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Background: Rabbit antithymocyte globulins (rATGs) are polyclonal antibodies used to prevent acute cellular rejection in kidney transplantation. Their dosing remains largely empirical and the question of an individualized dose is still unresolved., Methods: Data from a prospective study in 17 kidney transplant patients were used to develop a model describing the dose-concentration-response relationship of rATG with T-lymphocyte subpopulation counts over time. The model was validated using an independent cohort of kidney transplant patients treated by rATG in the same center., Results: Pharmacokinetics of rATG was described using a two-compartment model integrating a third compartment and a target-mediated elimination for active rATG. The kinetics of CD3 + , CD4 + , CD8 + , and CD3 - CD56 + cell counts over time were described by a pharmacokinetic-pharmacodynamic model with transit compartments, integrating both CD3 - CD56 + -independent and CD3 - CD56 + -dependent rATG-mediated lymphocyte depletion, and a positive feedback. Elimination of rATG was influenced by age and body surface area, while its distribution was also influenced by body surface area. CD3 + proliferation rate decreased with age and CD3 - CD56 + -mediated elimination was influenced by the V158F-FCGR3A polymorphism. Binary efficacy and tolerance endpoints were defined as a CD3 + count < 20 mm -3 for at least 7 days and a CD4 + count > 200 mm -3 at 1 year, respectively. Simulations showed that increasing or decreasing the standard 6-mg/kg dose will impact both tolerance and efficacy, while a dose decrease may be beneficial in elderly patients., Conclusions: Our results can be used to design prospective clinical trials testing dose individualization based on patients' characteristics., Clinical Trial Registration: Eudract No. 2009-012673-35., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn's disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future.

To describe long-term CD4+ T-cell reconstitution after rabbit antithymocyte globulin (rATG) treatment and identify predictive factors following kidney transplantation. A single-center retrospective study analyzed lymphocyte subsets in rATG-treated kidney transplant recipients (1986-2009). 589 patients were analyzed (maximum follow-up 21 years). A comparator group (n=298) received an anti-IL-2 receptor monoclonal antibody. CD4+ T-cell lymphopenia (<200/mm3) was present in 48.5%, 9.2%, 6.7%,2.0%, and 0% of patients at one, three, five, 10, and 20 years post-transplant, respectively. CD4+ T-cell count increased during the first 10 years but remained below the pretransplant count even after 20 years. At 1, 3, and 6 months post-transplant, mean CD4+ T-cell count was significantly lower in patients with CD4+ T-cell lymphopenia at 12 months versus patients without lymphopenia. On multivariate analyses, significant independent predictors for long-term impaired CD4 T-cell reconstitution were recipient age, pretransplant CD4+ T-cell count, 12-month CD4+ T-cell count, and tacrolimus or MMF therapy. Recipient age>40 years was identified as a cutoff point. CD4+ T-cell reconstitution following rATG treatment remains impaired even after 21 years. Most risk factors for long-term impaired CD4+ T-cell reconstitution may be evaluated pretransplant or are modifiable post-transplant., (© 2013 The Authors Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)

Introduction: Polyclonal antithymocyte globulins (ATG) have been used in transplantation for several decades, but the sources of the interindividual variability of their effect are poorly understood. An influence of the FCGR3A-158V/F genetic polymorphism on the horse ATG concentration-effect relationship was reported in kidney transplant patients. The objective of the present study was to confirm the influence of the FCGR3A polymorphism on the extent of lymphocyte depletion in kidney transplant patients treated with rabbit antithymocyte globulin (r-ATG)., Materials and Methods: Of the 194 transplant patients treated with r-ATG between 1998 and 2002 in our institution, 69 patients were eligible and included in this retrospective study. Biomarkers of response were CD3 and CD4 counts. Dose-effect data were analyzed using a population approach, and a two-compartment turnover model with stimulation of lymphocyte 'output'. Since r-ATG concentrations were not available, a K-PD model was used. The influence of FCGR3A genotype on estimated parameters was investigated., Results: The r-ATG infusion rate leading to a 50% stimulation of CD3+ output (EDK(50)), which is inversely related to patient sensitivity to r-ATG treatment, decreased with the number of V alleles (P=0.0016)., Conclusion: The genetic polymorphism of FCGR3A influences r-ATG effect on CD3 count in kidney transplant patients, those with the V allele being more sensitive to antilymphocyte serum. These results also suggest that r-ATG act, at least in part, by antibody-dependent cellular cytotoxicity.

Rabbit antithymocyte globulin (rATG; Thymoglobulin(®)) is currently used to prevent acute rejection in kidney transplantation. The dose and regimen of rATG have not been optimized. Moreover, the impact of different treatment regimens on T-cell phenotype reconstitution remains unknown. We conducted a prospective randomized study of 17 renal transplant patients to determine the pharmacokinetics of total and active (bound to human cells) rATG and T-cell phenotype reconstitution after rATG administration. Patients received rATG at a total dose of 6mg/kg, administered either as 1.5mg/kg/day on days 0-3 (Group 1, n=8) or 3mg/kg on days 0 and 3 (Group 2, n=9). All patients received tacrolimus, mycophenolate mofetil and steroids. Blood samples were assayed for total rATG by enzyme linked immunosorbent assay and active rATG by flow cytometry. Maximum concentrations and terminal half-lives were similar between the two groups but at month 3 Group 1 had significantly lower values for total rATG (concentration was 6.2±1.1μg/mL versus 10.2±2.9μg/mL in Group 2, p=0.027) and total rATG dose-normalized AUC (374±83dayg/mL versus 508±149dayg/mL in Group 2, p=0.046). Time to sub-therapeutic levels (<1μg/mL) of active rATG was significantly shorter in Group 1 (18.75±6.9days versus 20±7.5days in Group 2, p<0.001). rATG induced significant depletion followed by slow reconstitution of CD3(+), CD4(+) and CD8(+) cells, with no marked differences between groups. B-cell count was unaffected, whereas CD3(-)CD56(+) NK-cell depletion was observed in both groups. rATG induced a significant decrease in the proportion of naïve CD4(+) T-cells, which plateaued after month 1 in Group 1 and after month 6 in Group 2. The proportion of central memory CD4(+) T-cells increased to a similar extent in both groups (Group 1: 38±18% at baseline, 74±23% at one year, p=0.009; Group 2: 32±14% at baseline, 65±14% at one year, p=0.001). In conclusion, our results suggest that the dosing regimen for rATG induction influences pharmacokinetic parameters without affecting the quality of immune reconstitution., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The rabbit antithymocyte globulin Thymoglobulin first became available over 25 yr ago and is the most widely used lymphocyte-depleting preparation in solid organ transplantation. Thymoglobulin targets a wide range of T-cell surface antigens as well as natural killer-cell antigens, B-cell antigens, plasma cell antigens, adhesion molecules and chemokine receptors, resulting in profound, long-lasting T-cell depletion. Randomized studies have established the anti-rejection efficacy of Thymoglobulin in kidney transplantation. Experimental and clinical data suggest that Thymoglobulin administration may ameliorate ischemia reperfusion injury, thus reducing the incidence of delayed graft function (DGF). Studies have demonstrated the benefit of using Thymoglobulin to facilitate immunosuppression minimization, both for corticosteroid and calcineurin inhibitor (CNI) withdrawal or avoidance, with potential improvement in cardiovascular and renal outcomes. The optimal cumulative dose for Thymoglobulin induction is 6-7.5 mg/kg, with vigilant short- and long-term monitoring of hematological status. Induction with Thymoglobulin is now indicated in immunologically high-risk patients, in those at increased risk of DGF and to maintain efficacy in low-risk transplant recipients receiving steroid or CNI minimization or avoidance regimens. We suggest that in future trials Thymoglobulin be tested with costimulation signal blockers and other immunosuppressants with the objective of establishing operational tolerance., (© 2012 John Wiley & Sons A/S.)

The more than 25 years of clinical experience with rabbit antithymocyte globulin (rATG), specifically Thymoglobulin, has transformed immunosuppression in solid organ transplantation and haematology. The utility of rATG has evolved from the treatment of allograft rejection and graft-versus-host disease to the prevention of various complications that limit the success of solid organ and stem cell transplantation. Today, rATG is being successfully incorporated into novel therapeutic regimens that seek to reduce overall toxicity and improve long-term outcomes. Clinical trials have demonstrated the efficacy and safety of rATG in recipients of various types of solid organ allografts, recipients of allogeneic stem cell transplants who are conditioned with both conventional and nonconventional regimens, and patients with aplastic anaemia. Over time, clinicians have learnt how to better balance the benefits and risks associated with rATG. Advances in the understanding of the multifaceted mechanism of action will guide research into new therapeutic areas and future applications.

Aims: Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic-pharmacodynamic (PK-PD) study of ALG is available. Moreover, the genetic polymorphism of FcgammaRIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration-effect relationship., Methods: Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration-effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A., Results: Both the PK and the PK-PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T(1/2)-alpha and T(1/2)-beta-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC(50)) was lower in FCGR3A-V carriers than in FCGR3A-F/F patients (383 +/- 199 vs. 593 +/- 209 mg l(-1), P = 0.008)., Conclusions: This is the first description of the ALG effect on lymphocyte count using PK-PD modelling. Our results show that part of the variability in their concentration-effect relationship may be explained by FcgammaRIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC.

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

Purpose: Based on the data of clinical trial CHI-F-02 comparing the efficacy and safety of basiliximab (Simulect) vs. anti-thymocyte globulin (Thymoglobulin) in renal transplant induction, we carried out an economic evaluation., Method: This pharmacoeconomic study was a cost-minimization study, i.e. given the equivalent efficacy of the products, the strategy that minimized the cost of care was considered better. The cost of care was analyzed from the hospital perspective., Material: This 'piggyback' study of 100 patients estimated the direct medical costs incurred over 6 months of use of two strategies for renal transplant induction therapy. Direct medical costs are those of utilized medical resources: medications, hospital stays, dialysis, and physician visits and investigations not scheduled in the protocol., Results: In the Simulect arm, significant reductions were found in the initial hospital stay duration and number of infectious episodes. Therefore, although the average cost of treatment was slightly higher with Simulect) than with Thymoglobulin (2964 vs. 2298 Euros), the cost of the initial hospitalization was significantly lower in the Simulect arm (10 907 vs. 11 967 Euros; p = 0.02). Furthermore the mean cost of infectious episodes was significantly lower in the Simulect arm (1056 vs. 1790 Euros, p = 0.03). Cytomegalovirus infection accounted for a significantly smaller proportion of this cost in the Simulect arm than in the Thymoglobulin arm (30% vs. 53%, p = 0.001)., Conclusion: This study showed direct medical cost savings of 1159 Euros per patient in the Simulect arm, which more than compensated for the higher price of this immunosuppressive drug.

Background: Two hundred and forty cadaveric renal transplant recipients given anti-thymocyte globulin (Thymoglobulin) as induction immunotherapy were followed up prospectively to review safety and efficacy., Methods: The median number of infusions was 10 [2-21] with a cumulative dose of 8.8 mg/kg [2.0-23.2 mg/kg]. During the fortnight following transplantation, 231 patients (96%) received a calcineurin inhibitor; all patients were given steroids and azathioprine or mycophenolate mofetil. At 1 yr, 60% of patients were on tripletherapy, 38% on bitherapy, and 2% on monotherapy; 20% had discontinued steroids., Results: Tolerance was excellent with no cases of anaphylaxis. The commonest adverse event was fever (55%). Eighteen patients developed serum sickness on median day 11 [10-14]. Seven patients had thrombocytopenia; six patients had severe neutropenia. All of these adverse events recovered spontaneously. The overall incidence of delayed graft function was 24%. At 1 yr patient and graft survival were 98 and 95%, respectively, and creatinine was 135 +/- 43 micromol/L. Clinically suspected and biopsy-proven acute rejection were observed in 65 patients (27%) and 34 patients (14%), respectively. There were 62 non-cytomegalovirus (CMV) infections (two fatal) and 81 episodes of CMV infections. Eight malignancies were reported; two possibly related to immunosuppression., Conclusions: These results demonstrate that anti-thymocyte globulin has a safety profile with good tolerability and excellent efficacy.

Background: Induction therapy with antithymocyte globulin (ATG) reduces the incidence of acute rejection after transplantation. A study was undertaken to assess the efficacy and safety of ATG induction on tacrolimus-based and cyclosporine A (CsA)-based therapies compared with immediate tacrolimus triple therapy in kidney transplant recipients., Methods: In a 6-month, open-label, randomized, prospective study conducted in 30 European centers, 555 renal transplant patients were randomly assigned to tacrolimus triple therapy (Tac triple, n=185), ATG induction with tacrolimus (ATG-Tac, n=186), or ATG induction with CsA microemulsion (ATG-CsA, n=184); all were combined with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection episode confirmed by biopsy., Results: Patient demographics and clinical parameters at baseline were similar. Patient and graft survival rates were similar in all groups. The incidence of clinically apparent acute rejection was significantly higher (P=0.003) for Tac triple (33.0%) compared with ATG-Tac (22.6%) and the incidence for ATG-Tac was significantly lower (P=0.004) than for ATG-CsA (37.0%). The incidences of acute rejection confirmed by biopsy (primary endpoint) were 25.4%, 15.1%, and 21.2% for Tac triple, ATG-Tac, and ATG-CsA, respectively (Tac triple vs. ATG-Tac, P=0.004). The incidences of corticosteroid-resistant acute rejection were 7.0% (Tac triple), 4.8% (ATG-Tac), and 10.9% (ATG-CsA) (ATG-Tac vs. ATG-CsA, P=0.038). In the ATG groups, the incidences of leukopenia, thrombocytopenia, serum sickness, fever, and cytomegalovirus infection were significantly higher (P<0.05)., Conclusions: Acute rejection was significantly lower in the ATG-Tac group compared with the ATG-CsA and Tac triple groups. Significantly more hematologic and infectious adverse events were observed in both ATG induction groups.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20mg day 0-day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin' group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a non-significant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

Background: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients., Methods: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day., Results: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction)., Conclusion: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

Adhesion molecules are involved in several steps in the immune response: leukocyte adhesion to the endothelium, transendothelial migration, cooperation between immunocompetent cells, and cytotoxicity. Leukocyte function-associated antigen-1 plays a central role among adhesion molecules. In a multicenter randomized open trial, we compared a monoclonal antibody directed against the alpha chain of LFA-1 (Oduli-momab; IMTIX/Pasteur Mérieux Sérums et Vaccins) with rabbit antithymocyte globulin (rATG; IMTIX/Pasteur Mérieux Sérums et Vaccins), as part of a quadruple sequential protocol in 101 patients receiving a first kidney transplant. Clinical tolerance of anti-LFA-1 mAb was better than that of rATG. Short-term rejection rates (< 15 days) were not significantly different (15% and 16% for anti-LFA-1 mAb and rATG, respectively). However, 11% of the anti-LFA-1 mAb patients experienced rejection during the first 10 days of the treatment course compared with none of the patients treated with rATG. The incidence and severity of acute rejection in the first 3 months was not significantly different between groups. Of the LFA-1 and rATG patients, 96% and 92% of the grafts, respectively, were functioning at 12 months. The incidence and severity of infection, whatever the origin, were comparable in both groups. In addition, it was observed that fewer patients required posttransplantation dialysis in the anti-LFA-1 mAb group (19%, vs. 35% for rATG), although the difference was not statistically significant. Altogether, the beneficial action of this monoclonal antibody on short-term renal function recovery makes it a useful tool in the management of renal patients undergoing kidney transplantation.