viability. The 60-mg/kg/day dose also resulted in delayed sexual maturation, decreased spermatid counts, small prostates and testes, decreased implantations, reduced fertility, and increased resorptions of embryos. Based on these results, it was concluded that 30 mg/kg/day is the lowest-observable-adverse-effect level (LOAEL) and 10 mg/kg/day is the no-observable-adverse-effect level (NOAEL) for both reproductive and general toxicity. These findings are consistent with results from previously conducted studies wherein reproductive/developmental toxicity was observed only at doses that also induced general toxicity. It differs from previous findings in that the NOAEL for general toxicity is two to three times higher for the more pure product than for products produced and tested previously. In addition, the results did not indicate bioaccumulation of penta. Thus, penta did not selectively affect reproduction or development of the offspring of rats at a dose of 10 mg/kg/day, a dose that is 7000 to 20,000 times higher than human exposure.

Administration, Oral↗

PubMed2003

Prospective experience with a second-generation hand-assisted laparoscopic device and comparison with first-generation devices.

BACKGROUND AND PURPOSE: The GelPort Hand-Assisted Laparoscopy (HAL) device was licensed for use in the U.K. in September 2001. We compared our experience with this second-generation device with that of first-generation devices; i.e., the Handport, launched in 1999, and the Intromit, first marketed in 1998. MATERIALS AND METHODS: We prospectively compared a number of parameters for operations performed using the GelPort (13 radical nephrectomies, 4 nephroureterectomies) with those performed using the Handport (3 radical nephrectomies, 2 nephroureterectomies, 2 simple nephrectomies) and the Intromit (2 radical nephrectomies, 1 nephroureterectomy, 2 simple nephrectomies). The main outcome measures were ease of application, time required to place the device, and perioperative complications specific to the device. RESULTS: The device requiring the longest time to place was the Intromit (average 15 minutes) followed by the HandPort (average 10 minutes) and then the GelPort (average 5 minutes). There were two leaks with the Intromit (one major and one minor). Pop-outs were a frequent issue with the HandPort, necessitating repeated replacement and resufflation. There was also a need to resufflate every time the hand was removed for a change of swab. None of these problems was noted with the GelPort, which was also found to be the easiest to use. The major disadvantage of the GelPort was its price, which was about a third more than that of the first-generation devices. CONCLUSION: The GelPort is currently a more user-friendly and robust HAL device. It is, however, more expensive than first-generation devices.

Cohort Studies↗

PubMed1998

Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation.

In the present study we used an in-vitro technique to examine initiation and propagation of blood coagulation at the surface of tantalum coronary stents exposed to flowing platelet-rich and platelet-free plasma. The time course of factor IXa production at the surface of the stent was not influenced by platelets. In spite of a significant factor IXa production, no thrombin activity was detected when the tantalum stent was exposed to platelet-free plasma; only when the stent was exposed to platelet-rich plasma was extensive thrombin production observed. These findings indicate that tantalum triggers blood coagulation, but that (adherent) platelets are essential for thrombin generation. Heparin-coated tantalum stents exposed to flowing platelet-rich plasma showed that factor IXa generation was slightly reduced compared with the bare stent. However, the heparin coating drastically delayed the onset of thrombin generation and largely reduced the steady-state production of thrombin. We found a clear relationship between the antithrombin binding capacity and the antithrombogenic potential of the heparin-coated stents. The mode of action of immobilized heparin is thought to abrogate thrombin generation by inhibiting thrombin-dependent positive feedback reactions at the surface of the coronary stent.

Animals↗

PubMed2007

The whisking rhythm generator: a novel mammalian network for the generation of movement.

Using the rat vibrissa system, we provide evidence for a novel mechanism for the generation of movement. Like other central pattern generators (CPGs) that underlie many movements, the rhythm generator for whisking can operate without cortical inputs or sensory feedback. However, unlike conventional mammalian CPGs, vibrissa motoneurons (vMNs) actively participate in the rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae. We find that, in vitro, a serotonin receptor agonist, alpha-Me-5HT, facilitates a persistent inward current (PIC) and evokes rhythmic firing in vMNs. Within each motoneuron, increasing the concentration of alpha-Me-5HT significantly increases the both the magnitude of the PIC and the motoneuron's firing rate. Riluzole, which selectively suppresses the Na(+) component of PICs at low concentrations, causes a reduction in both of these phenomena. The magnitude of this reduction is directly correlated with the concentration of riluzole. The joint effects of riluzole on PIC magnitude and firing rate in vMNs suggest that the two are causally related. In vivo we find that the tonic activity of putative serotonergic premotoneurons is positively correlated with the frequency of whisking evoked by cortical stimulation. Taken together, these results support the hypothesized novel mammalian mechanism for movement generation in the vibrissa motor system where vMNs actively participate in the rhythmogenesis in response to tonic drive from serotonergic premotoneurons.

Animals↗

PubMed1992

Effects of a 5-lipoxygenase inhibitor, AA861, on lipoxygenase metabolism and superoxide anion generation by human polymorphonuclear leukocytes--potentiation of superoxide anion generation by LTB4.

We studied the influence of a selective 5-lipoxygenase inhibitor, AA861, on the generation of the superoxide anion (O2-) and the lipoxygenase metabolites by human polymorphonuclear leukocytes (PMN). PMN produce O2- in a dose-dependent manner following stimulation with arachidonic acid (AA), leukotriene B4 (LTB4), or C5a. When PMN were stimulated with one of those three agents in the presence of high doses of AA861 (1-10 micrograms/ml), a significant reduction of O2- release was observed. In contrast, the generation of O2- by PMN stimulated by LTB4 was potentiated at lower concentrations of AA861 (0.025-0.25 micrograms/ml). However, stimulation with AA or C5a did not influence O2- generation in the presence of AA861 at the same concentration range. Furthermore, treating the PMN with the cyclooxygenase inhibitor, acetylsalicylic acid, did not potentiate the generation of O2- by stimulation with LTB4 over a wide range of concentrations. Quantification of lipoxygenase metabolites by reverse-phase high-performance liquid chromatography revealed that a high concentration of AA861 (0.5-5 micrograms/ml) completely inhibited the production of LTB4 and its omega-oxidative metabolites by PMN following stimulation with 100 microM AA, but only partially inhibited that of 5-hydroxyeicosatetraenoic acid (5-HETE). AA861 at a concentration of 5 micrograms/ml significantly increased the production of 15-HETE by PMN following the same stimulation. AA861 did not influence catabolism of LTB4 added to the reaction mixture to its omega-oxidative products by PMN over a wide range of concentrations. These findings suggest that the inhibition of 5-lipoxygenase metabolism may stimulate 15-lipoxygenase in human PMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Anions↗

PubMed1996

Comparison between first-generation (fixed-caliber) and second-generation (self-expanding, large caliber) temporary prostatic stents.

In this study our aim was to compare a first-generation intraprostatic stent (Prostakath) with a second-generation one (ProstaCoil) in patients with prostatic obstruction. The comparison was made in terms of ease of insertion, need for repositioning, migration, infection, stone formation and length of time in place. One hundred and seventeen patients with an age range of 52-94 years were included in this study. Forty-nine of the patients were treated with gold-plated stainless-steel-made stent (Prostakath) inserted under sonographic and 68 of the patients were treated with a nitinol-made stent (ProstaCoil) inserted under fluoroscopic guidance. Indications for stent insertion were similar for both groups. We found that immediate correct positioning was 83% for the Prostakath and 100% for the ProstaCoil. In 42% of the cases the Prostakath necessitated later repositioning because of partial migration and in 12% of the cases removal because of complete migration into the bladder or the anterior urethra. No migration was observed with the ProstaCoil. In 10% of these cases the Prostakath could not be inserted because of the instability of the stent. Due to its larger caliber the second-generation stent caused more transient irritative symptoms. No difference was found in stent-induced infections (10% for all stents). Encrustations were found in 40% of the patients at 1 year with the Prostakath, but in 30% with the ProstaCoil at 2 years. Maximal indwelling time was 12 months with the Prostakath and 36 months with the ProstaCoil. We conclude that the second-generation stent was more advantageous because of its larger caliber allowing catheterization and endoscopic examinations, more flexibility and much longer indwelling time.

Aged↗

PubMed1999

Progesterone can block transmission of the estradiol-induced signal for luteinizing hormone surge generation during a specific period of time immediately after activation of the gonadotropin-releasing hormone surge-generating system.

The preovulatory GnRH/LH surge in the ewe is stimulated by a rise in the circulating estradiol concentration that occurs in conjunction with preovulatory ovarian follicle development. In the presence of high levels of progesterone, such as during the luteal phase of the estrous/menstrual cycle, the stimulatory effects of elevated estradiol on GnRH/LH secretion are blocked. Recent work in the ewe has shown that a relatively short period of estradiol exposure can stimulate a GnRH/LH surge that begins after estrogenic support has been removed. This result suggests that surge generation is characterized by an estradiol-dependent period (during which the signal is read) and an estradiol-independent period (during which a cascade of neuronal events transmits the stimulatory signal to the GnRH neurosecretory system, which releases a surge of GnRH). In this series of studies, we addressed the hypothesis that progesterone can block transmission of the stimulatory estradiol signal after it has been read. Nine ovariectomized ewes were run through repeated artificial estrous cycles by sequential addition and removal of exogenous steroids. In study one, ewes received three treatments in a randomized cross-over design. Exposure to a follicular phase estradiol concentration for 10 h (positive control treatment) stimulated an LH surge in all ewes, as determined in hourly jugular blood samples. Maintenance of luteal phase progesterone concentrations throughout the artificial follicular phase (2 x CIDR-G devices, negative control) blocked the stimulatory effects of a 10-h estradiol signal, and no ewes that received this treatment expressed an LH surge. In the experimental group, exposure to luteal phase levels of progesterone, during the period after the surge generating system had been activated by estradiol, blocked the LH surge in six of nine ewes. This result demonstrates that progesterone can block the surge, even when applied after the surge-generating system has been activated and, therefore, that it inhibits either the transmission of the estradiol signal and/or the release of the GnRH/LH surge. In study 2, we assessed whether sensitivity to the inhibitory effects of progesterone was confined to a specific stage of the transmission of the estradiol signal. Eight ewes were exposed to four treatments, over successive artificial estrous cycles. Positive and negative controls were similar to those described in Study 1, except the duration of the stimulatory estradiol signal was reduced to 8 h. The two experimental groups consisted of an EARLY P (progesterone) treatment, in which progesterone was given from hours 8-13 after estradiol insertion (immediately after estradiol removal), and a LATE P treatment, in which progesterone was given from hours 13-18 (immediately before LH surge secretion). As expected, LH surges were stimulated and blocked, in response to the positive and negative controls, respectively. Whereas the EARLY P treatment blocked the LH surge in seven of eight ewes, the LATE P treatment was only successful in inhibiting a surge in one of eight animals. This result demonstrates that progesterone can block the estradiol-induced surge-generating signal soon after the onset of signal transmission (immediately after estradiol removal) but not during the later stages of signal transmission (at the time of GnRH/LH surge onset).

Animals↗

PubMed2004

Educating generation X and generation Y: teaching tips for librarians.

This article provides a list of helpful teaching tips for instructional librarians who need to meet the changing generational needs of their patrons. Specific generational qualities and attitudes of Generation X and Generation Y are discussed along with educational techniques and software recommendations. These tips are based on the authors' experiences at Drexel University's Hahnemann Library and Thomas Jefferson University's Scott Memorial Library, both of which are academic health sciences libraries.

Adult↗

PubMed2006

Picosecond-pulse wavelength conversion based on cascaded second-harmonic generation-difference frequency generation in a periodically poled lithium niobate waveguide.

The wavelength conversion of picosecond optical pulses based on the cascaded second-harmonic generation-difference-frequency generation process in a MgO-doped periodically poled lithium niobate waveguide is studied both experimentally and theoretically. In the experiments, the picosecond pulses are generated from a 40 GHz mode-locked fiber laser and two tunable filters, with which the lasing wavelength can be tuned from 1530 to 1570 nm, and the pulse width can be tuned from 2 to 7 ps. New-frequency pulses, i.e., converted pulses, are generated when the picosecond pulse train and a cw wave interact in the waveguide. The conversion characteristics are systematically investigated when the pulsed and cw waves are alternatively taken as the pump at the quasi-phase-matching wavelength of the device. In particular, the conversion dependences on input pulse width, average power, and pump wavelength are examined quantitatively. Based on the temporal and spectral characteristics of wavelength conversion, a comprehensive analysis on conversion efficiency is presented. The simulation results are in good agreement with the measured data.

Journal Article↗

PubMed2006

Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation.

Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6-8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Bötzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.

Animals↗

PubMed1999

Cohort changes in illegal drug use among arrestees in Manhattan: from the Heroin Injection Generation to the Blunts Generation.

This paper identifies three inner-city cohorts differing by birth year and preferred drugs that routinely passed through Manhattan's criminal justice system from 1987 through 1997: The Heroin Injection Generation born 1945-54, the Cocaine/Crack Generation born 1955-69, and the Blunts (marijuana plus tobacco) Generation born since 1970. The future prospects for the Blunts Generation may be modestly enhanced by their continued avoidance of cocaine, crack, and heroin--despite the fact that many of them are being reared in severely distressed households and are developing few skills for legal jobs.

Adolescent↗

PubMed2004

To evaluate and compare the effects of first generation anti-histamine (chlorpheniramine maleate) and second generation anti-histamine (loratadine) on isolated trachea of rabbit.

OBJECTIVE: The incidence of respiratory allergy has increased gradually over the past several years and current estimates suggest that allergic rhinitis affects approximately 20% of the population. Large scales population surveys indicate that up to 38% of patients with rhinitis have asthma. The allergic response in the airways is an important pathogensis to cause bronchoconstriction owing to increased responsiveness of tracheo bronchial tree to various stimuli and also causes the release of histamine and other chemical mediators from mast cells. Histamine has been shown to be an important mediator of an allergic reaction in both the upper and lower respiratory airways. Chlorpheniramine maleate is a stable, most potent, sedative first generation anti-histamine and is effective in the treatment of allergic disorders. Loratadine is a highly potent, non-sedating, long acting tricyclic, second generation anti-histamine. It is indicated in allergic rhinits, chronic idiopathic urticaria and allergic bronchial asthma. The purpose of study was to evaluate the antagonistic effects of chlorpheniramine maleate and loratadine on histamine induced contractions in isolated trachea of rabbit and also to compare the effects of first generation anti-histamine (chlorpheniramine maleate and second generation anti-histamine loratadine). METHODS: In this study twenty-four experiments were performed on isolated trachea of rabbit, in the presence of selected standard concentration of histamine dihydrochloride, antagonistic effects of various concentrations of chlorpheniramine maleate (10-18 to 10(-3) gm/ml) and loratadine from concentrations 10(-18) to 10(-3) gm/ml were recorded by Polygraph Model 7B in terms of rate and amplitude. RESULTS: Chlorpheniramine maleate showed non-significant antagonistic effect from concentrations 10(-18) to 10(-3) gm/ml in case of rate and 10(-18) to 10(-8) gm/ml in case of amplitude. Significant response showed from concentrations 10(-8) to 10(-3) gm/ml in case of rate (P<0.001) and 10(-7) to 10(-3) gm/ml in case of amplitude (P<0.001) while, loratadine showed non-significant response from concentrations 10(-18) to 10(-12) gm/ml in case of rate and from concentration 10(-18) to 10(-14) gm/ml in case of amplitude. Significant response observed from concentrations 10(-11) to 10(-3) gm/ml in case of rate and 10(-13) to 10(-3) gm/ml in case of amplitude. CONCLUSION: It was concluded that chlorpheniramine maleate antagonized the histamine induced contractions 80.65% at concentration 10(-3) gm/ml in case of amplitude and 11.35% at concentration 10(-3) gm/ml in case of rate and loratadine 76.82% in case of amplitude and 10.59% in case of rate.

Animals↗

PubMed1978

The generation of memory cells. II. Generation of B memory cells with preformed antigen-antibody complexes.

Mice were immunized with preformed complexes of dinitrophenylated haemocyanin (DNP-KLH) and anti-DNP or anti-KLH antibodies, and subsequently assayed for the generation of B memory (BM) cells. Complexes formed at equivalence or in slight antigen excess were far more effective than antigen alone in generating memory: as little as 100 ng DNP-KLH-anti-DNP produced substantial B cell priming. Anti-carrier and anti-hapten antibodies were equally effective. Complexes generated memory more rapidly than antigen alone, and the adjuvant effect was not simply due to aggregation of the antigen. Optimal priming by complexes required the integrity of the Fc portion of the antibody: F(ab')2 antibody fragments were less effective. The capacity of complexes to prime BM cells was abrogated by depriving mice of C3. C3 was also required for localization of complexes within splenic lymphoid follicles; complexes made with F(ab')2 localized in follicles, but less efficiently than those made with intact antibody. These results extend earlier findings (Klaus & Humphrey, 1977) and strongly suggest that the generation of BM cells involves the C3-dependent localization of antigen-antibody complexes within lymphoid follicles and strengthen the concept that germinal centres are the birthplace of BM cells.

Animals↗

PubMed1977

Tissue factor generation by human mononuclear cells: effects of endotoxin and dissociation of tissue factor generation from mitogenic response.

The effects of the presence of endotoxin in a mononuclear cell culture system have been assessed. Endotoxin was shown to be mitogenic for human peripheral blood lymphocytes and capable of stimulating the generation of tissue factor. Concentrations of endotoxin, found to contaminate many commercial mitogens and antigens, activated mononuclear cells in a time-dependent manner. Generation of tissue factor was detected in cultures harvested from 2 to 72 hours following stimulation with endotoxin. Dose-response curves relating concentrations of endotoxin to mononuclear cell stimulation were determined; as little as 0.001 microng/ml. of E. coli endotoxin was capable of stimulating the generation of tissue factor in the cell cultures. The mitogenic effect of endotoxin was modest, however, and appeared to be unrelated to the ability of endotoxin to active tissue factor. Inhibition of DNA synthesis in the cell cultures by cytosine arabinoside or nonlethal irradiation failed to impair the generation of tissue factor. Endotoxin contamination of various reagents used in cell culture was evaluated with the Limulus assay, which detected as little as 1 X 10(-4) microng/ml. of endotoxin. Endotoxin was detected in preparations of phytohemagglutinin, purified protein derivative of the tubercle bacillus, mumps vaccine, tetanus toxoid, concanavalin A, and pokeweed mitogen. Because of the broad implications of contamination by endotoxin of various reagents, we assessed the specificity of the Limulus assay for the detection of endotoxin in the lectin, concanavalin A, and determined that the reaction was specific for endotoxin. Contamination by endotoxin of mononuclear cell culture systems should be considered as a possible factor in the production of various biological effects attributed to some commonly used mitogens and antigens.

Cytarabine↗

PubMed1988

Generation and characterization of B72.3 second generation monoclonal antibodies reactive with the tumor-associated glycoprotein 72 antigen.

Monoclonal antibody (MAb) B72.3 was generated using a membrane-enriched fraction of a human mammary carcinoma biopsy. It has demonstrated reactivity to the majority of human adenocarcinomas including colorectal, gastric, pancreatic, ovarian, endometrial, mammary, and non-small cell lung cancer and no or weak reactivity to normal adult tissues, with the exception of secretory endometrium. The B72.3-reactive antigen, termed tumor-associated glycoprotein (TAG)-72, has been purified and used as an immunogen to generate B72.3 second generation MAbs. Since the source of purified TAG-72 was a human colon cancer (CC) xenograft, these MAbs have been given a CC designation. Twenty-eight CC MAbs, all immunoglobulin Gs, have been generated and shown to be reactive with TAG-72 and via both radioimmunoassay and immunohistochemical analyses show differential reactivity to carcinoma versus normal adult tissue biopsies. Nine CC MAbs (CC11, 15, 29, 30, 40, 46, 49, 83, and 92) were selected for further characterization. As a result of analyses using direct-binding radioimmunoassay to a range of human carcinomas, Western blotting, live cell surface binding assays, five liquid competition radioimmunoassays, and Ka measurements, all nine CC MAbs could be distinguished from each other and from B72.3. The Ka of B72.3 was determined to be 2.54 X 10(9) M-1; all the CC MAbs demonstrated higher KaS with MAbs CC92, 49, and 83 having KaS of 14.26, 16.18, and 27.72 X 10(9) M-1, respectively. These studies thus demonstrate that one or more of the anti-TAG-72 CC MAbs may be more efficient than B72.3, or useful in combination with B72.3, toward the further study of human carcinoma cell population and the diagnostic and therapeutic procedures presently utilizing MAb B72.3.

Animals↗

PubMed1984

Generation of the alloreactive T cell repertoire: K region homology between H-2b T cell precursors and T cell maturation environment is required for the generation of the Kbm6-specific cytotoxic T cell repertoire.

The influence of T cell genotype and T cell maturation environment on the generation of the T cell alloreactive repertoire was evaluated in the H-2b cytotoxic T lymphocyte response to Kb mutant determinants expressed by the strain B6-H-2bm6. Specifically, by constructing radiation bone marrow chimeras with B6 or B10 (H-2b) donor cells and B10.BR, B10.A(4R), B10.MBR, and B6.C-H-2bm1 irradiated mice as recipients, it was possible to investigate the major histocompatibility complex (MHC)-encoded gene products of the host environment required for the generation of a bm6-specific H-2b CTL response. The results of such experiments confirmed the previous finding that the alloreactive T cell repertoire is influenced both by T cell MHC genotype and by the MHC gene products of the T cell maturation environment. In addition, the results of the present study further demonstrated that in the chimeric donor and host genetic combinations used, it was both necessary and sufficient that there be a homology of K region-encoded determinants for the generation of a bm6-specific CTL response. Experiments utilizing a mixed responder population of unresponsive B6----B10.D2 spleen cells and responsive Lyt-2 congenic B6.Lyt-2.1 spleen cell suggested that the cellular defect(s) underlying the unresponsiveness of the chimeric cells to bm6-encoded determinants was at the level of the CTL precursor. Together, these findings indicate that an interaction of the K region-encoded gene products of the T cell and its maturation environment play a critical role in the generation of the CTL repertoire specific for bm6 mutant determinants. We discuss here the possibility that this interaction may reflect a requirement that T cells recognize such mutant allodeterminants in association with self restriction elements present on the same mutant K region-encoded molecule.

Animals↗

PubMed1984

In vitro generation of human activated lymphocyte killer cells: separate precursors and modes of generation of NK-like cells and "anomalous" killer cells.

The activation of human peripheral blood mononuclear cells (PBM) in culture leads to the generation of nonspecific killer cells. These cells, termed activated lymphocyte killer (ALK) cells, can kill fresh tumor cells and tumor cell lines, in addition to the natural killer (NK) cell sensitive target K562. ALK cells have features in common with both T and NK cells, but their nature and origin are unknown. In the present study, it is shown that ALK cells are in fact heterogeneous and can be generated from both large granular lymphocytes with the same phenotype as NK cells and from T cells. Cell populations enriched for NK cells, when cultured with lymphokines, rapidly acquired a T cell phenotype, enhanced cytolytic activity against K562, and the ability to lyse NK-insensitive target cells such as a melanoma cell line LiBr; these ALK cells were described as NK-like cells. On the other hand, of the cloned cells derived from PBM stimulated with irradiated B lymphoblasts and grown in lymphokines, the major proportion of cytolytic T cells (CTC) able to kill the specific stimulator lymphoblasts were also found to kill LiBr but not K562 cells. These ALK cells, which were derived from the same precursors as CTC, were designated anomalous killer (AK) cells. Consistent with this, the presence of the pan T monoclonal antibody UCHT1 from the beginning of mixed cell cultures inhibited the generation of CTC and of the AK-type of ALK cell, which killed melanoma cells, but not the NK type, which killed K562 targets. By contrast, at the effector cell level, the antibodies UCHT1 and OKT8 only blocked specific killing by CTC but did not block the killing of LiBr or of K562 targets by ALK cells. However, at the effector cell level there was additional evidence for the heterogeneity of ALK cells. Thus, monoclonal antibody 9.1C3, which blocks killing by freshly isolated NK cells, also blocked the killing of K562 targets by NK-like cells, but did not block B lymphoblast killing by CTC or melanoma cell killing by AK cells. It is concluded that after mixed lymphocyte culture, the majority of ALK cells measured by the killing of melanoma target cells arise from the same precursors and are under the same influences as classical CTC (AK cells), whereas cells killing K562 targets are derived from NK cells (NK-like cells). Once generated, the AK cells have a different mechanism of killing from both classical CTC and from NK and NK-like cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗