The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation

Starzl, TE; Marchioro, Thomas L.; Porter, K. A.; Iwasaki, Yuzo; Cirelli, G J

doi:10.1097/00007890-196709000-00033

Cited by 64 publications

(84 citation statements)

References 5 publications

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“…The antilymphoid agents (93,94) and a variety of monoclonal antibodies have been particularly effective for tolerance induction in large outbred experimental animals. Figure 21 shows the steps at which some of the old and new drugs disrupt the function of the lymphocyte.…”

Section: Cell Traffic and Immunosuppressionmentioning

confidence: 99%

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

1993

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Section: Cell Traffic and Immunosuppressionmentioning

confidence: 99%

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

1993

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“…Polyclonal antibodies have multiple distinct antigen-combining sites resulting in the depletion of circulating T-cells, apoptosis of activated T cells and modulation of cell surface receptor molecules. The IS potential of heterologous antibodies has been demonstrated early [15] and the first clinical use of an antilymphocyte glogulin (ALG) is reported by Starzel in 1967 [16]. The heavily contamination with anti-red cells and anti-platelet antibodies was resolved by the use of human thymocytes as the antigen source, resulting in antithymocyte globulin (ATG).…”

Section: Polyclonal Antibodiesmentioning

confidence: 99%

Immunosuppressive Therapy After Cardiac Transplantation

Schweiger¹

2012

Cardiac Transplantation

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“…These were brought into an acceptable range by combining cyclosporine with dose-maneuverable prednisone 5 and later with the addition of third, fourth, and even fifth agents. These were more potent versions of the previous best azathioprine/prednisone 6 or azathioprine/antilymphocyte gloublin (ALG)/prednisone cocktails 7 that had been in common use for almost two decades. The cyclosporine-based recipes that were developed with kidney transplantation improved the prognosis of all organ recipients and elevated liver transplantation overnight to practical and widespread use.…”

Section: Cyclosporine Benchmarkmentioning

confidence: 99%

“…4,6,7,[31][32][33] This precedent was broken with the large-scale randomized liver transplant trials. The decision to go forward with the multicenter trials was made despite prima facie evidence of tacrolimus superiority from the increasingly well-documented rescue of liver allografts (see earlier) and shortly thereafter of intractably rejecting kidneys 34 and hearts.…”

Section: Kidney and Other Organ Transplantationmentioning

confidence: 99%

Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet

Starzl

Todo

Demetris

et al. 1998

American Journal of Kidney Diseases

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The pivotal issue of transplant rejection diagnosis and management is design, conduct, and analysis of clinical trials. The historical experience with clinical trials of major immunosuppressive drugs (cyclosporine and especially tacrolimus) is examined in this article. Cyclosporine was a turning point in transplantation, providing an extraordinary improvement over previous therapies. Additionally, early investigational experience with tacrolimus was shown to be important in rescue from cyclosporine failure. Experience with tacrolimus in liver recipients for primary therapy led to understanding that the side effect profile was similar to cyclosporine and that the important side effects of tacrolimus (toxicity and diabetes) could be lessened by altering the drug dose. Early dosing regimens were determined by attempts to balance the toxicities (representing a dose ceiling) against rejection (for minimum dosing). Drug levels became understandable and trough levels could be used to guide therapy. However, when the multicenter liver trial was implemented, high starting doses were included in the protocol design, ignoring information obtained with drug level monitoring. Disregard for this information led to a distortion of the potential value of tacrolimus. Historical controls from the Pittsburgh experience suggested that tacrolimus was a critical immunosuppressant, and the randomized trial against cyclosporine confirmed the drug's ability to compete. The multicenter liver trial, however, was not balanced across treatment arms for other immunosuppressive agents (ie, higher doses of prednisone from center to center, additional induction protocols at various centers). Additionally, analysis of study results differed across continents, and the role of tacrolimus in cyclosporine rescue was not examined thoroughly. When tacrolimus was proposed for use in extrahepatic organ transplantation, again the Pittsburgh experience, as well as experience from other single centers, was determined inadequate evidence of efficacy, and randomized trials were required by the FDA. The fact that multicenter trials in transplantation have historically been poorly designed or analyzed weighed against the dramatic improvements shown from historically controlled studies or single-center trials should lead to question of the regulatory requirement for multicenter randomized trials for all organ types. INDEX WORDSKidney; liver; transplantation; tacrolimus; cyclosporine; regulatory; clinical trials Much of the discussion at this consensus symposium on immunosuppressive drag testing has concerned the clinical and/or histopathological diagnosis of rejection. As important as this may be, it is not the core issue that we should be examining. Most errors in the evaluation of new immunosuppressants can be traced to the design, conduct, and analysis of clinical trials. In NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript turn, the scientific considerations that go into what is indisputably a human experiment are inseparabl...

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The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation

Cited by 64 publications

References 5 publications

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

Immunosuppressive Therapy After Cardiac Transplantation

Tacrolimus (FK506) and the pharmaceutical/academic/regulatory gauntlet

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