Adverse Influence of Recipient Lymphoid Resistance to in Vitro Immunosuppression on the Outcome of Kidney Transplants

Francis, D. M. A.; Dumble, Lynette J.; Bowes, Leanne; Clunie, G. J. A.; Macdonald, Ileene M.

doi:10.1097/00007890-198812000-00012

Cited by 23 publications

(12 citation statements)

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“…The differences and individual variations in the antiproliferative potencies of immunosuppressants on PBMCs obtained from healthy subjects and CRF patients awaiting renal transplantation have been observed [16,17,26,37,38] (Fig. 3).…”

Section: Organ Transplantationmentioning

confidence: 90%

“…Furthermore, as biopsy specimens, PBMCs are relatively easy to be prepared from 10-20 ml of venous blood. Separation and culture procedures of PBMCs in several reports are similar and have been generalized [13,[16][17][18][19][20][21][22], except when a variety of proliferation stimuli, which include concanavalin A and phytohemagglutinin as T cell mitogens [13,16,17,[19][20][21][22][23], interleukins (ILs) [25], or genetically heterogeneous lymphocytes [18,26], have been used. PBMCs are cultured for 3-4 days in vitro in the presence of any one of these stimuli and serial concentrations of immunosuppressive drugs.…”

Section: Drug Sensitivity Tests Using Cells Of Patient Originmentioning

confidence: 99%

“…PBMCs are cultured for 3-4 days in vitro in the presence of any one of these stimuli and serial concentrations of immunosuppressive drugs. Radioisotope-labeled thymidine has been used in most cases for estimation of the blastogenesis of lymphocytes [16,17,19,22,26]. After PBMCs were cultured as described above, the cells were incubated for longer periods (generally 16-20 h) in the presence of 3 Hthymidine, and then cell blastogenesis is determined by measuring the amount of 3 H-thymidine incorporated into the cells.…”

Section: Drug Sensitivity Tests Using Cells Of Patient Originmentioning

confidence: 99%

“…Based on the data for healthy subjects, the normal range upper-thresholds of PBMCresponse to immunosuppressants were established, and according to these ranges it might be possible to single out patient populations who are refractory to therapy with these drugs [16,17]. Many reports have also demonstrated the relationship between PBMC-response to GCs in vitro and the clinical efficacy of GCs in renal transplant recipients [16,26,39,40]. According to the findings of these reports, recipients whose PBMCs were relatively resistant to the blastogenesis-suppressing effects of GCs showed a significantly higher risk of acute rejection episodes or graft loss during GC therapy [16,26,39,40].…”

Section: Organ Transplantationmentioning

confidence: 99%

“…Many reports have also demonstrated the relationship between PBMC-response to GCs in vitro and the clinical efficacy of GCs in renal transplant recipients [16,26,39,40]. According to the findings of these reports, recipients whose PBMCs were relatively resistant to the blastogenesis-suppressing effects of GCs showed a significantly higher risk of acute rejection episodes or graft loss during GC therapy [16,26,39,40]. Similarly, renal transplant recipients who exhibited poor PBMC-responses to cyclosporine have also been reported to show unsatisfactory clinical outcomes when treated with cyclosporine [17,41].…”

Section: Organ Transplantationmentioning

confidence: 99%

See 4 more Smart Citations

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

Hirano

2007

International Immunopharmacology

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Section: Organ Transplantationmentioning

confidence: 90%

Section: Drug Sensitivity Tests Using Cells Of Patient Originmentioning

confidence: 99%

Section: Drug Sensitivity Tests Using Cells Of Patient Originmentioning

confidence: 99%

Section: Organ Transplantationmentioning

confidence: 99%

Section: Organ Transplantationmentioning

confidence: 99%

See 3 more Smart Citations

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

Hirano

2007

International Immunopharmacology

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Lymphocyte Responsiveness to Glucocorticoids, Cyclosporine, or Both

Briggs

Gao

Gimenez

et al. 1996

The Journal of Clinical Pharma

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The reason why some patients with glomerular diseases respond to steroid treatment and others do not remains obscure, and it is not possible to prospectively evaluate the probability of response in individual patients. One factor that might contribute to the clinical response to treatment could be the relative sensitivity of a patient's immune system to the suppressive effects of steroids or other immunosuppressive agents. To evaluate this possibility, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) from 16 patients with various biopsy-proven glomerulopathies were cultured with prednisolone or methylprednisolone in final concentrations of 10(-5) to 10(-8) mol/L. From the dose-response curves, the concentration of steroid required to cause 50% inhibition (IC50) of the PHA-induced proliferative response was determined. The PBMC from 10 patients also were cultured with 400 ng/mL cyclosporine both alone and with 10(-7) mol/L steroid, and the inhibitory effects were calculated. There was considerable heterogeneity in the sensitivities of individual patients to steroid inhibition, and the mean +/- SEM IC50 was significantly lower for methylprednisolone than for prednisolone. Cyclosporine caused 50% or greater inhibition in 6 of the 10 patients but had < 10% inhibitory effect in 2 patients. In most patients studied, cyclosporine plus steroid was significantly more inhibitory than cyclosporine alone, but the combination was usually no more effective than 10(-7) mol/L methylprednisolone alone. These results are consistent with the hypothesis that differences in the sensitivity of individual patient's immune systems to the immunosuppressive effects of steroids and cyclosporine might contribute to differences in their clinical responsiveness to treatment.

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Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170

Delaney

Smythe

Higgins

et al. 2000

Transplant International

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The present study examines whether resistance to Cyclosporin A (CyA) and Tacrolimus (FK506) develops in T cells from individual patients and the role of Pglycoprotein 170 (P-gp) in mediating drug resistance. IC,,s were established for CyA and FK506 in cell cultures from 46 renal allograft recipients. P-gp expression and functional activity were determined by flow cytometry. Mean ID,, for CyA was 29 yg/li (range 2.5-100) and for FK506 1.2 yg/li (range 0.085-5.5). The sensitivities to the two drugs were correlated ( P = 0.0001). There was variation in the ratio of the ID5,+ depending on the drug used for treatment ( P = 0.02). There was no difference in P-gp expression and functional activity in patients with sensitive or resistant cells. The data indicate an association between the sensitivities to CyA and FK506 and evidence of selective resistance to whichever drug was used. P-gp drug transport does not explain this variation.

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Adverse Influence of Recipient Lymphoid Resistance to in Vitro Immunosuppression on the Outcome of Kidney Transplants

Cited by 23 publications

References 0 publications

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

Cellular pharmacodynamics of immunosuppressive drugs for individualized medicine

Lymphocyte Responsiveness to Glucocorticoids, Cyclosporine, or Both

Constitutive and acquired resistance to calcineurin inhibitors in renal transplantation: role of P-glycoprotein-170

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