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Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings. ClinicalTrials.gov NCT00548405.

Chronic GvHD (cGvHD) is the leading cause of late non-relapse mortality (NRM) and morbidity after allogeneic hematopoietic stem cell transplant (AHSCT). We analyzed the late effects of a phase II trial testing the efficacy of intermediate dose rabbit anti-thymocyte globulin (Thymoglobulin Thymo) in combination with tacrolimus and sirolimus (TTS) in 47 patients (pts) for the prevention of acute and chronic GvHD after unrelated AHSCT. The median follow-up was 45.2 months. The cumulative incidence of NIH severe cGvHD at 48 months was 6.4% with no new occurrences past 6 months for the entire follow-up period. The overall cumulative incidence of cGvHD was 44.7%. Out of 20 pts who are alive and disease-free at the last follow-up, only 4 pts continue to need systemic immune suppression. We observed low late NRM with only 3 transplant-related deaths after 6 months post transplant. At 4 years of follow-up, the overall cumulative incidence of NRM and disease relapse was 27.7% and 30.0%, respectively. PFS and overall survival (OS) at 4 years were 42 and 47%. At long term follow-up, TTS was associated with low incidence of severe cGvHD and late NRM.

Background Induction immunosuppression with anti-thymocyte globulin (ATG) provides potential benefits after liver transplantation (LT). However, its use in patients with LT and hepatitis C (HCV) is controversial. Aim To evaluate the 1- and 2-year patient survival and HCV recurrence rate in patients receiving ATG during the induction phase of immunosuppression (IPI) after LT. Methods A total of 49 patients undergoing their first LT for HCV were randomized to receive ATG during IPI. Patient survival and HCV recurrence were determined at 1 and 2 years. The frequency of acute cellular rejection (ACR), infections, and neoplasms was also evaluated. Results Twenty-six patients were randomized to receive ATG (Arm-1) and 23 to standard induction therapy (Arm-2). Those given ATG had lower HCV recurrence (26.9 vs 73.9 %, p  = 0.001). The 1- and 2-year patient survival rates were similar for both arms ( p  = 0.33). Infections occurred in 46.1 % subjects in Arm-1 and 34.7 % in Arm-2 ( p  = 0.562). There was a greater proportion of fungal infections in Arm-1 (19.2 vs 0 %, p  = 0.032). Conclusions ATG during the IPI was associated with lower frequency of recurrence of HCV in patients undergoing LT. This, however, did not affect the 1- and 2-year survival and the frequency of ACR, infections, or neoplasms.

Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin ( GTKO.hCD46.hTBM ), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications ( GTKO.hCD46.hTBM ) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days. Tweaking immune characteristics of donors and recipients could allow for successful cross-species organ transplantation. Here, the authors show that an anti-CD40 antibody therapy of baboons that received heart transplants from genetically modified pigs is key to their long-term survival.

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation. The use of CTLA4-Ig fusion proteins in transplantation remains limited due to co-stimulation blockade-resistant rejection (CBRR). In this study, the authors demonstrate that IL-6 blockade reduces CBRR in murine cardiac transplants in the context of T cell-depleting induction regimens and CTLA4-Ig treatment.

Background and Objectives To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin ® , a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin ® as a first step towards an evidence-based dosing regimen of Thymoglobulin ® in pediatric HCT. Methods Serum active Thymoglobulin ® concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM ® version 7.2. Results A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin ® dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin ® was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin ® infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/or a lower lymphocyte count pre-Thymoglobulin ® infusion. Conclusion This model can be used to develop an individual dosing regimen for Thymoglobulin ® , based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT.

In this study, we aimed to compare the engraftment days, graft-versus-host disease (GVHD) development, relapse and overall survival rates in patients using myeloablative/reduced intensity conditioning regimens with posttransplant cyclophosphamide (PTCy) 25 mg/kg x2 with Anti-T lymphocyte Globulin (ATLG) ( n  = 29) and PTCy 50 mg/kg x2 doses ( n  = 41) in patients with acute leukemias. Matched related, matched unrelated, 1 mismatched unrelated, and haploidentical donors were selected for the patients. Platelet (median 11 vs 17 days) and neutrophil (median 14 vs 15 days) engraftment times were shorter in ATLG+ PTCy25 treated patients (both p  < 0.05); veno-occlusive disease rates, graft failure and poor graft functions were similar between the two approaches (all p  > 0.05); cumulative incidences of grade II-IV aGVHD at +100 days, grade III-IV aGVHD at +100 days, and grade II-IV cGVHD at 1-year were comparable between ATLG+PTCy25 and PTCy50 groups (all p  > 0.05). Cumulative incidences of relapse and non-relapse mortality at 1-year were similar in two cohorts (both p  > 0.05). PTCy50 was associated with a statistically significant benefit in terms of GVHD-free/relapse-free survival (GRFS) at 1-year ( p  = 0.03). Median GRFS was 115 (95% CI: 42–214) days and 248 (95% CI: 151-not reached) days, respectively [HR was 0.51 (0.28–0.95), p  = 0.03; GRFS at 1-year was 20.7% vs 44.3%, respectively]. However, the groups were comparable in terms of PFS and OS. Median PFS was 332 days (95% CI: 182 days-not reached) for ATLG+PTCy25 group. It was not reached (95% CI: 210 days-not reached) for the patients who received PTCy50. Median OS was not reached in either ATLG+PTCy25 (95% CI: 191 days-not reached) or PTCy50 groups (Log rank = 0.42). Our study showed that lowering PTCy dose with ATLG seems to accelerate platelet and neutrophil engraftment rates; confers similar survival and relapse rates, similar acute and chronic GVHD frequency despite increased GRFS at 1-year.

Post-transplantation cyclophosphamide (PTCy) has unique advantages for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single-center retrospective landmark analysis, we evaluated chronic GVHD (cGVHD) and clinical outcomes in patients receiving PTCy, tacrolimus, and post-engraftment low-dose anti-thymocyte globulin (PTCy-ATG) as GVHD prophylaxis after HLA-matched unrelated or haploidentical donor transplantation. Two historical patient groups receiving calcineurin inhibitor-based GVHD prophylaxis were used as control groups. A total of 71 patients with myeloid malignancies undergoing allo-HSCT with myeloablative conditioning regimens were included in the analysis. The 3-year cumulative incidences of cGVHD and moderate to severe cGVHD (M/S cGVHD) were 39.2% (95%CI 27.4%–51.0%) and 11.5% (95%CI 4.1%–18.9%), respectively, in the PTCy-ATG group, and only one instance of bronchiolitis obliterans (BO) was observed. The disease-free survival (DFS), overall survival (OS), and GVHD-free and relapse-free survival rates were 94.0% (95%CI 88.3%–99.7%), 93.0% (95%CI 87.1%–98.9%) and 83.8% (95%CI 75.0%–92.6%) respectively. Of note, the PTCy-ATG group presented with a significantly lower incidence of M/S cGVHD and BO, which translated into superior OS in multivariate analysis. In this retrospective analysis, we observed that PTCy-ATG–based GVHD prophylaxis was associated with a lower incidence of M/S cGVHD and better transplantation outcomes beyond day 100, which invites prospective evaluation.

The Japanese monkey has been used in several animal studies; however, its potential as a recipient model for xenotransplantation is unclear. The potential of the Japanese monkey as a recipient for xenotransplantation was assessed using two experimental models. The first model evaluated the optimal dose of tacrolimus without severe adverse events. The plasma tacrolimus levels, blood counts, and hepatic and renal function tests were evaluated. The second model assessed the immunosuppressive effects of thymoglobulin and tacrolimus. Immunosuppression was evaluated using blood counts and flow cytometry to measure lymphocytes in peripheral blood mononuclear cells (PBMCs). In the first model, the target trough level (10–15 ng/ml) was achieved and maintained with tacrolimus administration at 1.6 mg/kg/day in all monkeys. There were no adverse events related to the blood count or to liver, kidney, or nutrient parameters at this dose, except for hemoglobin. In the second model, a decrease in white blood cells was observed. Flow cytometry revealed a temporary decrease in T- and B-cell numbers among PBMCs on day 4. We consider that the Japanese monkey is acceptable to be used as a recipient model for preclinical xenotransplantation. The safe administration of tacrolimus and thymoglobulin is clarified for this model. Graphical Abstract

Although post-transplant cyclophosphamide (PTCy) is widely used to prevent graft-versus-host disease (GVHD), its protective effect remains inadequate in patients undergoing myeloablative haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). We retrospectively evaluated the efficacy of PTCy combined with either pre-transplant or post-transplant antithymocyte globulin (ATG) for GVHD prevention in 114 haplo-PBSCT recipients. The PTCy+FTATG group (n = 74) received ATG at a total dose of 5 mg/kg on days -3 to -1, together with PTCy at 25 mg/kg on days +3 and +4. The PTCy+PTATG group (n = 40) received PTCy at 50 mg/kg on days +3 and +4, followed by ATG at 2.5 mg/kg on day +8. Both univariate and multivariate analyses showed that PTCy+FTATG prophylaxis significantly lowered the risk of grade II-IV acute GVHD (9.5% vs 27.5% [HR 0.24; 95% CI: 0.10-0.59; = 0.002]) and grade III-IV acute GVHD (5.4% vs 17.5% [HR 0.19; 95% CI: 0.07-0.54; = 0.002]). The 2-year cumulative incidence of chronic GVHD was 16.7% in the PTCy+FTATG group and 27.5% in the PTCy+PTATG group ( = 0.15). At 2 years, overall survival (OS), progression-free survival (PFS), and graft-versus-host disease-free relapse-free survival (GRFS) were 87.8% vs 72.5% ( = 0.04), 82.2% vs 65.0% ( = 0.03), and 78.1% vs 55.0% ( = 0.005), respectively. These results suggest that half-dose PTCy combined with low-dose pre-transplant ATG may be a promising strategy for GVHD prophylaxis.