Drugs & Aging

, Volume 26, Issue 1, pp 87–94 | Cite as

Modulation of Human Peripheral Blood Mononuclear Cell Proliferative Response by Diltiazem

In Vitro Comparison in Younger versus Older Subjects
  • Antonella D’Ambrosio
  • Luciana Giordani
  • Manuela Colucci
  • Nicola Vanacore
  • Francesca Quintieri
Original Research Article

Abstract

Background

The gradual aging of population has increased the number of elderly patients receiving kidney transplants. In elderly transplant recipients, careful immunosuppression has to be maintained to avoid both rejection and adverse effects. Clinical protocols after kidney transplantation include use of the calcium channel antagonist diltiazem to ameliorate the hypertensive effect and nephrotoxicity of the immunosuppressant agent ciclosporin (cyclosporine).

Objective

Since immune response can be impaired by senescence, we evaluated the influence of diltiazem on lymphocyte proliferation both alone and in the presence of ciclosporin in younger versus older subjects.

Methods

Peripheral blood mononuclear cells (PBMC) from younger healthy donors (aged 19–24 years) and older subjects (aged 59–65 years) were isolated and stimulated with mitogens, recombinant human interleukin-2 (IL-2), purified protein derivative (PPD) antigen from Mycobacterium tuberculosis, and anti-CD3 monoclonal antibody (αCD3 moAb) in the presence or absence of 10−4, 10−5, 10−6, 10−7 mol/L concentrations of diltiazem. In some experiments, lymphocytes from younger and older subjects were used as responder cells in an allogeneic mixed lymphocyte reaction (MLR) in the presence of different concentrations of diltiazem and 10 ng/mL of ciclosporin.

Results

We found that PBMC from older subjects were more susceptible to immunosuppression induced by low concentrations of diltiazem when mitogens were used to stimulate cells. In particular, when pokeweed mitogen was used, diltiazem 10−7 mol/L was associated with statistically significant immunosuppression in older subjects compared with younger subjects. This effect was not observed when IL-2, PPD antigen and αCD3 moAb were used as stimulators. Moreover, in the allogeneic MLR, we found no differences between younger and older subjects when the 10−5, 10−6 and 10−7 mol/L concentrations of diltiazem were used alone or in the presence of ciclosporin. Only addition of the suprather-apeutic 10−4 mol/L concentration of diltiazem to ciclosporin was associated with statistically significant immunosuppression in older versus younger subjects.

Discussion

Our results show that PBMC from older subjects are no more susceptible than PBMC from younger subjects to therapeutic doses of diltiazem when T-cell receptors are directly or indirectly involved. On the contrary, when PBMC activation was not mediated by T-cell receptor involvement, as in the case of pokeweed mitogen, susceptibility to a therapeutic concentration of diltiazem in older subjects was enhanced. Moreover, co-administration of therapeutic doses of diltiazem and ciclosporin in an MLR showed no significant differences between younger and older subjects in an in vitro model of lymphocyte response to allogeneic transplantation.

Conclusion

Since we found no variations in immunosuppression between older and younger subjects when therapeutic doses of diltiazem were added to ciclosporin, our data do not discourage the use of diltiazem in older kidney transplant recipients receiving ciclosporin therapy.

Keywords

Peripheral Blood Mononuclear Cell Diltiazem Young Subject Proliferative Response Purify Protein Derivative 

Notes

Acknowledgements

This study was supported by a grant from Ministero della Sanità — Ricerca Finalizzata — Progetto donazioni e trapianti: epidemiologia e risultati clinici. Fasc. n. 3AM/F3. The authors thank the staff of the Department of Transfusional Medicine — University “La Sapienza”, Rome, Italy, for recruitment of subjects included in this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Pawelec G, Barnett Y, Forsey R, et al. T cells and aging, January 2002 update. Front Biosci 2002; 7: d1056–183PubMedGoogle Scholar
  2. 2.
    Wedel N, Brynger H, Blohme I. Kidney transplantation in patients 60 years and older. Scand J Urol Nephrol 1980; Suppl. 54: 106–8Google Scholar
  3. 3.
    Ismail N, Hakim RM, Helderman JH. Renal replacement therapies in the elderly. Part II: renal transplantation. Am J Kidney Dis 1994; 23(1): 1–15PubMedGoogle Scholar
  4. 4.
    Meier-Kriesche H-U, Kaplan B. Immunosuppression in elderly renal transplant recipients: are current regiments too aggressive? Drug Aging 2001; 18(10): 751–9CrossRefGoogle Scholar
  5. 5.
    Morales JM, Rodriguez-Paternina E, Araque A, et al. Long term protective effect of a calcium-antagonist on renal function in hypertensive renal transplant patients on cyclosporine therapy: a 5 years prospective randomized study. Transpl Proc 1994; 26: 2598–9Google Scholar
  6. 6.
    Ponticelli C. Should renal transplantation be offered to older patients? Nephrol Dial Transpl 2000; 15: 315–7CrossRefGoogle Scholar
  7. 7.
    Oniscu GC, Brown H, Forsythe JL. How old is old for transplantation? Am J Transplant 2004; 4(12): 2067–74PubMedCrossRefGoogle Scholar
  8. 8.
    Rao PS, Merion RM, Ashby VB, et al. Renal transplantation in elderly patients older than 70 years of age: results from the scientific registry of transplant recipients. Transplantation 2007; 83(8): 1069–74PubMedCrossRefGoogle Scholar
  9. 9.
    Hestin D, Frimat L, Hubert J, et al. Renal transplantation in patients over sixty years of age. Clin Nephrol 1994; 42(4): 232–6PubMedGoogle Scholar
  10. 10.
    Jassal SV, Opelz G, Cole E. Transplantation in the elderly: a review. Geriatr Nephrol Urol 1997; 7(3): 157–65PubMedCrossRefGoogle Scholar
  11. 11.
    Martins PNA, Pratschke J, Pascher A, et al. Age and immune response in organ transplantation. Transplantation 2005; 79(2): 127–32PubMedCrossRefGoogle Scholar
  12. 12.
    Meier-Kriesche H-U, Ojo AO, Hanson J, et al. Increased immu-nosuppressive vulnerability in elderly renal transplant recipients. Transplantation 2000; 69: 885–9PubMedCrossRefGoogle Scholar
  13. 13.
    Meier-Kriesche H-U, Ojo AO, Arndorfer JA, et al. Need for individualized immunosuppression in elderly renal transplant recipients. Transpl Proc 2001; 33: 1190–1CrossRefGoogle Scholar
  14. 14.
    Fabrizii V, Hörl WH. Renal transplantation in the elderly. Cur Opin Urol 2001; 11: 159–63CrossRefGoogle Scholar
  15. 15.
    Meier-Kriesche H-U, Ojo AO, Hanson JA, et al. Exponentially increased risk of infectious death in older renal transplant recipients. Kidney Int 2001; 59(4): 1539–43PubMedCrossRefGoogle Scholar
  16. 16.
    Neumayer H, Kunzendorf U, Schreiber M. Protective effects of calcium antagonists in human renal transplantation. Kidney Int 1992; 41 Suppl. 36: 87–93Google Scholar
  17. 17.
    Morales JM, Campistol JM, Andres A, et al. Immunosuppression in older renal transplant patients. Drugs Aging 2000; 16(4): 279–87PubMedCrossRefGoogle Scholar
  18. 18.
    Kumana CR, Tong MKL, Li CS, et al. Diltiazem co-treatment in renal transplant patients receiving microemulsion cyclosporine. Br J Clin Pharmacol 2003; 56(6): 670–8PubMedCrossRefGoogle Scholar
  19. 19.
    Rodicio JL. Calcium antagonists and renal protection from cyclosporine nephrotoxicity: long-term trial in renal transplantation patients. J Cardiovasc Pharmacol 2000; 35(3) Suppl. 1: S7–11PubMedCrossRefGoogle Scholar
  20. 20.
    McDonald SP, Russ GR. Association between use of cyclo-sporine-sparing agents and outcome in kidney transplant recipients. Kidney Int 2002; 61: 2259–65PubMedCrossRefGoogle Scholar
  21. 21.
    Marx M, Weber M, Merkel F, et al. Additive effects of calcium antagonists on cyclosporin induced inhibition of T-cell proliferation. Nephrol Dial Transplant 1990; 5: 1038–44PubMedCrossRefGoogle Scholar
  22. 22.
    D’Ambrosio A, Segoloni G, Quintieri F. The modulatory effect of diltiazem on human in vitro alloreactivity when used alone or in combination with cyclosporin A and/or methyl-prednisolone. Transpl Int 1997; 10: 426–31PubMedCrossRefGoogle Scholar
  23. 23.
    Aros CA, Ardiles LG, Schneider HO, et al. No gender-associated differences of cyclosporine pharmacokinetics in stable renal transplant patients treated with diltiazem. Transplant Proc 2005; 37: 3364–6PubMedCrossRefGoogle Scholar
  24. 24.
    Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus inter-leukin 2 and downregulated by tumor necrosis factor alpha. J Exp Med 1994; 179: 1109–18PubMedCrossRefGoogle Scholar
  25. 25.
    Chitwood KK, Heim-Duthoy KL. Immunosuppressive properties of calcium channel blockers. Pharmacotherapy 1993; 13: 447–54PubMedGoogle Scholar
  26. 26.
    Kelly JG, O’Malley K Clinical pharmacokinetics of calcium antagonists: an update. Clin Pharmacokinet 1992; 22: 416–433PubMedCrossRefGoogle Scholar
  27. 27.
    Aros CA, Schneider HO, Flores CA, et al. Correlation between C2 and AUCO-4 in renal transplant patients treated with diltiazem. Transplant Proc 2005; 37(3): 1580–2PubMedCrossRefGoogle Scholar
  28. 28.
    Douziech N, Seres I, Larbi A, et al. Modulation of human lymphocyte proliferative response with aging. Exp Gerontol 2002; 37: 369–87PubMedCrossRefGoogle Scholar
  29. 29.
    Krause D, Mastro AM, Handte G, et al. Immune function did not decline with aging in apparently healthy, well-nourished women. Mech Ageing Dev 1999; 112: 43–57PubMedCrossRefGoogle Scholar
  30. 30.
    Mazari L, Lesourd BM. Nutritional influences on immune response in healthy aged persons. Mech Ageing Dev 1998; 104: 25–40PubMedCrossRefGoogle Scholar
  31. 31.
    Ferrero E, Manfredi A, Bianchi E, et al. Age-related changes in interleukin 2 responsiveness of resting and activated human mononuclear cells. Haematologica 1991; 76: 14–9PubMedGoogle Scholar
  32. 32.
    Sansoni P, Fagnoni F, Vescovini R, et al. T lymphocyte proliferative capability to defined stimuli and costimulatory CD28 pathway is not impaired in healthy centenarians. Mech Ageing Dev 1997; 96: 127–36PubMedCrossRefGoogle Scholar
  33. 33.
    Sharon N. Lectin receptors as lymphocyte surface markers. Adv Immunol 1983; 34: 213–98PubMedCrossRefGoogle Scholar
  34. 34.
    Whitelegg A, Barber LD. The structural basis of T cell allorecognition. Tissue Antigens 2004; 63: 101–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Antonella D’Ambrosio
    • 1
  • Luciana Giordani
    • 2
  • Manuela Colucci
    • 1
  • Nicola Vanacore
    • 3
  • Francesca Quintieri
    • 1
  1. 1.Department of Infectious, Parasitic and Immuno-Mediated DiseasesIstituto Superiore di SanitàRome, 299Italy
  2. 2.Department of Therapeutic Research and Medicines EvaluationIstituto Superiore di SanitàRomeItaly
  3. 3.National Centre of EpidemiologyIstituto Superiore di SanitàRomeItaly

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