Abstract
Pediatric transplantation has always been challenging for transplant surgeons. Although the higher immunoreactivity and the faster metabolism showed by this unique population when compared with adults requires a heavy immunosuppressive regimen, the possibility of disrupting the delicate balance of correct psychophysical development calls for a regimen of more selective and less toxic immunosuppressive drugs. In the past decade several new drugs have been investigated and some of them appear to be very promising, although pleiotropic toxicities have not yet been eliminated. An appropriate pharmacokinetic approach and the evaluation of synergistic multi-drug combinations by rigorous mathematical models would lead to highly selective immunosuppressive regimens which may result in virtually no toxicity.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Kahan BD (1991) Transplantation timeline: mankind's three millennia—one maverick's three decades in the struggle against biochemical individuality. Transplantation 51: 1–21
Merrill JP, Murray JE, Harrison JH, Guild WR (1956) Successful homo-transplantation of the human kidney between identical twins. JAMA 160: 277–281
Starzl TE, Marchioro TL, Porter KA, Faris TD, Carey TA (1966) The role of organ transplantation in pediatrics. Pediatr Clin North Am 13: 381–422
DeShazo CV, Simmons RL, Bernstein DM, DeShazo MM, Willmart J, Kiellstrand GM, Najarian JS (1974) Results of renal transplantation in 100 children. Surgery 76: 461–468
Lilly JR, Giles G, Hurwitz R, Schroter G, Takagi H, Gray S, Penn I, Halgrimson CG, Starzl TE (1971) Renal homotransplantation in pediatric patients. Pediatrics 47: 548–557
Borel JF, Feurer C, Gubler HU, Stahelin H (1976) Biological effects of cyclosporine A: a new antilymphocytic agent. Agents Actions 6: 468–476
Murray JE, Merrill JP, Harrison JH et al (1963) Prolonged survival of human kidney homografts by immunosuppressive drug therapy. N Engl J Med 268: 1315–1323
Goodwin WE, Kaufman JJ, Mims MM, Turner RD, Glassok R, Goldman R, Maxwell MM (1963) Human renal transplantation. I. Clinical experiences with 6 cases of renal homotransplantation. J Urol 89: 13–24
Cosimi AB, Colvin RB, Burton RC, Rubin R, Goldstein G, Kung PC, Hansen WP, Delmonico FL, Russel PS (1981) Use of monoclonal antibodies to T-cell subset for immunological monitoring and treatment in recipients of renal allografts. N Engl J Med 305: 308–314
Synder DS, Unanue ER (1982) Corticosteroids inhibit immune macrophages Ig expression and interleukin-1 production. J Immunol 129: 1803–1805
Fowler B, Weltz G, Nieder RJ, Strom TB (1990) Evidence that glucocorticoids block expression of the human interleukin-6 gene by accessory cells. Transplantation 49: 183–189
Knudsen PJ, Dinarello CH, Strom TB (1987) Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin-1 in U937 cells. J Immunol 139: 4129–4134
Lee SW, Tson AP, Chou H (1988) Glucocorticoid selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin-1 beta mRNA. Proc Natl Acad Sci USA 8: 1204–1208
Rhoads CP (ed) (1954) 6-Mercaptopurine. Ann NY Acad Sci 60: 183–250
Winkelsiein A (1979) The effect of azathioprine and 6 MP on immunity. J Immunopharmacol 1: 429–454
Chan GLC, Canafax DM, Johnson CA (1987) The therapeutic use of azathioprine in renal transplantation. Pharmacotherapy 7: 165–177
Odlind B, Hartvig P, Lindstrom B, Lannerholm G, Tufveson G, Grefger N (1986) Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine therapy in uremic patients. Int J Immunopharmacol 8: 1–11
Al Safi SA, Maddoks JL (1983) Does azathioprine suppress the mixed lymphocyte reaction in the same way as 6-mercaptopurine? Br J Pharmacol 80: 492P
Elion GB (1972) Significance of azathioprine metabolites. JR Soc Med 62: 257–266
Bach MA, Bach JF (1972) Activities of immunosuppressive agents in vitro. Different timing of azathioprine and methotrexate in inhibition and stimulation of mixed lymphocyte reaction. Clin Exp Immunol 11: 89–98
Zweiman B (1973) Immunosuppression by thiopurines. Transplant Proc 5: 1197–1201
Szawloski PWS, Al Safi SA, Dooley T, Maddoks JL (1985) Azathioprine suppresses the mixed lymphocyte reaction of patient with Lesch-Nyhan syndrome. Br J Clin Pharmacol 20: 489–491
Turka LA, Dayton J, Sinclair G, Thompson CB, Mitchell BS (1991) Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of activation of the immunosuppressive drug mizorbine. J Clin Invest 87: 940–948
Amemiya H, Suzuki S, Watanabe H, Hayashi R, Niiya S (1989) Synergistically enhanced immunosuppressive effect by combined use of cyclosporine and mizorbine. Transplant Proc 21: 956–958
Morris RE, Hoyt EG, Murphy M, Engui EM, Allison AC (1990) Mycophenolic acid morphoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T and B cell purine systems. Transplant Proc 22: 1659–1662
Sollinger HW, Eugui EM, Allison AC (1991) RS-61443: mechanism of action, experimental and early clinical results. Clin Transplant 5: 523–526
Sollinger HW, Belzer FO, Deierhoi MH, et al (1992) RS-61442 (mycophenolate mofetil). A multicenter study for refractory kidney transplant rejection. Ann Surg 216: 513–520
Kahan BD, Tejpal N, Gibbons S, Tu Y, Wang M, Stepkowski S, Chow TC (1993) The synergistic interactions in vitro and in vivo of brequinar sodium with cyclosporine or rapamycin alone and in triple combination. Transplantation (in press)
Arnold H, Bonseaux F (1958) Synthese and Abbau cytostatisch wirksamer cyclisher N-phosphamidester des bis (b-clorathyl)-amins. Angew Chem 70: 539–544
Brock N (1983) The oxazaphosphorine. Cancer Treat Rev 10: 1524–1537
Hampel KE, Kober B, Rosch D (1964) The action of cytostatic agents on the chromosomes of human leukocytes in vitro. Blood 27: 816–823
Foley GE, Friedman OM, Drolet BP (1961) Studies on the mechanism of action of cytoxan. Evidence of activation in vivo and in vitro. Cancer Res 21: 52–63
Santos GW, Owens AH (1966) 19S and 7S antibody production in the cyclophosphamide or methotrexate-treated rat. Nature 209: 622–624
Berenbaum MC, Brown (1966) Dose-response relationships for agents inhibiting the immune response. Immunology 7: 65–71
Frish AW, Davies GH (1965) Inhibition of hemagglutinin synthesis by cytoxan. Cancer Res 25: 745–751
Hurd ER (1973) The effect of cyclophosphamide treatment on B and T lymphocytes in patient with connective tissue disease. Arthritis Rheum 16: 554–558
Clements P, Levy J, Barnett EV (1978) Immunosuppressive effects on B lymphocytes in rheumatoid arthritis. Rheum 16: 537–541
Fox M (1964) Suppression of tissue immunity by cyclophosphamide. Transplantation 2: 465–486
Starzl TE, Halgrimson CG, Penn I, Martineau G, Schroter G, Amemiya H, Putnam CW, Groth CG (1971) Cyclophosphamide and human organ transplantation. Lancet II: 70–74
Zinke H, Woods JE (1977) Donor pretreatment in cadaver renal transplantation. Surg Gynecol Obstet 145: 183–188
Guttmann RD, Beaudoin JG, Morehouse DD, Klassen J, Knaack J, Jeffrey J, Chassot PG, Abbou CC (1977) Donor pretreatment as an adjunct to cadaver renal allotransplantation. Transplant Proc 7: 117–121
Metchinkoff E (1899) Etúde sur la resorption des cellules. Ann Inst Pastcur 13: 737–769
Kung PC, Goldstein G, Reinhertz EL, Schlossman SF (1979) Monoclonal antibodies defining distinctive human T-cell surface antigens. Science 206: 347–349
Goldstein G (1987) Overview of the development of Orthoclone OKT3: monoclonal antibody for therapeutic use in transplantation. Transplant Proc 19: 1–6
Miller RA, Maloney DG, McKillop J, Levy R (1981) In vivo effects of murine hybridoma monoclonal antibody in a patient with T-cell leukemia. Blood 58: 78–83
Todd PA, Brogden RN (1989) Muromab CD3: a review of its pharmacology and therapeutical potential. Drug 37: 871–899
Hess AD, Tutschke PJ, Sentos GN (1982) The effect of cyclosporine A on T-lymphocyte sub-population. In: White DJG (ed) Cyclosporine A. Elsevier, Amsterdam, pp 209–233
Kalman VK, Klimpel GR (1983) Cyclosporine A inhibits the production of gamma interferon but does not inhibit production of virus induced IFNα/β. Cell Immunol 78: 122–129
Bunjes D, Hardt C, Rollinghoff M (1981) Cyclosporine A mediates immunosuppression of primary cytotoxic T cell responses by improving the release of interleukin 1 and interleukin 2. Eur J Immunol 11: 657–662
Kupiec-Weglinski JW, Filho MA, Strom TB, Tilney NL (1984) Sparing of suppressor cells: a critical action of cyclosporine. Transplantation 38: 97–103
Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DN (1984) Cyclophillin-A a specific cytosolic binding protein for cyclosporine A. Science 26: 544–555
Fesik SW, Gampe RT, Holzman TF, Egan DA, Edalji R, Luly JR, Simmer R, Helfrich R, Kishore V, Rich DH (1990) Isotope-edited NMR of cyclosporine A bound to cyclophilin. Evidence for a trans 9, 10 amide bond. Science 250: 1406–1409
Liu J, Farmer JD, Lane WS, Friedman J, Weissman F, Schreiber SL (1991) Calcioneurin is a common target of cyclophillin — cyclosporin A and FKBP-FK506 complexes. Cell 66: 807–815
Friedman J, Weissman I (1991) Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell 66: 799–806
Jeffery JR (1991) Cyclosporine analogues. Clin Biochem 24: 15–21
McKenna RM, Sztrum K, Jeffery JR, Rush DN (1989) Inhibition of cytokine production by cyclosporine A and G. Transplantation 47: 343–347
Faroci M, Vigenat C, Yale JF (1988) Pharmacokinetic profile of cyclosporine A and G and their effects on cellular immunity and glucose tolerance in male and female Wistar rats. Transplantation 45: 617–623
Heistand PC, Gunn H, Gale J (1985) The immunosuppressive profile of a new natural cyclosporine analogue: Nva2-cyclosporine. Transplant Proc 17: 1362–1364
Hiestand PC, Gunn HC, Gale JM, Ryffel B, Borel JF (1985) Comparison of the pharmacological profiles of cyclosporine (Nva2)-cyclosporine and (Val2) dihydro-cyclosporine. Immunology 55: 249–254
Hiestand PC, Graber M, Hurtenbach V, Herrmann P, Borel JF (1992) The new cyclosporine derivative, SDZ IMM 125: in vitro and in vivo pharmacologial effects. Transplant Proc 24: 31–38
Donatsch P, Mason J, Richardson BP, Ryffel B (1992) Toxicologic evaluation of the new cyclosporine derivative, SDZIMM 125 in a comparative subchronic toxicity study in rats. Transplant Proc 24: 39–42
Sokol RJ, Johnson KE, Koner FM, Narkewicz MR, Smith D, Kamm I (1991) Improvement of cyclosporine absorption in children after liver transplantation by means of water-soluble vitamin E. Lancet 338: 212–215
Kahan BD, Kramer WG, Wideman C, Flechner SM, Lorber MI, VanBuren CT (1986) Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 41: 459–464
Ettenger RB, Blifeld C, Prince H (1987) The pediatric nephrologist dilemma: growth after transplantation and its intersection with age as possible immunologic variable. J Pediatr 111: 1022–1205
Pennisi AJ, Costin G, Phillips LS (1979) Somatomedin and growth hormone studies. Am J Dis Child 133: 950–956
Kahan BD, Grevel J (1988) Optimization of cyclosporine therapy in renal transplantation by a pharmacokinetic strategy. Transplantation 46: 631–644
Kahan BD (1989) Cyclosporine. N Engl J Med 321: 1725–1738
Kahan BD (1989) Pharmacokinetics and pharmacodynamics of cyclosporine. Transplant Proc 21: 9–15
Ettenger RB, Rosenthal JT, Merik J, Malekzadeh M, Grimm PC, Salusky IB, Kamil ES, Fine RN (1991) Cadaver renal transplantation in children: long-term impact of new immunosuppressive strategies. Clin Transplant 5: 197–203
Dreckman R, Schlesinger M, Shapiro H, Drukker A (1989) The immune status of uremic children/adolescents with chronic renal failure and renal replacement therapy. Pediatr Nephrol 3: 305–308
Sawada S, Susuku G, Kawasre Y, Takaku F (1987) Novel immunosuppressive agent, FK506. In vitro effects on cloned T cell activation. J Immunol 139: 1797–1803
Kay JE, Benzie CR, Goodier MR, Wick CJ, Doe SE (1989) Inhibition of T-lymphocyte activation by the immunosuppressive drug FK-506. Immunology 67: 473–477
Dumont FJ, Starvch MJ, Koprak SL, Melino MR, Segal NH (1990) Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK506 and rapamycin. J Immunol 144: 251–256
Vathsala A, Goto S, Yoshimura N, Stepkowski S, Chow TC, Kahan BD (1991) The immunosuppressive antagonism of low doses of FK506 and cyclosporine. Transplantation 52: 121–128
Fung J, Abu-Elmagd K, Jain A, Gordon R, Tzakis A, et al (1991) A randomized trial of primary liver transplantation under immunosuppression with FK506 vs. cyclosporine. Transplant Proc 23: 2977–2983
Shapiro R, Jordan M, Scantlebury V, Fung J et al (1991) FK506 in clinical kidney transplantation. Transplant Proc 23: 3065–3067
Sigal NH, Lin CS, Siekierka JJ (1991) Inhibition of human T-cell activation by FK-506, rapamycin, and cyclosporine A. Transplant Proc 23: 1–5
Kahan BD, Chang JY, Seghal SN (1991) Preclinical evaluation of a new potent immunosuppressive agent, rapamycin. Transplantation 52: 185–191
Kuo CJ, Chung J, Fiorentino DF, Flanagan, WM, Blenis J, Crabtree GR (1992) Rapamycin selectively inhibits interleukin-2 activation of p 70 S6 kinase. Nature 358: 70–73
Metcalfe SM, Richards FM (1990) Cyclosporine, FK506, and rapamycin: some effects on early activation events in serum-free, mitogen-stimulated mouse spleen cells. Transplantation 49: 798–802
Kahan BD, Gibbons S, Tejpal N, Stepkowski SM, Chou TC (1991) Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro. Transplantation 51: 232–239
Chen SF, Ruben R, Dexter D (1986) Mechanism of action of the novel anti-cancer agent 6-fluoro2-(2-fluoro-1, 1 byphenze 4-yl) −3 methyl-4 quinoline carboxylic acid sodium salt. Inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Res 46: 5014–5018
Chen SF, Papp LM, Ardecky RJ (1990) Structure-activity relationship of quinoline carboxylic acids: a new class of inhibitors of dihydroorotate dehydrogenase. Biochem Pharmacol 40: 709–714
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ferraresso, M., Kahan, B.D. New immunosuppressive agents for pediatric transplantation. Pediatr Nephrol 7, 567–573 (1993). https://doi.org/10.1007/BF00852552
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00852552