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Beware: shifting paradigms ahead
THE LANCET
Beware: shifting paradigms ahead Randall Ellis Morris
New information from papers published in 1996 is challenging many established paradigms in transplantation. Although cytolytic T ceils have been assumed to be primarily responsible for acute allograft rejection, VanBuskirk has shown that noncytolytic CD4+ T cells transfused into recipients of mouse-heart allografts cause rejection. Furthermore, T cells recovered from these rejected grafts are not cytolytic. These and other studies (J Immunol 1996; 156:4114) show that cytotoxic T cells are not necessary for graft rejection to occur. Tacrolimus (FKS06) and mycophenolate mofetil (MMF), are two new, very effective, natural-product immunosuppressants that inhibit the Therapeutic index of immunosuppression shown as a balance between efficacy and enzymes calcineurin and inosine toxicity and newer immunosuppressants have been responsible for progressively less acute monophosphate dehydrogenase Cyclosporine rejection and less toxicity (defined by the combined incidences of malignancy and infection). (IMPDH), respectively (Brazelton). even its association with reduced rejection. The chimerism Three-dimensional structures of drug-enzyme complexes doctrine has been further eroded by the failure to correlate derived from X-ray diffraction studies show how these the presence of microchimerism in recipients of different drugs block the catalytic activities of their enzymatic organ graft with reduced incidence of acute rejection targets (Nature 1995; 378: 641, Cell 1995; 82: 507, Cell episodes (Hisanagas). 1996; 85: 921). This information is providing the Finally, Allan warns of the extreme risks of precision and freedom to create man-made calcineurin transplanting cells or tissues from baboon to man. The and I M P D H inhibitors. risk of transfer of b a b o o n infectious pathogens to The Tricontinental M M F Renal Transplantation Study recipients and the community at large far outweighs the Group has reported that substitution of M M F for potential benefits from any form of baboon-to-human azathioprine substantially reduces the incidence and transplantation. severity of acute rejection in recipients of cadaveric renal In 1997, the quixotic search for immunosuppressive allografts without increasing the incidence of opportunistic drug-free tolerance for all graft recipients will continue, as infection or cancer. Similarly, optimal use of tacrolimus in it has for nearly half a century. Although the clinical liver transplant recipients reduces rejection without relevance of results of graft tolerance in monkeys is increasing infection or cancer compared with cyclosporinbecoming ever more apparent, can the final goal of based regimens (Lancet 1995; 346: 1310). Unpublished ubiquitous and stable tolerance ever be achieved or is the results of trials with sirolimus (rapamycin) have shown attainment of this ideal an example of Zeno's paradox? even greater reduction of rejection without increased infection or cancer. These results are refuting the precyclosporin era paradign that states that increases in Key references for 1 9 9 6 immunosuppressive drug efficacy cannot be attained Allan J. Xenotransplantation and possible emerging infectious without directly proportional increases in infection and diseases. Mol Diagn 1996; 1: 209-17. Brazelton T, Morris R. Molecular m e c h a n i s m s of action of new malignancy (figure). xenobiotic immunosuppressive drugs: tacrolimus (FK506), Although persistence of graft donor-derived sirolimus (rapamycin), mycophenolate mofetil and haematopoietic cells (microchimerism) in recipient blood leflunomide. Curt Opin I m m u n o l 1996; 8: 710-20. and tissues has been invoked as the primary biologic event Hisanaga M, Hundrieser J, Boker K, et al. Development, stability and clinical correlations of allogenic m i c r o c h i m e r i s m after sofid leading to long-term graft acceptance, many have organ transplantation. Transplantation 1996; 61: 40-45. questioned not only microchimerism's causal role but Lancet 1 9 9 6 ; 3 4 8 (suppl II): 2 6 Transplantation Immunolog3, Department of Cardiethoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5247, USA (R E Morris MD)
sII26
The Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded, randomised clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029-37. VanBusklrk A, Wakely M, Orosz G. Acute rejection of cardiac ailografts by noncytolyticCD4+ T cell populations. Transplantation 1996; 62: 300-02.
End Of Year Review
Beware: shifting paradigms ahead Randall Ellis Morris
New information from papers published in 1996 is challenging many established paradigms in transplantation. Although cytolytic T ceils have been assumed to be primarily responsible for acute allograft rejection, VanBuskirk has shown that noncytolytic CD4+ T cells transfused into recipients of mouse-heart allografts cause rejection. Furthermore, T cells recovered from these rejected grafts are not cytolytic. These and other studies (J Immunol 1996; 156:4114) show that cytotoxic T cells are not necessary for graft rejection to occur. Tacrolimus (FKS06) and mycophenolate mofetil (MMF), are two new, very effective, natural-product immunosuppressants that inhibit the Therapeutic index of immunosuppression shown as a balance between efficacy and enzymes calcineurin and inosine toxicity and newer immunosuppressants have been responsible for progressively less acute monophosphate dehydrogenase Cyclosporine rejection and less toxicity (defined by the combined incidences of malignancy and infection). (IMPDH), respectively (Brazelton). even its association with reduced rejection. The chimerism Three-dimensional structures of drug-enzyme complexes doctrine has been further eroded by the failure to correlate derived from X-ray diffraction studies show how these the presence of microchimerism in recipients of different drugs block the catalytic activities of their enzymatic organ graft with reduced incidence of acute rejection targets (Nature 1995; 378: 641, Cell 1995; 82: 507, Cell episodes (Hisanagas). 1996; 85: 921). This information is providing the Finally, Allan warns of the extreme risks of precision and freedom to create man-made calcineurin transplanting cells or tissues from baboon to man. The and I M P D H inhibitors. risk of transfer of b a b o o n infectious pathogens to The Tricontinental M M F Renal Transplantation Study recipients and the community at large far outweighs the Group has reported that substitution of M M F for potential benefits from any form of baboon-to-human azathioprine substantially reduces the incidence and transplantation. severity of acute rejection in recipients of cadaveric renal In 1997, the quixotic search for immunosuppressive allografts without increasing the incidence of opportunistic drug-free tolerance for all graft recipients will continue, as infection or cancer. Similarly, optimal use of tacrolimus in it has for nearly half a century. Although the clinical liver transplant recipients reduces rejection without relevance of results of graft tolerance in monkeys is increasing infection or cancer compared with cyclosporinbecoming ever more apparent, can the final goal of based regimens (Lancet 1995; 346: 1310). Unpublished ubiquitous and stable tolerance ever be achieved or is the results of trials with sirolimus (rapamycin) have shown attainment of this ideal an example of Zeno's paradox? even greater reduction of rejection without increased infection or cancer. These results are refuting the precyclosporin era paradign that states that increases in Key references for 1 9 9 6 immunosuppressive drug efficacy cannot be attained Allan J. Xenotransplantation and possible emerging infectious without directly proportional increases in infection and diseases. Mol Diagn 1996; 1: 209-17. Brazelton T, Morris R. Molecular m e c h a n i s m s of action of new malignancy (figure). xenobiotic immunosuppressive drugs: tacrolimus (FK506), Although persistence of graft donor-derived sirolimus (rapamycin), mycophenolate mofetil and haematopoietic cells (microchimerism) in recipient blood leflunomide. Curt Opin I m m u n o l 1996; 8: 710-20. and tissues has been invoked as the primary biologic event Hisanaga M, Hundrieser J, Boker K, et al. Development, stability and clinical correlations of allogenic m i c r o c h i m e r i s m after sofid leading to long-term graft acceptance, many have organ transplantation. Transplantation 1996; 61: 40-45. questioned not only microchimerism's causal role but Lancet 1 9 9 6 ; 3 4 8 (suppl II): 2 6 Transplantation Immunolog3, Department of Cardiethoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5247, USA (R E Morris MD)
sII26
The Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded, randomised clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029-37. VanBusklrk A, Wakely M, Orosz G. Acute rejection of cardiac ailografts by noncytolyticCD4+ T cell populations. Transplantation 1996; 62: 300-02.
End Of Year Review