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Biomedical subjects

K H Stenzel

Publications and source records attributed to K H Stenzel.

At least 37 records · Page 2Linked to original sources
PubMed1988

Human memory T cell activation. Effects of monoclonal antibodies directed at interleukin-2, receptors for interleukin-2, or interferon-gamma.

Several polyclonal T cell activators can induce the differentiation of quiescent antigen-specific memory T cells (memory cells) into specific secondary cytotoxic T cells, in the absence of the original priming alloantigens. Such activation represents a potential pathway by which immunologically nonspecific signals can elicit specific antiallograft immunity. We therefore investigated the molecular basis for antigen-independent activation of memory cells using as probes recombinant interleukin-2 and monoclonal antibodies directed at IL-2, IL-2 receptors (IL-2R), or interferon-gamma (IFN-gamma). Antigen-specific memory cells, generated in human long-term-primary mixed lymphocyte cultures, were induced to proliferate, exhibit antigen specific secondary cytolytic activity, or produce IFN-gamma by recombinant DNA human IL-2 produced in E Coli. Monoclonal antibodies directed at the IL-2R or at IL-2 inhibited IL-2-mediated proliferation, cytolytic activity, or production of IFN-gamma. Monoclonal antibodies directed at IFN-gamma did not inhibit alloantigen or IL-2 mediated activation of memory cells. Our findings suggest that successful interaction between IL-2 and its receptor expressed on memory cells represents a plausible pathway by which an immunologically nonspecific signal might elicit specific antiallograft immunity. Moreover, therapeutic strategies that include antibodies directed at the IL-2 and/or IL-2R and not antibodies directed at IFN-gamma will inhibit IL-2-dependent alloimmunity.

Antibodies, Monoclonal↗
PubMed1988

Periodate and recombinant interleukin-2-activated autologous leukocytes can induce regression of metastases of renal cancer.

We present the results of a pilot study that determined the effects of both intermittent injections of periodate and recombinant interleukin-2 (rIL-2)-activated leukocytes and continuous infusions of low doses of rIL-2 on metastases of nine patients with stage IV renal cancer. Four patients experienced regressions, two patients stabilized, and only three patients did not respond. The responses of individual lesions in six patients were heterogeneous with regard to both the degree (ranging from cessation of growth to regression to undetectability) and the duration (ranging from less than 3 to up to 8 months). Survival times from the time of diagnosis and from the time of start of the protocol treatment ranged from 12 to 20 months and 6 to 12 months, respectively, for three patients who expired and from 10+ to 28+ months and 6+ to 12+ months, respectively, for six patients who are alive. Only one patient experienced a grade 4 toxicity (transient renal failure requiring hemodialysis). All other toxicities (grades 1-3) were easily controlled and resolved completely after 7 days. This pilot study deserves clinical testing on a larger scale, since it combines regression inductions in a hitherto treatment-resistant cancer with little complicating toxicity.

Adult↗
PubMed1987

Osmotic enhancement of mitogenic stimulation in PNA-negative murine thymocytes.

Increasing the osmolarity of the culture medium enhances the response of peanut agglutinin (PNA)-negative thymocytes to stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA), interleukin 1 (IL-1) and interleukin 2 (IL-2) in the presence of phytohemagglutinin (PHA). The effect was attained by the addition to the medium of salts such as NaCl and KCl or by addition of nonionized compounds such as sucrose and fucose. The enhanced response was monitored by determination of [3H]thymidine incorporation, IL-2 production, and blasts formation. The potentiating effect of hypertonic medium on PNA-negative thymocytes treated with PHA and TPA was most pronounced at suboptimal concentrations of PHA. Hypertonic medium did not enhance the response of thymocytes treated with TPA and supraoptimal concentrations of PHA. Increasing the osmolarity of the medium 44 hr after initiation of culture did not enhance [3H]thymidine incorporation in thymocytes that were pulsed between 52 and 72 hr. The enhancing effect of increased osmolarity in mitogenic stimulation of thymocytes may be related to osmotic activation of the Na+/H+ antiport.

Animals↗
PubMed1987

Adoptive immunotherapy for stage IV renal cell carcinoma: a novel protocol utilizing periodate and interleukin-2-activated autologous leukocytes and continuous infusions of low-dose interleukin-2.

In a pilot study involving 13 patients with advanced stage IV renal cell carcinoma, anti-tumor effects and toxicity of a novel form of adoptive immunotherapy were determined. The protocol utilizes infusions of autologous mononuclear leukocytes treated with the oxidizing mitogen sodium periodate (IO4-) and cultured in medium containing human recombinant interleukin-2 (IL-2), and continuous infusions of low-dose IL-2 (mean +/- SD dose = 39.5 +/- 8.6 X 10(3) U/kg/24 hours). Leukocytes (5 to 10 X 10(9] were removed by leukapheresis three times per week, mononuclear cells were separated, activated with IO4- and cultured in medium containing IL-2 (500 U/ml) for 48 to 72 hours. The cells were re-infused following the next leukapheresis procedure. IL-2 was administered five days per week. Treatment was continued for two three-week cycles. An increase in peripheral blood mononuclear cells bearing the natural killer cell (NK) surface marker, Leu 11, an increase in NK- and antibody-dependent cell-mediated cytotoxicity, and a slight increase in spontaneous cytotoxicity for non-NK targets were noted. Regressions (more than 50 percent decrease in tumor mass) of pulmonary, liver, bone, or soft tissue metastases were induced in six patients. Severe fluid retention did not develop in any patient and no patient required treatment in the intensive care unit. Five of the patients who showed a response have experienced a relapse at 5.2 +/- 1.0 (mean +/- SD) months. These observations indicate that IO4-/IL-2-activated killer cells plus continuous infusions of low-dose IL-2 can result in regression of metastatic renal cell carcinoma.

Adult↗
PubMed1987

Biochemical and ultrastructural alterations accompany the anti-proliferative effect of butyrate on melanoma cells.

The effect of sodium butyrate on mouse and human melanoma cell lines was evaluated. Sodium butyrate (0.1-2mM) is shown to reduce the clonogenic potential of several melanoma cell lines. The antiproliferative effect of sodium butyrate is accompanied by a marked increase in the activity of the plasma-membrane bound enzyme gamma-glutamyl transpeptidase. Sodium butyrate treated cells acquire a well developed rough endoplasmic reticulum and accumulate fat droplets. The development of the endoplasmic reticulum is associated with a marked increase in the activity of the enzyme marker NADPH cytochrome c reductase. It is suggested that the phenotypic alterations induced by sodium butyrate may serve as markers for the action of this agent on melanoma cells and other tumours.

Animals↗
PubMed1987

The anti-proliferative effect of lithium chloride on melanoma cells and its reversion by myo-inositol.

The effect of LiCl on melanoma cell growth and differentiation was studied in mouse and human melanoma cell lines. LiCl markedly inhibited B16 and HT-144 melanoma cell growth in vitro. Clonogenicity in soft agar of the melanoma cells was also markedly inhibited by LiCl. Pretreatment of B16 mouse melanoma cells with LiCl delayed the appearance of melanoma tumours in syngeneic mice. Growth inhibition of cells was accompanied by morphological and biochemical alterations. LiCl induced cell enlargement and formation of dendrite-like structures. The activity of NADPH cytochrome c reductase, an enzymatic marker of endoplasmic reticulum was significantly (2-3 fold) increased. Addition of myo-inositol to cell cultures partially reversed the anti-proliferative and morphological effects of LiCl on melanoma cells. This finding may suggest that the anti-proliferative effect of LiCl is related to its effect on phosphatidylinositol metabolism.

Animals↗
PubMed1987

Effect of immunosuppressants on OKT3 associated T cell activation: clinical implications.

The monoclonal antibody directed at the T cell differentiation antigen T3 (CD3, T.gp 20-25) appears to be superior to conventional high-dose steroids in the treatment of rejection in cadaveric renal graft recipients. Re-rejection episodes and other adverse reactions, probably secondary to T cell activating potential of anti-T3, continue to be clinical problems with anti-T3 therapy. We therefore examined the relative efficacy of cyclosporin A (CSA), methylprednisolone (MP), or 6-mercaptopurine (6-MP), at concentrations that are readily accomplished in clinical practice, on the activation of T cells by anti-T3. CSA or MP mediated marked and 6-MP mediated modest inhibition of anti-T3 induced proliferation of alloimmune memory T cells. CSA- or MP-inhibited anti-T3 elicited specific secondary cytolytic activity and natural killer (NK) cell activity, and 6-MP failed to prevent the augmentation of NK cell activity mediated by anti-T3. The immunosuppressants also exhibited differential effects on anti-T3-associated lymphokine production by peripheral blood mononuclear cells. Interleukin 2 production was completely inhibited by CSA, modestly inhibited by MP and not inhibited by 6-MP. Interferon gamma production was completely inhibited by CSA or MP and not inhibited by 6-MP. Our findings, in addition to providing a plausible immunological basis for some of the complications of anti-T3 therapy, provide experimental support for therapeutic strategies that include the use of CSA and/or MP along with anti-T3.

Antibodies, Monoclonal↗
PubMed1987

Optimization of donor specific blood transfusion in kidney transplantation.

1. One hundred milliliters of stored whole blood DST, three times at weekly intervals is a practical, less immunizing and effective approach to enhance graft survival in recipients of a living-related donor kidney. 2. This protocol could also be used in sibling donor/recipient pairs who do not share a haplotype as well as in those who share two haplotypes to enhance graft survival. 3. The use of a short course of Cs (6 mg/kg/d for three weeks) along with DST appears to reduce the sensitization rate even lower. The dose of Cs used in this study produced no clinically significant adverse reactions, whereas Aza (1 mg/kg/d) often produces leukopenia. 4. DST produces significantly suppressed donor specific MLC responses in the early post-DST period; however, it increases the response at a later time. DST modulates immune responses in such a way that secondary responses upon grafting are more readily reversible by immunosuppressive agents.

Adult↗
PubMed1986

Anti-tumor properties of lymphocytes activated by the oxidizing mitogens.

Human peripheral blood mononuclear cells when activated with the oxidizing mitogens, neuraminidase/galactose oxidase or sodium periodate, express cytolytic activity for freshly isolated tumor cells and for a variety of cell lines, including NK-resistant solid tumor lines. Normal lymphoid cells are not targets for cytotoxicity and do not inhibit lysis of susceptible targets mediated by the oxidizing mitogen-activated mononuclear cells. The cytotoxic response is rapidly generated and reaches peak levels at 48 hr. The oxidizing mitogens induce expression of IL 2 receptors on peripheral blood mononuclear cells. Combined treatment of cells with IL 2 and the oxidizing mitogens results in a marked enhancement of cytotoxicity. Enhancement is achieved at levels of IL 2 that alone result in minimal generation of cytotoxic cells. Growth of a human renal cancer cell line in nude mice was inhibited when the renal cancer cells were injected together with oxidizing mitogen-activated human mononuclear cells. These studies indicate that oxidizing mitogen-activated cells provide a potentially valuable source of material for the adoptive immunotherapy of tumors.

Adjuvants, Immunologic↗
PubMed1986

Growth inhibition of murine melanoma by butyric acid and dimethylsulfoxide.

Treatment of B16-F10 melanoma cells with dimethylsulfoxide (DMSO) or butyric acid (BA) inhibits cell growth and delays tumor appearance in syngeneic mice. Both agents induce morphological changes in these cells. Treatment of melanoma cells with DMSO results in a marked increase in tyrosinase activity and melanin content. BA, on the other hand, does not increase melanin content and decreases tyrosinase activity. The data show that there are marked differences in the effect of DMSO and BA on melanin biosynthesis, whereas both agents inhibit cell growth and cause a delay in tumor appearance. These findings indicate that decreased proliferation of melanoma cells and induction of melanin biosynthesis are not necessarily associated phenomena.

Animals↗
PubMed1986

Early effects of TPA on protein kinase activity in murine thymocytes. Reduction of protein kinase C activity in the cytosol and increase of Ca2+ and phospholipid-independent kinase activity in the particulate fractions.

Brief treatment of intact thymocytes with TPA and other tumor promoters causes a reduction in protein kinase C activity from the cytosol and an increase in kinase activity in the particulate fraction. In contrast to the activity in the cytosol, which is absolutely dependent on the addition of Ca2+, phosphatidylserine and diolein, the activity in the particulate fraction is independent of these agents. Analysis of target specificity of the particulate kinase activity using exogenous and endogenous substrates suggests that the increased phosphorylation in the particulate fraction is catalysed by protein kinase C with altered catalytic properties. Although interleukin-1 and TPA are both co-mitogens for murine thymocytes, interleukin-1 does not share with TPA its property to alter protein kinase activity in the cytosolic and particulate fractions.

Animals↗
PubMed1985

Differential effects of tumor promoters on cAMP production: inhibition of receptor-mediated and potentiation of cholera toxin-mediated stimulation.

Tetradecanoylphorbol-acetate and other tumor promoters inhibit prostaglandin E2 and isoproterenol-induced cAMP accumulation in mouse thymocytes but markedly potentiate cAMP production induced by cholera toxin. Cholera toxin is known to stimulate cAMP production by inducing ADP-ribosylation of the alpha-subunit of a guanine nucleotide-binding regulatory (G) protein, resulting in activation of the catalytic unit of adenylate cyclase. G proteins have been implicated as plasma membrane transducers for a variety of additional signals. It is possible that the growth promoting and co-mitogenic properties of tumor promoters are related to their effects on G proteins.

Animals↗
PubMed1985

12-O-Tetradecanoylphorbol-13-acetate enhances glycolysis in rat thymocytes.

The potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a rapid increase in glycolysis in rat thymocytes. The increase in the glycolytic flux was also reflected by elevated fructose 1,6-diphosphate levels. TPA treatment did not result in an increase of hexokinase, phosphofructokinase or pyruvate kinase when measured in cell homogenates. It is suggested that the early increase in glycolysis in TPA treated lymphocytes may result from TPA-mediated increase in glucose transport.

Animals↗
PubMed1985

Human B lymphoblastoid cell lines provide an interleukin 1-like signal for mitogen-treated T lymphocytes via direct cell contact.

The B lymphoblastoid cell lines (B-LCL) 8392, SB, 1788, and Daudi provide accessory cell activity for mitogen-treated T cells, whereas the T lines MOLT-4, 8402, CEM, and HSB do not provide this function. Direct cell contact is required for the accessory cell activity, and active lymphocyte growth factors could not be detected in the supernatants of the B-LCL. The B-LCL also present alloantigens to responding T cells, and this response is independent of additional accessory cells. The target for the B-LCL is the responding T cell itself, rather than a minor contaminating population of endogenous accessory cells. This conclusion is based on the finding that, under culture conditions in which T cells do not proliferate in response to PHA, accessory cell activity of the B-LCL is maintained. Paraformaldehyde- or glutaraldehyde-treated B-LCL retain their accessory cell activity at levels of these agents that completely eliminate metabolic activity of the B-LCL, as determined by incorporation of leucine, thymidine, and uridine into macromolecules. This treatment eliminates alloantigen presentation by the B-LCL. T cells treated with IO-4 or with monoclonal anti-T3 antibodies fail to respond to highly purified IL 1, and respond minimally to supra-optimal concentrations of IL 2. Nevertheless, these cells respond maximally to the accessory cell activity of the B-LCL. The IO-4 treated cells or cells exposed to anti-T3 also proliferate in response to TPA. Together, our data suggest that the B-LCL provide an IL 1-like signal for mitogen-treated T cells via direct cell contact, in the absence of detectable soluble IL 1.

Antigen-Presenting Cells↗
PubMed1979

Parainfluenza type 3 in a transplant unit.

We observed an epidemic of parainfluenza type 3 viral infection in a renal transplantation service among 16 recent transplant recipients. To assess the effect of infection on transplant function, we retrospectively compared the infected patients with a matched, uninfected control group. In addition to symptoms of a mild upper respiratory tract infection associated with the epidemic, there was an increase in the frequency of acute rejection episodes during the period of infection in the infected group. Nevertheless, outcome in terms of patient and graft survival at six months was not affected when compared with the survival rates of the control group.

Acute Disease↗