Tolerogenic immunosuppression for organ transplantation

Starzl, Thomas E.; Murase, Noriko; Abu‐Elmagd, Kareem; Gray, Edward A.; Shapiro, Ron; Eghtesad, Bijan; Corry, Robert J.; Jordan, Mark L.; Fontes, Paulo; Gayowski, Timothy; Bond, Geoffrey; Scantlebury, Velma P.; Potdar, Santosh; Randhawa, Parmjeet; Zeevi, Tong Wu Adriana; Nalesnik, Michael A.; Woodward, Jennifer E.; Marcos, Amadeo; Trucco, Massimo; Demetris, Anthony J.; Fung, John J.

doi:10.1016/s0140-6736(03)13175-3

Cited by 473 publications

(294 citation statements)

References 29 publications

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“…25 These principles have been applied in Pittsburgh since 2001 with encouraging results in liver and other organ recipients. [31][32][33][34] The same principles can be readily identified in the strategy reported by Donckier et al Immunosuppression was begun on the day of liver replacement. This consisted of 5 daily doses of antithymocyte globulin (ATG, thymoglobulin ), a 1-week course of mediumdose prednisone that was tapered at the time of stem cell infusion, and conventional doses of sirolimus until liver function normalized.…”

Section: See Article On Page 1523mentioning

confidence: 99%

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: 99%

Tolerance for organ recipients: A clash of paradigms

Marcos¹,

Lakkis²,

Starzl³

2006

Liver Transpl

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“…Patients were conditioned with pretransplant thymoglobulin (5 mg/kg) and treated postoperatively with minimal tacrolimus-based immunosuppression [12]. Donor splenocytes and pretransplant recipient blood samples were used as positive and negative controls, respectively.…”

Section: Studies Of Organ Recipientsmentioning

confidence: 99%

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

et al. 2003

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Passenger leukocytes have been demonstrated to play significant roles in initiating and also regulating immune reactions after organ transplantation. Reliable techniques to detect donor leukocytes in recipients after organ transplantation are essential to analyze the role, function, and behavior of these leukocytes. In this report we describe a simple, reliable method to detect donor cells with low frequencies using peripheral blood samples. Detection of small numbers of major histocompatibility complex (MHC) mismatched cells was first studied using four-color flow cytometry in artificially created cell mixtures. By selecting the CD45 + population and simultaneous staining with several leukocyte lineage markers (CD3, CD4, CD8, CD56, and CD19), MHC-mismatched leukocytes were consistently detected in cell suspensions prepared from directly stained whole blood samples with a threshold sensitivity as low as 0.1%-0.2%. When the fresh peripheral blood mononuclear cells were separated by conventional Ficoll gradient purification, similar, but slightly lower levels of donor cells were detected. Blood samples obtained 1-5 months after liver, kidney, and intestine transplants revealed that the kind of organ allograft influenced levels and lineage pattern of the circulating donor cells. This procedure provided a simple and reliable method in determining early chimerism in transplant recipients. However, the detection of MHC-mismatched leukocytes of all lineages was much lower when frozen peripheral blood mononuclear cells were used.

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“…However, despite multiple reports demonstrating reasonable safety and possible medical advantages to SD‐rATG induction in renal transplantation, there remains a concern in the transplant community as to the early safety of this approach 9, 10, 13, 18, 19. The present multicenter study was designed to rigorously address these remaining safety concerns using a primary composite end point based on either the physiologic consequences of a severe rATG reaction (fever, hypotension, hypoxia) or the possible severe sequelae (cardiac events and DGF) 20, 21, 22, 23, 24.…”

Section: Discussionmentioning

confidence: 99%

A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation

Stevens

Wrenshall

Miles

et al. 2016

American Journal of Transplantation

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A previous nonblinded, randomized, single‐center renal transplantation trial of single‐dose rabbit anti‐thymocyte globulin induction (SD‐rATG) showed improved efficacy compared with conventional divided‐dose (DD‐rATG) administration. The present multicenter, double‐blind/double‐dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD‐rATG versus DD‐rATG induction for noninferiority in early (7‐day) safety and tolerability. Ninety‐five patients (randomized 1:1) received 6 mg/kg SD‐rATG or 1.5 mg/kg/dose DD‐rATG, with tacrolimus‐mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12‐month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD‐rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD‐rATG induction to be noninferior to DD‐rATG induction in early tolerability and equivalent in 12‐month safety. (Clinical Trials.gov #NCT00906204.)

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Tolerogenic immunosuppression for organ transplantation

Cited by 473 publications

References 29 publications

Tolerance for organ recipients: A clash of paradigms

Tolerance for organ recipients: A clash of paradigms

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation

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