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P Daloze

Publications and source records attributed to P Daloze.

At least 19 recordsLinked to original sources
PubMed1995

Rapamycin graft pretreatment in small bowel and kidney transplantation in the rat.

The effect of rapamycin (RAPA) as graft pretreatment was evaluated in orthotopic small bowel and kidney allotransplantation (Tx) in the rat. In the small bowel Tx model, six groups were involved, each including three combinations for evaluation of host-versus-graft (HVG) [Lewis (LEW) x Brown Norway (BN) (LBN)-F1-->Lewis], graft-versus-host (GVH) (LEW-->F1), and combined HVG and GVH immune responses (BN-->LEW). RAPA graft pretreatment alone (16 micrograms/ml x 3 ml) was able to induce a modest but significant prolongation of survival in all three combination models compared with controls (P < 0.05). The same was observed for low dose CsA treatment (2 mg/kg/day x 14 days) of the recipient only (P < 0.05). Combination of graft pretreatment with RAPA and CsA recipient treatment produced a marked prolongation of survival especially in HVG response. Recipients treatment with one 48-microgram bolus of RAPA i.v. immediately after graft revascularization failed to achieve any prolongation of survival for the GVH or combined HVG and GVH responses. This seems to exclude a "carry-over" effect of RAPA from graft to recipient. RAPA efficacy was also clearly confirmed in the kidney graft pretreatment model as compared to recipient treatment with an equivalent RAPA dose. These results demonstrate that graft RAPA pretreatment prolongs SB survival after Tx in the rat for HVG, GVH, and bidirectional immune responses. Intragraft interaction with passenger leukocytes or APC function appears as one of the possible mechanisms. RAPA graft pretreatment potentiates low dose CsA recipient treatment suggesting a possible use in clinical organ Tx.

Animals↗
PubMed1992

Effects of rapamycin on human HLA-unrestricted cell killing.

Rapamycin (RAPA) is a potent immunosuppressant and can effectively prevent allograft rejection at a dosage 10- to 100-fold lower than that of cyclosporin A. RAPA strongly inhibits proliferation and function of T and B cells. In this study, we investigated the effect of RAPA on human HLA-unrestricted cell killing. It was shown that in vitro RAPA inhibited the cytolytic effect of natural killer cells and lymphokine-activated killer cells (LAK) and inhibited antibody-dependent cell-mediated cytotoxicity. The effective concentration of RAPA was 10- to 100-fold higher than that required for inhibiting T cell proliferation. These results suggest that there could be a therapeutic dose window at which RAPA inhibits T cell activity while it leaves HLA-unrestricted cell killing unaffected. We also demonstrated that while IL4 inhibited LAK activity, and RAPA inhibited IL4-promoted T cell proliferation, RAPA was not able to antagonize IL4's inhibitory effect on LAK. This indicates that the mechanism of interaction between RAPA and IL4 on LAK is different from that on T cells.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1992

Inhibition of host-versus-graft and graft-versus-host responses after small bowel transplantation in rats by rapamycin.

The effect of rapamycin (RAPA) on both host-versus-graft (HVG) and graft-versus-host (GVH) immune responses was examined in small bowel transplant models using strongly histoincompatible donor-recipient combinations. Normal Wistar Furth (WFu; RT-1u) recipients rejected Buffalo (BUF; RT-1b) small bowel allografts within a mean survival time (MST) of 10.5 +/- 0.5 days. Administration of RAPA (0.8 mg/kg) by continuous intravenous infusion for 14 days via an osmotic pump prolonged graft survival to 25.0 +/- 4.6 days (P = 0.01). In a second strain combination, the 12.5 +/- 2.2 day survival of Brown Norway (BN; RT-1n) small bowel allografts in Lewis (RT-1l) recipients was prolonged to 21.6 +/- 2.0 and 28.5 +/- 2.8 days by 14 days of i.v. RAPA at doses of 0.8 and 1.6 mg/kg, respectively. In this model RAPA is five times more effective than cyclosporine, which at 4.0 mg/kg prolongs BN small bowel allografts in Lewis recipients to 21.6 +/- 6.3. To isolate HVG and GVH immune responses, (BN x Lewis)F1 hybrid rats served as the graft donor or host, respectively. In the HVG model, (BN x Lewis)F1 small bowel allografts, which were rejected by normal Lewis recipients at 12.2 +/- 3.6 days, were prolonged to 40.8 +/- 5.8 days (P = 0.001) by RAPA (0.8 mg/kg x 14 days). In the GVH model, the ability of Lewis small bowel allografts to produce severe GVH disease in untreated (BN x Lewis)F1 recipients at 12.3 +/- 2.8 days was delayed to 21.3 +/- 5.2 days by 0.8 mg/kg RAPA (P = 0.025). Thus, RAPA protects small bowel allografts more effectively against HVG than GVH immune responses.

Animals↗
PubMed1992

Inhibition of in vitro immunoglobulin production by rapamycin.

Like FK506, rapamycin, a structural analog of FK506, is a strong immunosuppressant. The immunosuppressive effect of Rapa in in vitro IgG, IgM, and IgA production by human lymphocytes was examined in this study. To inhibit spontaneous or pokeweed mitogen-stimulated production of Ig by human peripheral blood lymphocytes, about one thousandfold lower concentrations of Rapa (IC50 = 0.3 nM-2 nM) were required than of cyclosporine (IC50 = 0.3 microM-2 microM). T cells were the direct targets of Rapa, because preincubation of T cells with Rapa abolished the T cells helper effect to T-dependent Ig production. Rapa also had direct suppressive effect on B cells, since Rapa suppressed IgG production by pure B cells stimulated with IL2 and Staphylococcus aureus Cowan I. Kinetic studies measuring IgG production and cell proliferation revealed that Rapa acted at the activation stage of T and B cells. Exogenous IL2 substantially reversed the inhibitory effect of CsA but not that of Rapa in Ig production. This study is the first report on the strong suppressive effect of Rapa on human humoral immune response with a quantitative comparison with that of CsA. The underlying mechanisms are also explored. The results indicate the potential usefulness of this drug in treatment of presensitized transplantation patients, with whom cytotoxic Ab is a major obstacle to a successful transplantation.

Antibody Formation↗
PubMed1991

In vitro IgE production by interleukin 4-stimulated human peripheral blood mononuclear cells is suppressed by rapamycin.

Rapamycin (RAPA) is a new immunosuppressant which is 50-fold to 100-fold more potent than cyclosporin A (CyA) in inhibiting cellular immune responses and allograft rejection in animal models of organ transplantation. The drug's effect on in vitro IgE synthesis by interleukin (IL)4-stimulated human peripheral blood mononuclear cells was examined and compared with CyA's effect in this study. RAPA was found to be about 100-fold more potent than CyA in inhibiting IgE synthesis. Its inhibitory effect on IgE production was significant if it was added to the culture before Day 6 of a 14-day culture. The suppression was accompanied by the inhibitory effect on cell proliferation and on IgE-binding factor (IgE-BF) production. IL2 was able to partially reverse CyA- but not RAPA-induced inhibition of IgE production. Commercial B cell growth factor (cBCGF) was not able to reverse either RAPA- or CyA-induced suppression of IgE synthesis. The strong inhibitory effect of RAPA in IgE synthesis may be useful in certain clinical applications where overproduction of pathogenic IgE is a key issue. RAPA can also be used as a tool to dissect the regulation of IgE production.

Cell Division↗
PubMed1991

Rapamycin, a potent immunosuppressive drug for vascularized heart, kidney, and small bowel transplantation in the rat.

The effectiveness of rapamycin (RAPA) was examined for heart, kidney, and small bowel allografts in rats. Untreated or vehicle only-infused Wistar Furth (RT1u) recipients rejected Buffalo (RT1b) heart allografts within a mean survival time (MST) of 6.5 +/- 0.5 and 6.3 +/- 0.5 days, respectively. In contrast, a 14-day continuous intravenous (i.v.) infusion by an osmotic pump of 0.08 mg/kg/day RAPA to WFu recipients prolonged BUF heart allograft survival to an MST of 34.4 +/- 12.1 days (P = 0.0001). There was a graded dose-response to 0.16 mg/kg (39.0 +/- 8.7 days; P = 0.0001), 0.32 mg/kg (55.7 +/- 3.3 days; P = 0.0001) and 0.8 mg/kg (48.0 +/- 3.6; P = 0.0001). Furthermore, intraarterial/intragraft but not i.v. infusion of 0.02 mg/kg/day prolonged BUF heart allografts--namely, an MST of 14.6 +/- 1.4 days versus 8.6 +/- 2.6 days (P = 0.0001), respectively. Local delivery doses of RAPA were about as effective as the same dose delivered i.v.: 0.08 mg/kg MST 37.0 +/- 18.3 days (P = 0.0001); 0.32 mg/kg, 40.0 +/- 3.9 days (P = 0.0001); and 0.8 mg/kg, 54.8 +/- 8.2 days (P = 0.0001). Systemic i.v. RAPA therapy with 0.08 or 0.8 mg/kg/day prolonged the survival of BUF kidney grafts in WFu recipients--namely, an MST of 52.7 +/- 42.7 (NS) and 90.2 +/- 62.4 (P = 0.001) days, respectively, versus an MST of 11.6 +/- 1.5 days in control WFu recipients only infused with vehicle. While normal WFu rats reject heterotopic BUF small bowel allografts within an MST of 10.0 days, a 14-day course of i.v. RAPA treatment significantly (P = 0.0001) prolonged small bowel allograft survival to an MST of 26.8 +/- 3.7 days.

Animals↗
PubMed1991

[Development of organ transplantation in Quebec from 1985 to January 1990].

In Québec, the first organ transplantations have been realized in 1958. Several kidney transplant programs started at that time. Cardiac, liver, pancreas and lungs programs followed and reached a full development in the eighties when Cyclosporin became available. Today, there are 4 university transplant programs in Québec (McGill, Montréal, Laval and Sherbrooke) with a total of 7 kidney, 4 liver, 4 heart, 2 pancreas and 2 lungs centers. More than 2,900 transplantations have been realized. Since 1970, organ procurement and distribution is organized by a central agency called Québec-Transplant (previously Métro-transplantation). Organ donation is done on a voluntary basis as every where in North America. More than 90% of the organs comes from cadaveric donors and more than 90% of the relatives accept organ donation. 50% of the donors have deceased from head trauma and 50% from cerebral hemorrhage. In 1989, multi-organ harvesting has been realized in 64% of the donors. Despite efforts and progresses, the number of patients awaiting an organ transplant is steadily growing and outlast the number of available organs. It is hoped that maximal utilisation of the donors and growing exchanges at a national and international level will help to solve this crucial problem.

Heart Transplantation↗
PubMed1990

One-stage hepatectomy in the dog.

This report describes a technique for total hepatectomy in the dog. The procedure maintains the integrity of the gastrointestinal tract and the pancreas in the normothermic, anesthetized animal. The technique involves (i) a mesentericocaval shunt, (ii) a temporary external bypass between the femoral and jugular veins, and (iii) a permanent internal bypass between the abdominal and thoracic inferior vena cava through the tendinous area of the diaphragm. This 60- to 70-min procedure yields a preparation useful for short-term metabolic studies in nonhepatic tissues.

Animals↗
PubMed1990

Pseudoketogenesis in hepatectomized dogs.

Overestimation of ketone body turnover in vivo, measured by tracer kinetics, could occur if specific activity or molar percent enrichment is diluted in extrahepatic tissues by label exchange via reversal of 3-oxoacid-CoA transferase, a process we call pseudoketogenesis. To test this hypothesis, euglycemic hepatectomized dogs were injected with a bolus of acetoacetate (0.8 mmol/kg), 32% enriched in [3,4-13C2]acetoacetate. Concentrations and labeling patterns of blood acetoacetate and R-3-hydroxybutyrate were measured by selected ion-monitoring gas chromatography-mass spectrometry. During the 60 min after bolus injection of [3,4-13C2]acetoacetate, the molar percent enrichment of blood [3,4-13C2]acetoacetate decreased to 73 +/- 3% (n = 5) in controls and to 11.5 +/- 0.8% (n = 3) during infusion of dichloroacetate, an activator of pyruvate dehydrogenase. The enrichment of R-3-hydroxy-[3,4-13C2]butyrate followed closely that of [3,4-13C2]acetoacetate. These dilutions occurred despite a net uptake of ketone bodies. Concomitantly, 10.6 +/- 2.2 (n = 5) and 6.0 +/- 2.9% (n = 3) of [13C]acetoacetate molecules were labeled on all four carbons in control and dichloroacetate-treated dogs, respectively. This uniformly labeled acetoacetate arises from partial equilibration between [3,4-13C2]acetoacetate and [1,2-13C2]acetyl-CoA via the reactions catalyzed by 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. Our data demonstrate the reversibility of the 3-oxoacid-CoA transferase in intact extrahepatic tissues and support the concept of pseudoketogenesis. This phenomenon has been quantitated by kinetic analysis of the data.

3-Hydroxybutyric Acid↗