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Biomedical subjects

G R Catto

Publications and source records attributed to G R Catto.

At least 19 recordsLinked to original sources
PubMed1992

The effects of rapamycin on humoral immunity in vivo. Suppression of primary responses but not of ongoing alloantibody synthesis or memory responses.

The effect of rapamycin on primary and secondary alloantibody responses to major histocompatibility complex class I antigens was investigated in inbred rat strains. Primary anti-MHC class I alloantibody responses, detected by indirect hemagglutination and complement-dependent cytotoxicity assays, were abrogated in high-responder WAG (RT1u) recipients of DA (RT1a) blood transfusions, given on days 0 and 7 of a 14-day course of rapamycin (3 mg/kg/day). Antibody class studies showed that both IgM and IgG responses were equally effectively inhibited. Moreover, when these animals were rechallenged with DA transfusions, 28 days after drug withdrawal, they exhibited donor-specific humoral unresponsiveness. Similar results were observed in cyclosporine-treated rats. In preimmunized high-responder LEW (RT1(1)) rats with high titer anti-DA class I alloantibodies, a 35-day course of rapamycin (3 mg/kg/day) had no significant suppressive effect on serum alloantibody levels when compared with untreated preimmunized control animals. WAG rats were immunized by DA transfusions and serum antibody levels then allowed to decay over 16 weeks. The animals were then challenged with a further DA transfusion given on the second day of a 14-day course of rapamycin (3 mg/kg/day). Alloantibody responses to the challenge transfusion in this group were not, however, significantly suppressed when compared with a non-drug-treated control group. The results of this study indicate that rapamycin is a potent inhibitor of primary alloantibody synthesis in high-responder rat strains, but does not significantly suppress alloantibody synthesis in animals with established humoral reactivity. These results may be of relevance if rapamycin is to be used in clinical renal transplantation, because in man similar antibodies mediate hyperacute rejection, and when they develop after transplantation are associated with very high rates of rejection.

Animals↗
PubMed1992

The short term effects of oral labetalol in patients with chronic renal disease and hypertension.

This double-blind, controlled, crossover study compared the effects on blood pressure control, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) of labetalol, methyldopa and placebo in patients with chronic renal disease and hypertension. When compared with placebo, BP was significantly lower during treatment with both labetalol and methyldopa (P greater than 0.05) but did not differ significantly between the two active treatment periods; post-exercise heart rates were also significantly lower on labetalol than placebo (P less than 0.05). After treatment with labetalol, ERPF was significantly greater than with the placebo (P less than 0.05) but did not differ significantly between the active treatments. GFR did not differ significantly between the three groups. No significant differences were observed in haematology or liver function test results on labetalol compared with placebo. Labetalol is a safe and effective antihypertensive in patients with hypertension associated with chronic renal disease. In the short term it leads to an increase in ERPF which may be beneficial for such patients.

Administration, Oral↗
PubMed1991

Immunological aspects of clinical renal transplantation.

Improved facilities for treating patients with end-stage renal failure have resulted in more elderly and debilitated patients being accepted for treatment. Renal transplantation is now the optimum form of treatment but organ procurement has failed to match clinical demand. Future developments may focus on further non-specific immunosuppressive agents. As one year survival rates for first cadaver allografts now exceed 85% in many units, the significance of new developments will be increasingly difficult to evaluate.

Graft Survival↗
PubMed1991

Influence of antiidiotypic antibody activity on renal transplant outcome.

The presence of cytotoxic HLA antibodies (Ab1) against donor lymphocytes in pretransplant sera is almost always associated with rapid rejection of the renal transplant. We have investigated the possibility that antiidiotypic antibodies (Ab2) to cytotoxic HLA antibodies might modulate the immune response and favorably influence renal allograft outcome. The role of antibodies (Ab3) which potentiate the cytotoxic effect of Ab1 was also studied. Pretransplant sera from 63 patients were tested for inhibitory or potentiating activity in the short antiidiotypic assay. Inhibitory activity was detected in 30 patients and in 28 the transplant survived more than a year. Of patients without antibody activity 11 of 17 had grafts surviving more than one year, and of those showing potentiating activity 11 of 16 were functioning at a year. The difference in transplant survival between the first group and the other two groups was statistically significant (P less than 0.05). There was no significant difference in survival rates between the latter two groups. Potentiating activity is therefore not an independent predictor of transplant failure, whereas the presence of antiidiotypic antibody activity did correlate with improved allograft survival.

Antibodies, Anti-Idiotypic↗
PubMed1991

Effect of cyclosporin A on immunoglobulin class in patients receiving blood transfusions.

IgG antibodies detected by flow cytometry in sera from potential renal transplant recipients are associated with an increased number of rejection episodes and impaired graft function. Furthermore, cytotoxic antibodies may develop if pre-transplant blood transfusions are given to such patients. We have investigated the effect of cyclosporin A on the development of IgM and IgG antibodies detected by flow cytometry after blood transfusions in 16 previously untransfused dialysis patients. Eight (group 1) received three to five third-party blood transfusions at two weekly intervals and the remaining eight (group 2) received transfusions with concomitant cyclosporin A therapy (10 mg/kg/day). Sera obtained after each transfusion were tested using flow cytometry against lymphocytes from six normal donors. In all 462 serum/cell combinations were tested. Sera from six out of eight patients in group 1 showed IgG antibody activity following blood transfusions and none developed IgM antibodies alone. In contrast IgG antibody activity was detected in one serum sample from only one of the eight patients in group 2 (P less than 0.02); a further three patients developed IgM but not IgG antibody activity during the transfusion protocol. IgG antibodies were found in 25/228 serum/cell combinations in group 1 but in 1/234 in group 2 (P less than 0.001). The patient in group 2 who developed IgG antibodies in one serum/cell combination was known to have red cell autoantibodies. This IgG activity was removed by red cell absorption, suggesting that the autoreactive red cell antibody cross-reacted with lymphocytes. Cytotoxic antibodies were detected in two serum/cell combinations in group 1 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗
PubMed1991

Cyclosporin A and the humoral response to blood transfusion in the rat: definition of antigens which suppress alloantibody formation.

1. Blood transfusions improve renal allograft survival rates, but may induce antibodies which are directed to class I major histocompatibility complex antigens and mediate hyperacute transplant rejection. A model to study the development of such antibodies was developed in inbred strains of rats. 2. The influence of transplantation antigens shared between an initial course of blood transfusions, given with cyclosporin A, and a subsequent antigenic challenge (blood transfusion), given without cyclosporin A, on alloantibody responses to class I major histocompatibility complex antigens was then investigated. 3. Cyclosporin A administration prevented the development of alloantibodies to class I major histocompatibility complex antigens during the initial transfusion period. 4. After the challenge transfusions, alloantibody responses to class I major histocompatibility complex antigens were suppressed when class I major histocompatibility complex or minor histocompatibility antigens were shared between the initial and final transfusions. 5. This suppression only extended to third party class I antigens when minor histocompatibility complex antigens were shared between the initial and final transfusions. Sharing of class I or class II antigens had no effect on alloantibody responses to third party class I antigens coexpressed on the same cell. 6. These studies suggest that cyclosporin A given with blood transfusions may prevent clinical sensitization while permitting the development of suppressor activity, mediated by shared minor histocompatibility complex determinants, to a broad range of potential donor antigens.

Animals↗
PubMed1991

Lymphocytotoxins in sera from highly sensitized multiparous dialysis patients: antibody class, relationship with the HLA and with paternal antigens.

1. Sera from 11 highly sensitized multiparous dialysis patients were studied in order to define the target antigens, antibody class and relationship with paternal HLA class I antigens of the underlying lymphocytotoxic antibodies. All sera contained lymphocytotoxic antibodies to over 70% of a panel of lymphocytes from 24 donors (panel reactivity greater than 70%). 2. Inhibition of cytotoxic activity against paternal lymphocytes by monoclonal antibodies to HLA framework determinants indicated that all 11 sera contained lymphocytotoxic antibodies to paternal class I antigens. In addition, five sera contained lymphocytotoxic antibodies to paternal class II antigens. 3. In order to determine the extent to which lymphocytotoxic antibodies were directed to paternal antigens, the panel reactivity of sera was compared before and after absorption with paternal peripheral blood lymphocytes. Over 50% of panel reactivity was absorbed from eight out of 11 sera, and in three of these 11 over 80% was absorbed. In the majority of patients this change in panel reactivity could be ascribed to binding of lymphocytotoxic antibodies to specific paternal class I antigens. 4. Digestion of sera with dithiothreitol had no significant effect on panel reactivity, indicating that the lymphocytotoxic antibodies were of immunoglobulin G class. 5. No sera reacted with either autologous lymphocytes or K562 cells, indicating an absence of autoantibodies. 6. These studies imply that panel-reactive lymphocytotoxic antibodies in the sera of highly sensitized multiparous patients are those which mediate hyperacute renal allograft rejection. Their development may be related to secondary humoral responses to antigens in blood transfusions from donors who share paternal class I specificities.

Adult↗
PubMed1991

The effect of cyclosporin administered during a third-party blood transfusion protocol on humoral immune responses.

Antigen pre-treatment in animals undoubtedly prolongs graft survival. In man, however, routine pre-transplantation blood transfusions have recently become controversial, principally because of the adverse effect of transfusion-induced sensitisation on graft survival rates. We have monitored the effect of cyclosporin administered during a planned programme of third-party blood transfusions on the development of both cytotoxic and anti-idiotypic antibodies. A total of 24 patients were recruited to the study; ten received cyclosporin with blood transfusions (BT) (group 1), 14 received BT alone (group 2). Anti-HLA antibodies developed in 3 of 9 patients in group 1 and 8 of 12 patients in group 2 (P less than 0.05). Anti-idiotypic antibody activity was detectable in 9 of 9 patients in group 1 and 7 of 12 patients in group 2 (P less than 0.006). The mechanism by which cyclosporin can prevent an anti-HLA antibody response and promote an anti-idiotypic response is unclear.

Antibodies, Anti-Idiotypic↗
PubMed1991

Reduction of sensitization induced by blood transfusion in the rat by monoclonal antibodies.

Primary and secondary alloantibody responses were monitored in (AOxPVG)F1 hybrid rats after three transfusions of DA blood; the initial transfusion was either untreated or pretreated with monoclonal antibody directed to class I antigens or other cell surface markers. Mean antibody activity in recipient sera against class I DA antigens was significantly decreased by pretreatment with the monoclonal antibodies. The most marked suppression was associated with pretreatment by antibodies to the four major nonoverlapping epitopes of the RT1Aa antigen. Subsequent transfusions of DA blood failed to stimulate a secondary response. Crossreactivity of the alloantibody reactivity with BDIX antigens was diminished by pretreating the transfusions with rat anti-RT1A antibodies and, to a lesser extent, with a mouse monoclonal antibody (OX-18) to a common class I determinant. Monoclonal antibody pretreatment had no effect on the humoral response to class II DA antigens. These studies indicate that blood transfusions pretreated with monoclonal antibodies induce a less-potent cytotoxic humoral immune response and that reactivity is most effectively suppressed by completely masking the class I antigen. This technique may prove of clinical value in preventing the sensitization caused by blood transfusions in potential transplant recipients.

Animals↗
PubMed1991

Immune responses to noninherited maternal RT1A antigens in inbred rats.

Humoral responses to non-inherited maternal class I antigens (class I NIMAs) were assessed in 3 groups of inbred rats expressing the RT1u phenotype. Group 1 consisted of the progeny of (AO X DA)F1 X PVG matings; their haplotype was RT1u/c and their non-inherited maternal haplotype RT1a. Group 2 were the progeny of (AO X LEW)F1 X PVG matings the haplotype of which was also RT1u/c, but their non-inherited maternal haplotype was RT1l. Group 3 comprised 8 (AO X PVG)F1 (RT1u/c) hybrids. All rats received 2 intravenous blood transfusions (0.5 ml) from male DA (RT1Aa) donors on days 0 and 7. They were bled at weekly intervals for 6 weeks and again at 20 weeks after the first transfusion. Alloantibody responses to RT1Aa were assessed by an indirect hemagglutination assay (IHA)* and by a 51Chromium-release complement-dependent red cell cytotoxicity assay. All groups exhibited vigorous anti-class I antibody responses to the DA transfusions. No significant differences were detected, however, in antibody titers between the groups either by IHA or CDC or in the rates of decay of antibody titers up to week 20. In addition no blocking activity was found in sera obtained on day 0 from group 1 animals and tested for antiidiotypic antibody activity to cytotoxic anti-RT1Aa antibodies. In order to assess whether suppressor activity had been activated by the initial transfusions, in the animals in which class I NIMA was RT1Aa, all groups were rechallenged with a DA transfusion at week 20. All animals exhibited vigorous anamnestic responses to this challenge and no significant differences were detected between groups. In order to determine whether cellular tolerance to the noninherited maternal haplotype was present in group 1 animals, proliferative responses were assessed by one-way mixed lymphocyte cultures, using DA lymph node stimulator cells. No significant differences were detected in proliferative or kinetic responses between lymph node cells from rats the noninherited maternal haplotype of which was RT1a or from naive (AO X PVG)F1 hybrids. Peak proliferative responses to DA cells in rats the noninherited maternal haplotype of which was RT1l were similar, but maximal on day 4 as opposed to day 3. Hence in these inbred rat strains no evidence of humoral tolerance to class I NIMAs was detected. In addition there was no evidence of cellular tolerance to the noninherited maternal MHC haplotype.

Animals↗
PubMed1990

Glomerulotubular function in long-term renal allograft recipients. A comparison of conventional therapy with cyclosporine.

Glomerular and tubular function were assessed, using a lithium clearance technique, in two groups of renal allograft recipients at least one year after transplantation. Group 1 comprised 14 patients receiving low-dose prednisolone and cyclosporine, and group 2, 14 patients receiving low-dose prednisolone and azathioprine. There were no significant differences in creatinine clearances between the two groups, although the clearances of lithium (which is absorbed almost exclusively from the proximal tubule) and sodium were significantly lower in the cyclosporine-treated group. Fractional lithium excretion was also significantly lower in group 1 than in group 2, but there was no significant difference in fractional sodium excretion. The absolute proximal reabsorption of sodium and water did not differ between the groups, although the fractional proximal reabsorption of sodium and water was significantly higher in group 1. In contrast, the distal reabsorption of sodium and of water was significantly lower in the cyclosporine-treated patients than in the azathioprine-treated patients; there were, however, no significant differences in the distal fractional reabsorptions of sodium and water between the two groups. In addition there was no correlation in group 1 between whole-blood cyclosporine levels or time since transplantation and any of the assessed parameters of renal function. These results indicate that tubular concentrating abnormalities in cyclosporine-treated renal allograft recipients are similar to those observed in rodent models of cyclosporine nephrotoxicity. They suggest that the pathogenesis of cyclosporine nephrotoxicity may be similar in renal allograft recipients to that in experimental models.

Adult↗
PubMed1990

FK506--its influence on anti-class 1 MHC alloantibody responses to blood transfusions.

The influence of FK506 on in vivo alloantibody responses to major histocompatability class 1 antigens was investigated in inbred rat strains, and compared with the effect of cyclosporine. AO rats received transfusions of DA blood on days 0 and 7. From days 0 to 14 the rats also received, daily, either FK506 0.3 mg/kg suspended in saline or dissolved in olive oil, or CsA 10 mg/kg. The administration of FK506 suspended in saline at the time of blood transfusion completely abrogated the development of anti-MHC class 1 alloantibodies as detected by indirect hemagglutination (IHA)* and 51Cr release complement dependent cytotoxicity assays (CDC). Isotyping studies showed that FK506 suspended in saline suppressed IgM production and inhibited the switch to IgG production. Similar responses were seen in CsA-treated animals. In contrast, rats treated with FK506 dissolved in olive oil developed high titers of anti-class 1 alloantibodies. On days 49 and 56 the rats were challenged with further DA blood transfusions given without immunosuppression. In the groups given FK506 suspended in saline or CsA, cytotoxic antibodies did not develop; low titer antibodies were, however, detected by IHA in the animals that had previously received FK506 suspended in saline. The results indicate that FK506, in common with CsA, inhibits anti-class 1 MHC alloantibody production, and at the same time enables the development of tolerance. The vehicle in which FK506 is administered is, however, critical to its efficacy at the low doses used. These results may be of relevance to clinical transplantation as similar antibodies mediate hyperacute renal allograft rejection in man.

Animals↗
PubMed1990

The detection of antibodies in pregnancy: a comparison of two assay systems.

In this study we have compared the ability of two assay systems, erythrocyte antibody rosette inhibition (EAI) and cellular enzyme-linked immunospecific assay (CELISA) to detect maternal alloantibody activity during pregnancy. Antibody activity to antigens on paternal lymphocytes was present in nine of 23 primigravid sera tested by EAI and in seven of 23 by CELISA. In multiparous sera, antibodies directed to paternal lymphocytes were detected in 11 of 15 individuals by EAI and in six of 15 by CELISA. The techniques correlated significantly when assaying the humoral response in sera from multiparous women. The lack of correlation when assaying primigravid sera suggests that both assays encounter difficulty in detecting the low titres of antibodies present.

Enzyme-Linked Immunosorbent Assay↗