PubMed Health⌕ Search

Biomedical subjects

M Carver

Publications and source records attributed to M Carver.

13 recordsLinked to original sources
PubMed1992

The development of a posttransplant TLI treatment strategy that promotes organ allograft acceptance without chronic immunosuppression.

The effectiveness of fractionated TLI in promoting allograft tolerance without chronic drug therapy is well established experimentally. TLI has not been widely applied in clinical transplantation, largely due to logistic and medical limitations of pretransplant TLI conditioning. Potential use of posttransplant TLI (PT-TLI) has not been critically evaluated. In this study we investigated PT-TLI in combination with rabbit antithymocyte globulin (RATG) in the absence of chronic immunosuppressive drugs as a strategy for inducing long-term kidney allograft acceptance. Recipients were studied with and without infusion of DR-CD3- donor bone marrow cells (DBMC). Normal rhesus monkeys, which received no pretransplant treatment, underwent bilateral intrinsic nephrectomy and splenectomy at the time of transplantation. RATG was administered daily for 3-5 consecutive days beginning on day 0. A total dose of 500-625 cGy of fractionated TLI was given in 4-5 treatments at 125 cGy per day beginning on day +1. Whereas neither PT-TLI nor RATG monotherapy induced long-term graft acceptance in splenectomized recipients, the combination of these modalities was remarkable in promoting long-term allograft acceptance without immunosuppressive drug therapy. Of 4 recipients given RATG x 5, splenectomy and PT-TLI, all were free of acute rejection. Of these, 3/4 had graft survivals greater than 100 days, 2/4 were greater than 150 days and 1/4 greater than 365 days. Of 5 recipients given this treatment plus an infusion of DR-CD3-DBMC, 4/5 grafts survived greater than 150 days and 3/5 still have normal functioning grafts at greater than 365 days. PT-TLI accentuated and prolonged changes in PBL subpopulations that were initially affected by RATG. Depressed levels of CD3+ cells were present for 4-5 months, with large numbers of circulating CD4+CD3- and especially CD8+ CD3- cells. In addition, antibody responses to RATG and alloantigens were suppressed in PT-TLI-treated recipients. Overall, the combination of PT-TLI, splenectomy, and RATG was found to be effective in promoting long-term allograft acceptance without chronic immunosuppressive drug therapy. The infusion of DR-CD3- DBMC in recipients treated with PT-TLI, RATG and splenectomy appeared to further increase the incidence of stable long-term survivors. If infectious complications can be improved, this approach may provide a clinically applicable posttransplant treatment strategy for inducing functional allograft tolerance.

Animals↗
PubMed1990

Membrane ionic currents in Rhodobacter capsulatus. Evidence for electrophoretic transport of K+, Rb+ and NH4+.

1. The cytoplasmic membrane ionic current of cells of Rhodobacter capsulatus, washed to lower the endogenous K+ concentration, had a non-linear dependence on the membrane potential measured during photosynthetic illumination. Treatment of the cells with venturicidin, an inhibitor of the H(+)-ATP synthase, increased the membrane potential and decreased the membrane ionic current at values of membrane potential below a threshold. 2. The addition of K+ or Rb+, but not of Na+, led to an increase in the membrane ionic current and a decrease in the membrane potential in either the presence or absence of venturicidin. Approximately 0.4 mM K+ or 2.0 mM Rb+ led to a half-maximal response. At saturating concentrations of K+ and Rb+, the membrane ionic currents were similar. The membrane ionic currents due to K+ and Rb+ were not additive. The K(+)-dependent and Rb(+)-dependent ionic currents had a non-linear relationship with membrane potential: the alkali cations only increased the ionic current when the membrane potential lay above a threshold value. The presence of 1 mM Cs+ did not lead to an increase in the membrane ionic current but it had the effect of inhibiting the membrane ionic current due to either K+ or Rb+. 3. Photosynthetic illumination in the presence of either K+ or Rb+, and weak acids such as acetate, led to a decrease in light-scattering by the cells. This was attributed to the uptake of potassium or rubidium acetate and a corresponding increase in osmotic strength in the cytoplasm. 4. The addition of NH4+ also led to an increase in membrane ionic current and to a decrease in membrane potential (half-maximal at 2.0 mM NH4+). The relationship between the NH4(+)-dependent ionic currents and the membrane potential was similar to that for K+. The NH4(+)-dependent and K(+)-dependent ionic current were not additive. However, illumination in the presence of NH4+ and acetate did not lead to significant light-scattering changes. The NH4(+)-dependent membrane ionic current was inhibited by 1 mM Cs+ but not by 50 microM methylamine. 5. It is proposed that the K(+)-dependent membrane ionic current is catalysed by a low-affinity K(+)-transport system such as that described in Rb. capsulatus [Jasper, P. (1978) J. Bacteriol. 133, 1314-1322]. The possibility is considered that, as well as Rb+, this transport system can also operate with NH4+. However, in our experimental conditions NH4+ uptake is followed by NH3 efflux.(ABSTRACT TRUNCATED AT 400 WORDS)

Ammonia↗
PubMed1989

Promotion of incompatible allograft acceptance in rhesus monkeys given posttransplant antithymocyte globulin and donor bone marrow. II. Effects of adjuvant immunosuppressive drugs.

Previous studies from this laboratory demonstrated prolonged acceptance of MHC-mismatched kidney allografts in rhesus monkeys treated with posttransplant rabbit antithymocyte globulin (RATG)* and donor-specific bone marrow (DBM). Here we have investigated the effect of adjunctive immunosuppressive drugs on induction of allogeneic unresponsiveness in this primate model. Parameters examined included median kidney allograft survival time (MST), development of specific antidonor T lymphocyte-mediated cytotoxicity (LMC) and antidonor antibody-dependent cellular cytotoxicity (ADCC). Posttransplant infusion of DBM in RATG-treated kidney allograft recipients resulted in 70 days MST and a dramatic reduction in the incidence of antidonor LMC. However, development of antidonor ADCC was similar to that of RATG controls, suggesting an immune deviation or split tolerance in these animals. Adjunctive azathioprine did not have a beneficial effect in recipients given RATG & DBM, resulting in decreased MST and increased antidonor LMC responses. In contrast, adjunctive cyclosporine (CsA) and low-dose prednisone (P) exerted an additive immunosuppressive effect resulting in a 50% increase in MST and no detectable antidonor LMC. However, CsA & P appeared to enhance the humoral alloimmune response, increasing the incidence of recipients with antidonor ADCC. Long-term graft survival in this group was limited by chronic rejection and especially by CsA-associated toxicity. These studies point out deterrents and also directions for optimizing adjunctive immunosuppression in primates treated with posttransplant RATG & DBM. The results with CsA are relatively encouraging. However, the prevalence of alloantibody and of chronic rejection in these animals suggests that more homogeneous success with tolerance induction in this model may require adjunctive immunosuppressive strategies that reduce humoral immunity.

Adjuvants, Immunologic↗
PubMed1979

Effect of rabbit anti-human thymocyte globulin on lymphocyte subpopulations and functions following allotransplantation in the rhesus monkey.

The survival time of skin allografts from RhLA-nonidentical, unrelated donors was increased from a mean of 7.69 days in controls (n = 20) to a mean of 32.53 days in rhesus monkeys (n = 21) receiving a total dose of 250 mg of rabbit anti-human thymocyte globulin (RATG) per kg. Immunological monitoring studies were performed on the peripheral blood of mononuclear cells in control and treated monkeys. After administration of RATG, the percentage of E rosette-forming cells (E-RFC) was greater than 90% depressed, and the percentage of EAC rosette-forming cells was increased 5-fold in the circulation. Significant numbers of RATG-coated cells were detected only during the first week after RATG treatment. The percentage of E-RFC recovered to pretreatment levels within 3 to 4 weeks after RATG treatment, although the absolute E-RFC count remained depressed for 2 to 3 months. In addition, the in vitro proliferative responsiveness to polyclonal mitogens and to allogeneic lymphocytes remained greater than 80% depressed for 2 to 3 months after RATG treatment. The incidence of post-transplant-specific antidonor lymphocyte-mediated cytotoxicity (LMC) was similar in controls (85%) and RATG-treated monkeys (81%), and the appearance of LMC was correlated (r = 0.711) with partial recovery of absolute ERFC counts in the treated group. The appearance and peak of LMC were delayed (P less than 0.001) in RATG-treated monkeys, but preceded and correlated with rejection. Prior to rejection, the serum of RATG-treated monkeys inhibited LMC. Antibody-dependent cellular cytotoxicity appeared after rejection in the majority of recipients in both groups. The appearance and peak of antibody-dependent cell-mediated cytotoxicity (ADCC) were delayed (P less than than 0.001) in RATG-treated monkeys, but did not exhibit a significant correlation with the time of rejection.

Animals↗
PubMed1978

Diffusion disk susceptibility testing with cefaclor.

The reliability of the standardized 30-mug cephalothin disk and that of an experimental 30-mug cefaclor disk in predicting probable clinical susceptibility to cefaclor were compared. Quantitative determinations of cefaclor susceptibility were measured by the World Health Organization International Collaborative Study agar dilution procedure; diffusion disk tests were performed by the standardized U.S. Food and Drug Administration disk test. The cephalothin disk erred in predicting probable susceptibility in 52% of isolates of Enterococcus spp. resistant to 16 mug or less of cefaclor per ml; the cefaclor disk did not. The cephalothin disk erred in correctly predicting susceptibility in only 20% of cefaclor-susceptible isolates of Enterobacter spp.; the cefaclor disk correctly predicted susceptibility for 70%. These results indicate the need for further evaluation of a separate cefaclor disk for use in susceptibility testing with this new cephalosporin.

Cephalosporins↗
PubMed1978

In vitro and in vivo studies with BL-S786, cefoxitin, and cefamandole.

The in vitro antimicrobial activities of BL-S786, cefoxitin, and cefamandole against 90 isolates of Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae and E. aerogenes, were studied by using an agar dilution procedure. Comparison of geometric mean minimal inhibitory concentrations showed that BL-S786 was half as active as cefamandole against Enterobacter species, 2 to 4 times more active than cefamandole against all other species, and 4 to 25 times more active than cefoxitin against all species. In vivo experiments employed acute protection tests in infected mice, using five isolates each of the five genera. Drugs were administered intramuscularly in two doses 3 h apart at dosages of 2.5, 5, 10, 20, and 40 mg per mouse. In most instances, BL-S786 was the most efficacious drug, being some 1.3 to 9.1 times more active than cefoxitin in all experiments and 1.5 to 8.7 times more active than cefamandole in most experiments. BL-S786 and cefamandole were comparable in activity in experiments with E. aerogenes, whereas BL-S786 was superior in experiments with E. cloacae.

Animals↗
PubMed1977

In vitro activities of five oral cephalosporins against aerobic pathogenic bacteria.

Cefaclor (Lilly 99638) and cefatrizine (BL-S640, SK&F 70771) are orally absorbed, broad-spectrum semisynthetic cephalosporins. They were compared in vitro with cephalexin, cephaloglycin, and cepharadine against a variety of aerobic pathogenic bacteria by an agar dilution procedure. Cefaclor and cefatrizine were found to be similar or superior to cephalexin, cephaloglycin, and cephradine in terms of activity against gram-positive cocci other than enterococci. Only cefatrizine demonstrated any potentially useful activity against some susceptible isolates of enterococci. Cefaclor and cefatrizine also were highly active, equally or more so than the other oral cephalosporins, against several gram-negative species including Escherichia coli, Enterobacter aerogenes, and Klebsiella pneumoniae. None of the cephalosporins were particularly active against Enterobacter cloacae. Both cefaclor and cefatrizine were active against Proteus mirabilis; cefatrizine was uniquely active against indolepositive Proteus species.

Aerobiosis↗