Weaning of Immunosuppression in Liver Transplant Recipients12

Mazariegos, George; Reyes, Jorgé; Marino, Ignazio R.; Demetris, Anthony J.; Flynn, Bridget; Irish, William; McMichael, John; Fung, John J.; Starzl, Thomas E.

doi:10.1097/00007890-199701270-00012

Cited by 394 publications

(271 citation statements)

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“…14,15 Assessment of the completeness and durability of the tolerance may require follow-ups of 2 or more years since the effects of conditioning with a potent lymphoid depleting antibody are long-lasting. Nevertheless, the observations in the 3 cases described by Donckier et al add to the considerable historical evidence 15,34,[38][39][40][41][42] that drug-free tolerance in a significant number of HLA-mismatched liver transplant recipients is a realizable objective.…”

Section: See Article On Page 1523mentioning

confidence: 96%

Tolerance for organ recipients: A clash of paradigms

Marcos¹,

Lakkis²,

Starzl³

2006

Liver Transpl

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Section: See Article On Page 1523mentioning

confidence: 96%

Tolerance for organ recipients: A clash of paradigms

Marcos¹,

Lakkis²,

Starzl³

2006

Liver Transpl

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“…[6][7][8] Early reports identified small numbers of patients in whom successful withdrawal took place. Such patients usually were more than 5 years posttransplantation and had not experienced recent or significant episodes of rejection (Table 1).…”

Section: Commentsmentioning

confidence: 99%

Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?

McCaughan

2002

Liver Transplantation

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CommentsThere is a long-held belief that liver allografts are more tolerogenic than other vascularized organs, and as such, it has been predicted that some human liver transplant recipients may survive long term without immunosuppressive drugs. This belief is founded on the following evidence 1-5 : (1) liver transplants may be spontaneously accepted in outbred animal strains; particularly pigs and rodents; (2) single episodes of allograft rejection in humans do not adversely affect allograft outcomes; (3) chronic liver allograft rejection is uncommon (Ͻ5%); and (4) reports of isolated cases of withdrawal of immunosuppression with favorable long-term outcomes. These cases have arisen in the setting of noncompliance or intolerable side effects of immunosuppression, in particular, lymphoproliferative disorders.However, it should be noted that liver allograft rejection occurs at relatively the same frequency as in other allografts (30% to 50%).These data consequently led to programs of immunosuppressive withdrawal in human liver allograft recipients. [6][7][8] Early reports identified small numbers of patients in whom successful withdrawal took place. Such patients usually were more than 5 years posttransplantation and had not experienced recent or significant episodes of rejection (Table 1). Patients considered for withdrawal in these studies usually had considerable side effects from therapy. Successful withdrawal was seen in 20% to 30% of patients, although 20% to 30% developed allograft rejection on withdrawal of therapy.What about this recent report? 9 Does it significantly advance the concept and/or feasibility of withdrawal of immunosuppression?On the surface, this report is encouraging. Unlike previous studies, a significant number of patients were part of a proactive program of immunosuppression withdrawal in the sense that patients were electively weaned, rather than weaned because of drug side effects. The study also was conducted in children and recipients of live donor allografts; both situations theoretically might increase success. Sixty-three patients were selected for drug withdrawal (only 26 patients, elective); withdrawal was slow, taking 3 to 6 months; and overall success was obtained in 24 of 63 patients (38.1%).Well, what is the problem? The problem is in the detail, particularly the denominator. We all would like some estimate of the percentage of patients in our clinics who can be withdrawn electively from therapy. This information is not available from earlier studies. It is available in this report, but not presented in the abstract. The group performed transplantation on 407 patients between 1990 and October 1999. They studied 255 patients who were 408Liver Transplantation, Vol 8, No 4 (April), 2002: pp 408-410 Abstract Unavailable.Please See Print Journal.

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“…More-complete information was obtained in a prospective weaning trial of liver recipients who had at least five years of stable allograft function 42 . The majority of these patients were able to stop immunosuppression or are still in an uninterrupted weaning process 43 ; 30% developed rejection, necessitating resumption of immunosuppression. No grafts were lost or had permanent impairment of function.…”

Section: Chimerism: Level and Durationmentioning

confidence: 99%

The lost chord: microchimerism and allograft survival

et al. 1996

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Recent evidence suggests that passenger leukocytes migrate after organ transplantation and produce persistent chimerism, which is essential for sustained survival of the allografts. Here, Thomas Starzl and colleagues argure that this hematolymphopoietic chimerism provides an important framework for the interpretation of basic and therapeutically oriented transplantataion research.Medawar's characterization of rejection 1 as a host-versus-graft (HVG) reaction (Fig. 1a) was the cornerstone of transplantation immunology. A decade later, this concept was transposed in the context of a graft-versus-host (GVH) reaction (Fig. 1b), in which histoincompatible hematolymphopoietic grafts rejected the immunologically defenseless recipients 2,3 . The resulting assumption that allograft acceptance or rejection could be understood by studying HVG or GVH immunologic responses in isolation led to prompt acceptance of the one-way in vitro tests of immune reactivity as 'minitransplant' surrogates. However, this assumption did not provide a blanket explanation for observations made in animal and human allograft recipients. The one-way paradigmUntil 1959, preparatory donor leukocyte infusion into cytoablated organ recipients was an expected natural extension of the neonatal tolerance model of Billingham, Brent and Medawar 4 and its adult cytoablation analogues 3 . However, when long-term survival of human kidney allografts was accomplished in a few sublethally irradiated recipients without donor leukocyte infusion, and then regularly without cytoreduction under continuous pharmacologic immunosuppression, the need either for chimerism or host preconditioning lost favor.The identification of 'passenger leukocytes' as the primary antigenic component of organs 6,7 led to the belief that their destruction by the host immune system was essential for organ engraftment. When these cells were found to be migratory 8 , including dendritic cells (DCs) 9 , their sensitization effects and presumed elimination at peripheral and intragraft sites was taken for granted. Bone marrow transplantationMajor histocompatibility complex (MHC)-restricted models of acquired tolerance were widely considered to have validated Burnet's prediction that developing lymphocytes could be purged of self-reactive cells before they achieved functional maturity, even following bone marrow transplantation. The alternative possibility that donor and recipient immunecell populations coexisted in neonatally tolerant animals in a mutually nonreactive state while retaining the ability to function collaboratively (e.g. in a joint immune response to infection) was abandoned when no direct experimental support could be found 10 it has since been learned that the outcome in the neonatal tolerance model is highly variable and that a state approaching permanent clonal deletion is uncommon 11 . Recently, it has been shown that the ability of donor-derived leukocyte subsets to proliferate in response to a skin graft challenge was a more critical determinant of neonatal tole...

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Weaning of Immunosuppression in Liver Transplant Recipients12

Cited by 394 publications

References 20 publications

Tolerance for organ recipients: A clash of paradigms

Tolerance for organ recipients: A clash of paradigms

Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?

The lost chord: microchimerism and allograft survival

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