A quantitative flow cytometry assay for the preclinical testing and pharmacological monitoring of rabbit antilymphocyte globulins (rATG)

Préville, Xavier; Nicolas, Ludovic; Flacher, Monique; Revillard, Jean‐Pierre

doi:10.1016/s0022-1759(00)00271-4

Cited by 31 publications

(22 citation statements)

References 15 publications

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“…Of note, leukopenia and thrombocytopenia were prevented by use of lowerthan-standard doses of RATG not only in the study group as a whole but also in renal transplant recipients who were dialysis dependent because of DGF. This is consistent with the possibility that RATG preparations contain cross-reactive antibodies that entail risk for leukopenia and neutropenia in a dosedependent way (30). This also could explain the excess of symptomatic anemia, in particular in patients who had DGF and were receiving standard-dose RATG.…”

Section: Discussionsupporting

confidence: 83%

Basiliximab Combined with Low-Dose Rabbit Anti-Human Thymocyte Globulin

Ruggenenti

Codreanu²,

Cravedi³

et al. 2006

Clinical Journal of the American Society of Nephrology

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In high-risk kidney transplant recipients, induction therapy with rabbit anti-human thymocyte globulin (RATG) reduces the risk for acute rejection but is associated with significant toxicity, opportunistic infections, and cancer. Using reduced doses of RATG combined with anti-IL-2 antibodies may achieve the same antirejection activity of standard-dose RATG but with a better safety profile. This randomized, open-label study compared the efficacy, tolerability, and costs of low-dose RATG (0.5 mg/kg per d) plus basiliximab (20 mg 4 d apart) versus standard-dose RATG (2 mg/kg per d) in 33 consecutive high-risk renal transplant recipients (living-related transplant recipients, sensitized patients or patients who received another transplant, and patients with delayed graft function) over 6 mo of follow-up. All patients received concomitant therapy with steroids, cyclosporin A, and azathioprine or mycophenolate mofetil. Seventeen patients received low-dose RATG plus basiliximab, and 16 received standard-dose RATG. Patient (100 versus 100%) and graft (94 versus 100%) survival were comparable in the two groups, but the incidence of fever (17.6 versus 56.5%; P ‫؍‬ 0.01), leukopenia (23.5 versus 56.3%; P < 0.05), anemia (29.4 versus 62.5%; P < 0.05), cytomegalovirus reactivations (17.6 versus 56.5%; P ‫؍‬ 0.01), the number of transfused units (0.5 ؎ 0.9 versus 2.0 ؎ 2.4; P < 0.001), and treatment costs (3652 ؎ 704 versus 5400 ؎ 1960 euro; P ‫؍‬ 0.001) were lower with low-dose RATG plus basiliximab than with standard-dose RATG. There was one episode of biopsy-proven acute rejection on low-dose RATG plus basiliximab, and there were two on standard-dose RATG. In renal transplantation, induction therapy with basiliximab plus low-dose RATG effectively prevents acute rejection and is safer and more cost-effective than induction with standard-dose RATG.

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Section: Discussionsupporting

confidence: 83%

Basiliximab Combined with Low-Dose Rabbit Anti-Human Thymocyte Globulin

Ruggenenti

Codreanu²,

Cravedi³

et al. 2006

Clinical Journal of the American Society of Nephrology

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“…ATG-S has a much higher concentration of active antibodies as ATG-F and is therefore used at lower doses. 24 However, in the setting of hematopoietic stem cell transplantation, no data exist as to what doses may be equivalent. Recent publications suggest that median doses of 6-8 mg/kg b.w.…”

Section: Discussionmentioning

confidence: 99%

Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group

Basara

Baurmann

Kolbe

et al. 2005

Bone Marrow Transplant

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“…Fresenius ATG is given at doses 4 to 5 times higher, because of lower antilymphocyte antibody content per milligram IgG. 19 During lymphoglobuline treatments of aplastic anemia, the peak levels of horse ATG measured by enzyme-linked immunosorbent assay (ELISA) were in the range of 100 to 1000 g/kg in 10 patients who received 15 mg/kg/d. 41 Thus, supramitogenic ATG concentrations are readily achieved during ATG treatments for bone marrow transplantation 7,8 (2.5 mg/kg or more for 2-4 days) and during the recently introduced short-term induction treatments in kidney transplantation 6 but sufficiently high ATG concentrations are unlikely to be achieved during treatment with thymoglobulin at 1 mg/kg/d (for 8-10 days) or their equivalent with ATGs from other manufacturers.…”

Section: Discussionmentioning

confidence: 99%

“…ATG concentrations required to achieve apoptosis vary from one manufacturer to the other, in parallel with the total antilymphocyte antibody content as determined by indirect fluorescence or complement-dependent lysis. 19 Those concentrations were higher with horse ATG than rabbit ATG. Apoptosis was moderate at mitogenic concentrations of ATGs and increased rapidly with a symmetrical drop in proliferative responses when ATG concentrations were raised.…”

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confidence: 95%

Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion

Michallet

Saltel

Préville

et al. 2003

Blood

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Antithymocyte globulins (ATGs), the immunoglobulin G (IgG) fraction of sera from rabbits or horses immunized with human thymocytes or T-cell lines, are used in conditioning regimens for bone marrow transplantation, in the treatment of acute graft-versus-host disease, in the prevention or treatment of acute rejection in organ transplantation, and in severe bone marrow aplasia. In nonhuman primates, ATGs induce rapid, dose-dependent, T-cell depletion in peripheral lymphoid tissues, where apoptotic cells can be demonstrated in T-cell zones. We show here that increasing ATG concentrations in vitro resulted in reduced lymphocyte proliferative responses, associated with a rapid increase in the percentage of apoptotic cells. Apoptosis did not require prior exposure to interleukin-2, nor did it result in CD178/CD95 or tumor necrosis factor/tumor necrosis factor receptor (TNF/TNF-R) interactions; it was therefore clearly different from activationinduced cell death. Cytochrome c release, caspase-9, and caspase-3 activation were not implicated, excluding a direct involvement of the intrinsic mitochondrial pathway. The cysteine protease inhibitor E64d and cathepsin-B-specific inhibitors conferred significant protection, whereas apoptosis was associated with the release of active cathepsin B into the cytosol. These data demonstrate a role for cathepsin B in T IntroductionPolyclonal antithymocyte globulins (ATGs) are the purified immunoglobulin G (IgG) fraction of sera from rabbits, horses, or, more rarely, goats immunized with human thymocytes or T-cell lines. Antilymphocyte globulins were first studied in various animal species by Metchnikoff 1 at the end of the 19th century, then in the context of allograft rejection, 2,3 and then they were introduced in the clinic for the treatment of corticosteroid-resistant rejection in organ transplantation. Human thymocytes are the most common source of antigen for the preparation of ATGs. Clinical indications for ATGs include prevention (induction therapy) of acute rejection in organ transplantation, 4-6 rescue treatment of acute rejection, conditioning for hematopoietic stem cell transplantation from unrelated HLA-matched 7 or haploidentical donors, 8 treatment of graft-versus-host disease, 9 and treatment of severe aplastic anemia. 10 The doses used in bone marrow transplantation are usually higher than those used in organ transplantation.Because ATGs contain many different antibody specificities, [11][12][13] they are expected to induce a variety of biologic activities. For instance, we recently demonstrated that ATGs contain functional antibodies against several integrins and their ligands and against the chemokine receptors CXCR4, CCR5, and CCR7. 14 However, the most common effect of ATG administration is the depletion of peripheral blood T cells, which progressively reverses after treatment ceases but may be long-lasting in the CD4 ϩ subset in adults. 15 Our experiments in monkeys showed that T-cell depletion was not restricted to the blood compartment. 16 Indeed, T-cell apopt...

show abstract

A quantitative flow cytometry assay for the preclinical testing and pharmacological monitoring of rabbit antilymphocyte globulins (rATG)

Cited by 31 publications

References 15 publications

Basiliximab Combined with Low-Dose Rabbit Anti-Human Thymocyte Globulin

Basiliximab Combined with Low-Dose Rabbit Anti-Human Thymocyte Globulin

Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group

Cathepsin-B-dependent apoptosis triggered by antithymocyte globulins: a novel mechanism of T-cell depletion

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