CD4 T-HELPER CELL COUNT IS AN ALTERNATIVE PROMISING MARKER FOR DOSING CYCLOSPORINE IN KIDNEY TRANSPLANT PATIENT

Authors

  • Jaafar Jaber Ibraheem Al-tamimi Professor Assistant Dr. Jaafar Jaber Ibraheem Al- Tamimi, Ph. D. in Biopharmaceutics and clinical pharmacokinetics from Uppsala University, Sweden, 1985
  • Qutaiba Ahmed Ibrahim Al-khames Aga Department of clinical pharmacy, College of Pharmacy, the University of Baghdad, Iraq
  • Hassan Mohammed Abass Dr. Hassan Mohammed Abass, Ph. D. in clinical pharmacy, Baghdad Teaching Hospital, Medical City, Baghdad, Iraq

DOI:

https://doi.org/10.22159/ijpps.2016.v8i9.12030

Keywords:

Cyclosporine, Kidney transplantation, TDM, (Clusters of Differentiation 4) CD4 T-helper cell, Trough blood concentration of cyclosporine (C0), Maximum blood concentration of cyclosporine (C2)

Abstract

Objective: The study was aimed to find out the correlation between cyclosporine blood concentrations and (Clusters of Differentiation 4) CD4 T-helper cell count (percentage) in order to use the latter parameter as an alternative marker for cyclosporine dosing. Besides, the study was also aimed to find out the optimum dosing strategy for Iraqi patients requiring cyclosporine therapy in Iraqi hospitals using TDM approach.

Methods: One hundred and twenty subjects participated in the study. The subjects are involved two groups; group A was 80 patients (53 males and 27 females) using cyclosporine twice daily (Sandimmune® oral solution containing cyclosporine 100 mg/ml) and they had kidney transplantation for more than one year. The ages of the patients were 15-45 y (mean±SD =31.962±8.8207); and. Group B included 40 healthy control subjects (24 males and 16 females) with ages of 15-45 y (mean±SD =31.666±8.1606). According to the condition and the need of the patients, they were administered cyclosporine dose range of 1-10 mg/kg/d. Ten ml blood samples were withdrawn from each patient after fasting for about 12 h for monitoring trough/minimum blood concentration (C0) of cyclosporine and for determination of (Clusters of Differentiation 4) CD4 T-helper cells count at C0. Other 10 ml of blood was then withdrawn after 2 h of cyclosporine administration to be used for monitoring maximum/peak cyclosporine blood cyclosporine (Cmax) after 2 h of drug intake (C2) and for determination of (Clusters of Differentiation 4) CD4 T-helper cells count at C2. Five ml of blood samples were withdrawn from each control subject for determination of (Clusters of Differentiation 4) CD4 T-helper cells count.

Results: Good correlations were found between cyclosporine dose administered to each patient and the resulted C0 and C2. The majority of patients (66 patients=82.5%) had C0 of 150-200 ng/ml and C2 of 700-900 ng/ml, which are within the therapeutic range. The range of cyclosporine doses that produce therapeutic C0 and C2 was 4.1-9 mg/kg/d. The mean total lymphocyte count and percentage decreased significantly in all patients compared to the control subjects (1.26±0.60 vs.1.98±0.66 e3/uL) and (19.92±13.77 vs. 28.88±10.22), respectively. A similar trend was found for the total lymphocyte count and percentage of patients with cyclosporine C0, and C2 within the therapeutic range (66 patients) compared to the control subjects (1.34±0.57 vs. 1.98±0.66) and (18.98±10.93 vs. 28.88±10.22), respectively. Good negative correlations were found between lymphocyte count and percentage versus C0 for all patients and for patients with C0 within the therapeutic range. Similarly, good negative correlations were found between lymphocyte count and percentage versus C2 for all patients and for patients with C2 within the therapeutic range. The (Clusters of Differentiation 4) CD4 T-helper cell percentage at C0 decreased significantly in all patients and patients with cyclosporine blood concentrations within the therapeutic range (66 patients) compared to the control subjects (24.33±10.31 vs. 35.83±9.11) and (25.50±2.44 vs. 35.83±9.11), respectively. Similarly, (Clusters of Differentiation 4) CD4 T-helper cell percentage at C2 decreased significantly in all patients and patients with cyclosporine blood concentrations within the therapeutic range compared to the control subjects (22.60±9.28 vs. 35.83±9.11) and (21.50±2.16 vs. 35.83±9.11), respectively. The range of (Clusters of Differentiation 4) CD4 T-helper cell percentages at C0 for patients with cyclosporine blood levels above the therapeutic concentrations was 21.65-23.43; for patients with cyclosporine blood levels within the therapeutic concentrations, the range was 23.70-29.00; and for patients with cyclosporine blood levels below the therapeutic concentrations, the range was 29.80-34.60. Good negative correlations were found between (Clusters of Differentiation 4) CD4 T-helper cell percentage and C0 for all patients and for patients with blood concentrations of cyclosporine within the therapeutic range. The (Clusters of Differentiation 4) CD4 T-helper cell percentage range at C2 for patients with cyclosporine blood levels above the therapeutic concentrations was 13.40-18.20; for patients with cyclosporine blood levels within the therapeutic concentrations, the range was 18.50-22.23; and for patients with cyclosporine blood levels below the therapeutic concentrations, the range was 22.76-24.42. Identically, good negative correlations were found between (Clusters of Differentiation 4) CD4 T-helper cell percentage and C2 for all patients and for patients with blood concentrations of cyclosporine within the therapeutic range. For patients with cyclosporine blood levels above therapeutic concentrations; the minimum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C2 was 13.40, whereas, the maximum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C0 was 20.23. For patients with cyclosporine blood levels within therapeutic concentrations; the minimum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C2 was 18.50, whereas, the maximum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C0 was 29.00. For patients with cyclosporine blood levels below therapeutic concentrations; the minimum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C2 was 23.40, whereas, the maximum percentage of (Clusters of Differentiation 4) CD4 T-helper cell at C0 was 34.60.

Conclusion: Good negative (reciprocal) correlations were demonstrated between cyclosporine blood concentrations at C0 and C2 versus The percentage of (Clusters of Differentiation 4) CD4 T-helper cell. Therefore, the percentage of (Clusters of Differentiation 4) CD4 T-helper cell may be used as an alternative or surrogate marker for optimum cyclosporine dosing than the traditional dosing strategy using TDM, since the former approach is direct for reflecting drug safety and efficacy, beside, it is the affordable, fast and simple approach. The range of cyclosporine doses that produce therapeutic C0 and C2 in Iraqi kidney transplant patients was 4.1-9 mg/kg/d.

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References

Carol Mattson Porth. Essentials of Pathophysiology: Concepts of Altered Health State. 3rd ed. Lippincott Williams and Wilkins; 2011.

Bueno V, Pestana JOM. The role of CD8+T cells during allograft rejection. Braz J Med Biol Res 2002;35:1247–58.

Kissinger P, Chan-Sik Park, Moon Kim, Polly Matzinger, Colin C. Thymic cortical epithelium induces self-tolerance. Eur J Immunol 2005;35:709–17.

Scott G, Stuart LaForge, Viresh P, Christina M, M Carrie, Jerome A. T-lymphocytes cells express either the CD4 or the CD8 surface glycoprotein but not both. Am Soc Hematol 2002;99:1.

Kyle Woodward, Esma Yolcu, Hong Zhao, Laura Bandura-Morgan, Nadir Askenasy, Haval Shirwan. Pancreatic islets engineered with sa-fas l protein establish robust localized tolerance by inducing regulatory t cells in mice. J Immunol 2011;187:5901-9.

Robert O Bonow, Douglas L Mann, Douglas P Zipes, P Zipes, Peter Libby. Heart disease: a textbook of cardiovascular medicine. Peter Libby Elsevier Health Sci 2011;37:989-10.

Kirsten Geneugelijk, Kirsten Anne Thus, Eric Spierings. Predicting alloreactivity in transplantation. J Immunol Res 2014;12. Doi.org/10.1155/2014/159479.

Janeway CA Jr, Travers P, Walport M. The Immune System in Health and Disease. 5th ed. Garland Science 2001.

Sindhi R, LaVia MF, Paulling E. Stimulated response of peripheral lymphocytes may distinguish cyclosporine effect in renal transplant recipients receiving a cyclosporine+ rapamycin regimen. Transplant 2000;69:432-6.

Miroux C1, Moralès O, Carpentier A, Dharancy S, Conti F, Boleslowski E, et al. Inhibitory effects of cyclosporine on human regulatory T cells in vitro. Transplant Proc 2009;41:3371-4.

Hulgan T1, Donahue JP, Smeaton L, Pu M, Wang H, Lederman MM, et al. Oral cyclosporine a inhibits CD4 T cell P-glycoprotein activity in HIV-infected adults initiating treatment with nucleoside reverse transcriptase inhibitors. Eur J Clin Pharmacol 2009;65:1081-8.

Hoerning A1, Köhler S, Jun C, Lu J, Fu J, Tebbe B. Cyclosporine but not Everolimus inhibits chemotaxine receptor expression on CD4+T cell subsets circulating in the peripheral blood of renal transplant recipients. Clin Exp Immunol 2012;168:251-9.

Robert S Gaston. Maintenance immunosuppression in the renal transplant recipient. Am J Kidney Dis 2001;38:25.

Z Tolou-Ghamari, A Palizban, M Gharavi. Cyclosporine trough concentration and its relationship. Medical Sciences and Health Services, J Nephr 2002;1:1-6.

Michael Brown Carl Wittwera. Flow cytometry: principles and clinical applications in hematology. Clin Chem 2000;46:1221-9.

Qume Drive, San Jose. Introduction to flow cytometry: a learning guide. Manual Part Number: 11-11032-01. 2350 CA 95131, USA; 2000.

Robert R Rich, Thomas A Fleisher, William T Shearer. Clinical Immunology, Principles and Practice. Clinical Immunology. 4th ed. Health Sciences; 2012. p. 396.

Kenshiro Tsuda, Keiichi Yamanaka, Tomoko Akeda, Hiroshi Kitagawa, Tomoko Akeda, Masanao Naka, et al. Calcineurin inhibitors suppress cytokine production from memory t cells and differentiation of naïve t cells into cytokine-producing mature t cells. PLoS One 2012;7:e31465.

Martin Markowitz, Florin Vaida, C Bradley Hare, Daniel Boden, Hiroshi Mohri, Frederick M Hecht, et al. The virologic and immunologic effects of cyclosporine as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection. J Infect Dis 2011;201:1298-302.

Published

01-09-2016

How to Cite

Al-tamimi, J. J. I., Q. A. I. Al-khames Aga, and H. M. Abass. “CD4 T-HELPER CELL COUNT IS AN ALTERNATIVE PROMISING MARKER FOR DOSING CYCLOSPORINE IN KIDNEY TRANSPLANT PATIENT”. International Journal of Pharmacy and Pharmaceutical Sciences, vol. 8, no. 9, Sept. 2016, pp. 85-92, doi:10.22159/ijpps.2016.v8i9.12030.

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