View More View Less
  • 1 Semmelweis Egyetem, Általános Orvostudományi Kar Transzplantációs és Sebészeti Klinika Budapest
  • 2 Pécsi Tudományegyetem, Általános Orvostudományi Kar Immunológiai és Biotechnológiai Intézet Pécs
Open access

A szervtranszplantáció ötvenéves történetében az immunszuppresszív terápia fejlődésének köszönhetően egyre jobb szerv- és betegtúlélési eredményekről számoltak be világszerte, azonban a bázisgyógyszereknek minősülő kalcineurin inhibitorok káros mellékhatásait, elsősorban a nephrotoxicitast mellőző vegyületek kifejlesztése csak az elmúlt két évtizedben zajlott. A gazdaszervezet számára idegennek minősülő implantált szerv a recipiensből komplex immunválaszt vált ki. A dolgozatban az immunválasz vázlatos áttekintését követően a szerzők bemutatják az új, eltérő támadáspontokon ható gyógyszereket. Ezek vagy már gyakorlati alkalmazásban lévő, vagy rövid időn belül esetlegesen forgalomba kerülő vegyületek, amelyek távlati lehetőségeket nyújtanak a kalcineurin inhibitorok leváltására. Kiemelt hangsúlyt kap a kostimulációs blokádon keresztül ható belatacept és az elmúlt években egyre nagyobb kutatási teret nyerő toleranciaindukció, mint jövőbeli lehetőség. Orv. Hetil., 2012, 153, 1294–1301.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Ford, M. L., Larsen, C. P.: Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol. Rev., 2009, 229, 294–306.

    Larsen C. P. , 'Translating costimulation blockade to the clinic: lessons learned from three pathways ' (2009 ) 229 Immunol. Rev. : 294 -306.

    • Search Google Scholar
  • Knight, R. J., Podder, H., Kerman, R. H., et al.: Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation. Transplantation, 2010, 89, 727–732.

    Kerman R. H. , 'Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation ' (2010 ) 89 Transplantation : 727 -732.

    • Search Google Scholar
  • Chhabra, D., Grafals, M., Cabral, B., et al.: Late conversion of tacrolimus to sirolimus in a prednisone-free immunosuppression regimen in renal transplant patients. Clin. Transplant., 2010, 24, 199–206.

    Cabral B. , 'Late conversion of tacrolimus to sirolimus in a prednisone-free immunosuppression regimen in renal transplant patients ' (2010 ) 24 Clin. Transplant. : 199 -206.

    • Search Google Scholar
  • Zhang, W., Zhang, D., Shen, M., et al.: Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance. J. Immunol., 2010, 185, 4750–4759.

    Shen M. , 'Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance ' (2010 ) 185 J. Immunol. : 4750 -4759.

    • Search Google Scholar
  • Chen, J. F., Gao, J., Zhang, D., et al.: CD4+Foxp3+ regulatory T cells converted by rapamycin from peripheral CD4+CD25(-) naive T cells display more potent regulatory ability in vitro. Chin. Med. J. (Engl)., 2010, 123, 942–948.

    Zhang D. , 'CD4+Foxp3+ regulatory T cells converted by rapamycin from peripheral CD4+CD25(-) naive T cells display more potent regulatory ability in vitro ' (2010 ) 123 Chin. Med. J. (Engl). : 942 -948.

    • Search Google Scholar
  • Manuelli, M., De Luca, L., Iaria, G., et al.: Conversion to rapamycin immunosuppression for malignancy after kidney transplantation. Transplant. Proc., 2010, 42, 1314–1316.

    Iaria G. , 'Conversion to rapamycin immunosuppression for malignancy after kidney transplantation ' (2010 ) 42 Transplant. Proc. : 1314 -1316.

    • Search Google Scholar
  • Sumethkul, V., Tankee, P., Chalermsanyakorn, P., et al.: Long-term outcome of very early cyclosporine minimization and de novo everolimus therapy in kidney transplant recipients: a pharmacokinetic guided approach. Transplant. Proc., 2010, 42, 4040–4042.

    Chalermsanyakorn P. , 'Long-term outcome of very early cyclosporine minimization and de novo everolimus therapy in kidney transplant recipients: a pharmacokinetic guided approach ' (2010 ) 42 Transplant. Proc. : 4040 -4042.

    • Search Google Scholar
  • Rostaing, L., Kamar, N.: mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J. Nephrol., 2010, 23, 133–142.

    Kamar N. , 'mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? ' (2010 ) 23 J. Nephrol. : 133 -142.

    • Search Google Scholar
  • Cooper, J. E., Wiseman, A. C.: Novel immunosuppressive agents in kidney transplantation. Clin. Nephrol., 2010, 73, 333–343.

    Wiseman A. C. , 'Novel immunosuppressive agents in kidney transplantation ' (2010 ) 73 Clin. Nephrol. : 333 -343.

    • Search Google Scholar
  • Busque, S., Leventhal, J., Brennan, D. C., et al.: Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients. Am. J. Transplant., 2009, 9, 1936–1945.

    Brennan D. C. , 'Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients ' (2009 ) 9 Am. J. Transplant. : 1936 -1945.

    • Search Google Scholar
  • Gupta, G., Womer, K. L.: Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation. Drug Des. Devel. Ther., 2010, 4, 375–382.

    Womer K. L. , 'Profile of belatacept and its potential role in prevention of graft rejection following renal transplantation ' (2010 ) 4 Drug Des. Devel. Ther. : 375 -382.

    • Search Google Scholar
  • Linsley, P. S., Nadler, S. G.: The clinical utility of inhibiting CD28-mediated costimulation. Immunol. Rev., 2009, 229, 307–321.

    Nadler S. G. , 'The clinical utility of inhibiting CD28-mediated costimulation ' (2009 ) 229 Immunol. Rev. : 307 -321.

    • Search Google Scholar
  • Pettypiece, S.: Bristol-Myers transplant drug wins U.S. Panel Backing (Update1). Bloomberg, March 1, 2010 17:49 EST

  • Latek, R., Fleener, C., Lamian, V., et al.: Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation. Transplantation, 2009, 87, 926–933.

    Lamian V. , 'Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation ' (2009 ) 87 Transplantation : 926 -933.

    • Search Google Scholar
  • www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM201859.pdf.

  • Gandhi, A. M., Fazli, U., Rodina, V., et al.: Costimulation targeting therapies in organ transplantation. Curr. Opin. Organ Transplant., 2008, 13, 622–626.

    Rodina V. , 'Costimulation targeting therapies in organ transplantation ' (2008 ) 13 Curr. Opin. Organ Transplant. : 622 -626.

    • Search Google Scholar
  • Vincenti, F., Charpentier, B., Vanrenterqhem, Y., et al.: A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study). Am. J. Transplant., 2010, 10, 535–546.

    Vanrenterqhem Y. , 'A phase III study of belatacept-based immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study) ' (2010 ) 10 Am. J. Transplant. : 535 -546.

    • Search Google Scholar
  • Grinyó, J., Charpentier, B., Pestana, J. M., et al.: An integrated safety profile analysis of belatacept in kidney transplant recipients. Transplantation, 2010, 90, 1521–1527.

    Pestana J. M. , 'An integrated safety profile analysis of belatacept in kidney transplant recipients ' (2010 ) 90 Transplantation : 1521 -1527.

    • Search Google Scholar
  • Larsen, C. P., Grinyó, J., Medina-Pestana, J. M., et al.: Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation, 2010, 90, 1528–1535.

    Medina-Pestana J. M. , 'Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies ' (2010 ) 90 Transplantation : 1528 -1535.

    • Search Google Scholar
  • Bremer, S., Vethe, N. T., Rootwelt, H., et al.: Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study. J. Transl. Med., 2009, 7, 64.

    Rootwelt H. , 'Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study ' (2009 ) 7 J. Transl. Med. : 64 -.

    • Search Google Scholar
  • Kinnear, G., Wood, K. J., Marshall, D., et al.: Anti-OX40 prevents effector T-cell accumulation and CD8+ T-cell mediated skin allograft rejection. Transplantation, 2010, 90, 1265–1271.

    Marshall D. , 'Anti-OX40 prevents effector T-cell accumulation and CD8+ T-cell mediated skin allograft rejection ' (2010 ) 90 Transplantation : 1265 -1271.

    • Search Google Scholar
  • Burrell, B. E., Lu, G., Li, X. C., et al.: OX40 costimulation prevents allograft acceptance induced by CD40-CD40L blockade. J. Immunol., 2009, 182, 379–390.

    Li X. C. , 'OX40 costimulation prevents allograft acceptance induced by CD40-CD40L blockade ' (2009 ) 182 J. Immunol. : 379 -390.

    • Search Google Scholar
  • Weaver, T. A., Charafeddine, A. H., Agarwal, A., et al.: Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat. Med., 2009, 15, 746–749.

    Agarwal A. , 'Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates ' (2009 ) 15 Nat. Med. : 746 -749.

    • Search Google Scholar
  • Lo, D. J., Weaver, T. A., Stempora, L., et al.: Selective targeting of human alloresponsive CD8(+) effector memory T cells based on CD2 expression. Am. J. Transplant., 2011, 11, 22–33.

    Stempora L. , 'Selective targeting of human alloresponsive CD8(+) effector memory T cells based on CD2 expression ' (2011 ) 11 Am. J. Transplant. : 22 -33.

    • Search Google Scholar
  • Xie, B., Chen, J., Xia, J., et al.: Combined costimulation blockade inhibits accelerated rejection mediated by alloantigen-primed memory T cells in mice. Immunol. Invest., 2009, 38, 639–651.

    Xia J. , 'Combined costimulation blockade inhibits accelerated rejection mediated by alloantigen-primed memory T cells in mice ' (2009 ) 38 Immunol. Invest. : 639 -651.

    • Search Google Scholar
  • Ahmed, E. B., Daniels, M., Alegre, M. L., et al.: Bacterial infections, alloimmunity, and transplantation tolerance. Transplant. Rev. (Orlando), 2011, 25, 27–35.

    Alegre M. L. , 'Bacterial infections, alloimmunity, and transplantation tolerance ' (2011 ) 25 Transplant. Rev. (Orlando) : 27 -35.

    • Search Google Scholar
  • Li, X. C., Turka, L. A.: An update on regulatory T cells in transplant tolerance and rejection. Nat. Rev. Nephrol., 2010, 6, 577–583.

    Turka L. A. , 'An update on regulatory T cells in transplant tolerance and rejection ' (2010 ) 6 Nat. Rev. Nephrol. : 577 -583.

    • Search Google Scholar
  • Hanidziar, D., Koulmanda, M.: Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance. Curr. Opin. Organ Transplant., 2010, 15, 411–415.

    Koulmanda M. , 'Inflammation and the balance of Treg and Th17 cells in transplant rejection and tolerance ' (2010 ) 15 Curr. Opin. Organ Transplant. : 411 -415.

    • Search Google Scholar
  • Heidt, S., Segundo, D. S., Chadha, R., et al.: The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr. Opin. Organ Transplant., 2010, 15, 456–461.

    Chadha R. , 'The impact of Th17 cells on transplant rejection and the induction of tolerance ' (2010 ) 15 Curr. Opin. Organ Transplant. : 456 -461.

    • Search Google Scholar
  • Casiraghi, F., Aiello, S., Remuzzi, G.: Transplant tolerance: progress and challenges. J. Nephrol., 2010, 23, 263–270.

    Remuzzi G. , 'Transplant tolerance: progress and challenges ' (2010 ) 23 J. Nephrol. : 263 -270.

    • Search Google Scholar
  • Francis, R. S., Feng, G., Tha-In, T., et al.: Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. Eur. J. Immunol., 2011, 41, 726–738.

    Tha-In T. , 'Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells ' (2011 ) 41 Eur. J. Immunol. : 726 -738.

    • Search Google Scholar
  • Gill, D., Tan, P. H.: Induction of pathogenic cytotoxic T lymphocyte tolerance by dendritic cells: a novel therapeutic target. Expert Opin. Ther. Targets, 2010, 14, 797–824.

    Tan P. H. , 'Induction of pathogenic cytotoxic T lymphocyte tolerance by dendritic cells: a novel therapeutic target ' (2010 ) 14 Expert Opin. Ther. Targets : 797 -824.

    • Search Google Scholar
  • Yamano, T., Watanabe, S., Hasegawa, H., et al.: Ex-vivo expanded DC induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin allografts. Blood, 2011, 117, 2640–2648.

    Hasegawa H. , 'Ex-vivo expanded DC induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin allografts ' (2011 ) 117 Blood : 2640 -2648.

    • Search Google Scholar
  • Rodriguez-García, M., Boros, P., Bromberg, J. S., et al.: Immunotherapy with myeloid cells for tolerance induction. Curr. Opin. Organ Transplant., 2010, 15, 416–421.

    Bromberg J. S. , 'Immunotherapy with myeloid cells for tolerance induction ' (2010 ) 15 Curr. Opin. Organ Transplant. : 416 -421.

    • Search Google Scholar
  • Kawai, T., Benedict Cosimi, A.: Induction of tolerance in clinical kidney transplantation. Clin. Transplant., 2010, 24 (Suppl. 22), 2–5.

    Benedict Cosimi A. , 'Induction of tolerance in clinical kidney transplantation ' (2010 ) 24 Clin. Transplant. : 2 -5.

    • Search Google Scholar
  • Lan, Z., Lian, D., Liu, W., et al.: Prevention of chronic renal allograft rejection by soluble CD83. Transplantation, 2010, 90, 1278–1285.

    Liu W. , 'Prevention of chronic renal allograft rejection by soluble CD83 ' (2010 ) 90 Transplantation : 1278 -1285.

    • Search Google Scholar
  • Lan, Z., Ge, W., Arp, J., et al.: Induction of kidney allograft tolerance by soluble CD83 associated with prevalence of tolerogenic dendritic cells and indoleamine 2,3-dioxygenase. Transplantation, 2010, 90, 1286–1293.

    Arp J. , 'Induction of kidney allograft tolerance by soluble CD83 associated with prevalence of tolerogenic dendritic cells and indoleamine 2,3-dioxygenase ' (2010 ) 90 Transplantation : 1286 -1293.

    • Search Google Scholar
  • Crisa, L.: Pancreatic islet transplants and IDO: when starving the enemy does you good. Diabetes, 2010, 59, 2102–2104.

    Crisa L. , 'Pancreatic islet transplants and IDO: when starving the enemy does you good ' (2010 ) 59 Diabetes : 2102 -2104.

    • Search Google Scholar
  • Fändrich, F.: Cell therapy approaches aiming at minimization of immunosuppression in solid organ transplantation. Curr. Opin. Organ Transplant., 2010, 15, 703–708.

    Fändrich F. , 'Cell therapy approaches aiming at minimization of immunosuppression in solid organ transplantation ' (2010 ) 15 Curr. Opin. Organ Transplant. : 703 -708.

    • Search Google Scholar
  • Pilat, N., Wekerle, T.: Mechanistic and therapeutic role of regulatory T cells in tolerance through mixed chimerism. Curr. Opin. Organ Transplant., 2010, 15, 725–730.

    Wekerle T. , 'Mechanistic and therapeutic role of regulatory T cells in tolerance through mixed chimerism ' (2010 ) 15 Curr. Opin. Organ Transplant. : 725 -730.

    • Search Google Scholar
  • Ge, W., Jiang, J., Liu, W., et al.: Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells. Am. J. Transplant., 2010, 10, 1760–1773.

    Liu W. , 'Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells ' (2010 ) 10 Am. J. Transplant. : 1760 -1773.

    • Search Google Scholar