During the past 20 years, wider application of easily available haploidentical donor hematopoietic cell trans- plant (haplo-HCT) has been made possible through the T cell-replete (TCR) regimens including T cell regula- tion with anti-thymocyteglobulin (ATG)/granulocyte colony-stimulating factor (GCSF) and post-transplant cyclophosphamide (PTCy) [1–9]. To achieve decreased non-relapse mortality (NRM) and improved long-term outcomes in haploidentical transplant, the joint use of ATG and PTCy might effectively reduce graft-versus- host disease (GVHD) and mortality associated with se- vere forms of GVHD [10–14]. There are multiple papers using ATG/PTCy (high-dose) in patients with Fanconi anemia, aplastic anemia, and sickle cell disease . To date, the combination of conditioning regimens with low- dose ATG and high-dose PTCy after haplo-HCT [11–14] or unrelated donor (URD) HCT [15, 16] for hematological malignancies has been documented in several reports with reduced rates of GVHD and acceptable relapse rate albeit with somewhat high rates of graft failure (8%)  or de- layed engraftment . Recently, results of a prospective trial have been available which analyze the efficacy of combined use of low-dose ATG and 1-day high-dose PTCy (50 mg/kg at + 3 days) in preventing GVHD among haplo patients .
ATGAM is an anti-thymocyteglobulin that differs from thymoglobulin by being produced in horses rather than rabbits. Typically, thymoglobulin is preferred over ATGAM in the U.S. as thymoglobulin has been associated with higher event free survival  and provided signi icant cost savings of when compared to ATGAM [5,6]. We present a case of a highly sensitized transplant recipient with prior serum sickness from thymoglobulin with severe vascular rejection.
suggest the use of basiliximab is to be limited to the conditions where ATG use is not suitable or recommended. Some centers in America are known to use Alemtuzumab. Few studies tried to compare it with rabbit anti-thymocyteglobulin (rATG) especially in the population who received a simultaneous kidney and pancreas transplant, failed to draw major conclusions due to improper study designs and randomization and population but higher morbidity, mortality and graft loss was observed. Alemtuzumab and emergence of some autoimmune diseases. This effect has been attributed to memory T-cell 56 . ATG is
PCT and CRP levels were investigated in two groups of patients undergoing OLTx with different regimens of the immu- nosuppressive therapy and in one group of patients undergo- ing liver resection as a surgical control. In the first group of patients (n = 21), polyclonal antibodies against T lymphocytes were administered together with the anti-thymocyteglobulin (ATG) (9 mg/kg) (Fresenius, Fresenius Biotech GmbH, Gräfelfing, Germany) and methylprednisolone 250 mg during the anhepatic phase. Afterward, patients received a combina- tion of ATG (3 mg/kg up to postoperative day 3), cyclosporin A (7.5 mg/kg per day), and methylprednisolone. In the second group, 7 patients perioperatively received methylprednisolone 250 mg only. Subsequent therapy involved methylpred- nisolone and tacrolimus (0.1 mg/kg per day FK 506, tac- rolimus [Fujimycin] immunosuppressive drug, macrolide antibiotic). The serum levels of PCT and CRP were measured before the induction of anesthesia, in the fourth and eighth hours after graft reperfusion, and continued daily to the fourth day after surgery.
Antibody induction agents are divided into two broad categories, based on their activity on T-lymphocytes, as lymphocyte-depleting antibodies and nondepleting anti- bodies (Table 1). Lymphocyte-depleting antibodies, including rabbit anti-thymocyteglobulin (rATG), equine anti-thymocyteglobulin (eATG), monomurab-CD3 (OKT3), and alemtuzumab, are generally recommended in patients at high immunologic risk of rejection. Possible benefits of intense immunosuppression must be balanced with increased risks of infection and malignancy. On the other hand, nondepleting antibodies, including basiliximab and daclizumab, reduce the risk of acute allograft rejection with less intense adverse effects, and are typically used in patients at lower risk of acute rejection. The current Kidney Disease: Improving Global Outcomes guidelines
Anti-thymocyteglobulin (ATG) is frequently used as part of a conditioning regimen in patients scheduled for allogeneic hematopoietic stem cell transplantation. In those patients, freedom from infection before engraftment is of the utmost importance. ATG administration could be associated with sys- temic reaction, including fever and hypotension, comparable to sepsis. The ATG-induced depletion of leukocytes makes one of the key diagnostic criteria of SIRS/sepsis  useless. Thus, biochemical markers of inflammation could be beneficial to differentiate between infectious versus non-infectious com- plications in this specific population. We prospectively evalu- ated the validity of CRP and PCT to diagnose infection in
We and others have questioned whether combination therapy using drugs that have already received regulatory approval might produce a synergistic response and provide for clinically meaningful preservation of β cell function (9–11). Perhaps the most aggressive and effective combination approach in T1D to date used autologous nonmyeloablative stem cell transplantation. With a regimen of cyclo- phosphamide, autologous stem cell harvest, anti-thymocyteglobulin (ATG), stem cell infusion, granulocyte CSF (G-CSF), and intensive inpatient and outpatient support, this approach demonstrated the capacity to achieve short-term insulin independence, while simul- taneously raising questions regarding equipoise (12–16). As such, we sought to deconstruct the autologous nonmyeloablative approach, eliminate the use of cyclophosphamide, and develop a lower risk, effective combinatorial approach to preserve β cell function in T1D.
Background: Lymphoproliferative disorders are among the most serious and potentially fatal complications of chronic immunosuppression in kidney trans- plant recipients. The principle risk factors for development of PTLD are the de- gree of overall immunosuppression and the EBV serostatus of the recipient. In this study, the risk of PTLD in kidney transplant recipients who received Anti- Lymphocyte Globulin (ALG) or AntiThymocyteGlobulin (ATG) was evaluated.
Background: Allogenic hematopoietic stem cell transplantation (allo-SCT) is the most effective post-remission treatment for adults with high-risk acute lymphoblastic leukemia (ALL). The aim of the study was to analyze results of unmanipulated haploidentical allo-SCT (haplo-SCT) for adults with ALL and to identify prognostic factors. Methods: We performed a retrospective analysis on 208 adults transplanted in EBMT centers from 2007 to 2014. Results: Median age at haplo-SCT was 32 years and median follow-up, 31 months. Forty-four percent of the patients were in first complete remission (CR1). Stem cell source was the bone marrow (BM) for 43% and peripheral blood (PB) for 57% of patients. Myeloablative conditioning (MAC) was used for 66% and reduced intensity regimen (RIC) for 34% of patients. GVHD prophylaxis was based on post-transplant cyclophosphamide (PT-Cy) for 118 (57%) or on anti- thymocyte-globulin (ATG) for 90 (43%) plus standard prophylaxis. One hundred eighty-four (92%) patients achieved engraftment. Cumulative incidence (CI) of grade II – IV acute-graft-versus-host-disease (GVHD) was 31%, grade III – IV 11%, and chronic GVHD 29%. Non-relapse mortality (NRM) and relapse-incidence (RI) were 32 and 37%, respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free-survival (GRFS) at 3 years were 33, 31, and 26%. For patients in CR1, OS, LFS, and GRFS were 52, 47, and 40%, respectively. Disease status was the main factor associated with transplant outcomes. Use of BM was independently associated with improvement in NRM, acute GVHD, GRFS, LFS, and OS.
Renal transplantation is the treatment of choice for patients with end- stage renal disease, to improve both qualities of life and life expectancy. Controlling the alloimmune reaction is imperative for successful renal transplantation. The occurrence of delayed graft function (DGF) and acute rejections (AR) during the early post-transplantation period may have a negative effect on graft survival [1,2]. Patients with DGF have a greater risk of AR, and graft survival is better in those who do not have DGF or AR compared with those who have either or both . DGF has been defined as the need for dialysis within the first week after transplantation and/or a serum creatinine level, in the absence of dialysis, 250 mmol/L or more at day 10 of post-transplantation . The activation and subsequent proliferation of resting T lymphocytes is an essential factor in the development of AR episodes . Therefore, drugs that affect either T-cell activation or proliferation are used to prevent AR and DGF. Such drugs are known as induction agents. Induction therapy is administered at the time of transplantation to reduce the incidence of AR or to prevent DGF. Long-term graft survival is improved by induction therapy [1,5]. At present, 90% of renal transplant recipients is treated with induction therapy. Two types of induction agents are used as (1) lymphocytes-depleting agents and (2) interleukin-2 (IL-2) receptor antagonists (non-lymphocyte- depleting agent). Basiliximab or daclizumab, an IL-2 receptor antagonist, is used in 36.8% of renal allograft recipients, and T-cell- depleting agents such as anti-thymocyteglobulin (ATG) (lymphocyte-
There are no speci ﬁ c guidelines for the treatment of immune-related myocarditis and the recommended approach consists of immunosuppression and classical heart failure man- agement. GC are the drugs more frequently used as immuno- suppressive treatment, and they are recommended in the management of another immune-related AE. However, when patients have not achieved a successful response to GC, other medicaments are used. Anti-thymocyteglobulin (ATG) has been classically used in the prophylaxis of graft versus host disease due to its ability to deplete T lymphocytes, among others. It has been reported as an effective drug against immune-related myocarditis, like giant cell myocarditis. 26,27 For this reason, it has also been successfully used in immune- related myocarditis secondary to medication. 14,28 Indeed, in ﬂ iximab, an anti-TNF drug, has also been considered for the treatment of myocarditis related to autoimmune or infec- tious diseases. 29,30 Therefore, it has been used in some cases of myocarditis induced by ICI. 16 With patients where myocarditis is concurrent with myasthenia crisis, nonspeci ﬁ c human Igs have been utilized. 20,25
The Flu-ivBu 4 regimen is usually performed with per- ipheral blood stem cells (PBSC) to favor engraftment and enhance the graft-versus-leukemia (GVL) effect [11, 12]. However, use of PBSC from HLA-matched related (MRD) or unrelated (MUD) donors with MAC increases the risk of chronic graft-versus-host disease (cGVHD) [11 – 13]. Prospective randomized studies have shown that in vivo T cell depletion with anti-thymocyteglobulin (ATG) reduces the incidence of cGVHD without increasing the risk of re- lapse in allo-SCT performed with PBSC from MRD or MUD after conventional cyclophosphamide-based MAC regimens for AML [14 – 16]. These results raise the ques- tion of the impact of use of ATG in the Flu-ivBu4 RTC, in which the balance between the GVH and GVL effects of allo-SCT might be more sensitive to T cell depletion. Very scarce data exist on the potential effect of ATG in this transplant context. Russel et al. reported reduced non- relapse mortality (NRM) due to lower incidence of cGVHD in a retrospective study of patients transplanted with MRD after Flu-Bu-based MAC and ATG compared to conventional cyclophosphamide-based MAC without ATG but a trend towards higher relapse incidence . A Korean study comparing the outcomes of 16 patients re- ceiving Flu-ivBu for 3 or 4 days and ATG to 45 patients receiving the same type of conditioning without ATG for various hematological malignancies transplanted with MRD did not observe any benefit of adding ATG, with also concerns about its possible negative impact on
Untreated primary HLH is rapidly fatal within a few weeks . Prompt and adequate treatment is of crucial importance for a positive outcome. Th erapy should be started in all cases with high suspicion after diagnostic tests have been initiated but regardless of whether the results of all examinations have been obtained. Th e initial therapy consists of immunosuppressive and/or chemo- thera peutic agents and aims at suppressing the hyper- inﬂ ammatory component of the disease as well as eliminating activated cytotoxic lymphocytes and macro- phages. Steroids inhibit inﬂ ammation by attenuating cytokine responses and inhibiting diﬀ erentiation of dendritic cells and also have cytotoxic eﬀ ects on lympho- cytes. Cyclosporin A directly aﬀ ects CTL activation as well as macrophage function. Etoposide induces apop- tosis in lymphocytes as well as in APCs. Anti-thymocyteglobulin (ATG) directly targets T cells, whereas alemtu- zu mab, an anti-CD52 antibody, targets lymphocytes in general and APCs. Intrathecal therapy with methotrexate and steroids is targeted at central nervous system disease.
Patient and disease characteristics are summarized in Table 1. Per protocol, all patients received a TBF-MAC-based regimen. The two populations were overall homogeneous in terms of patients and disease characteristics, except for median age at transplant which was older for NTD-Haplo (44 [range, 19–66] vs. 42 [range, 18–68], p = 0.046). Most patients were in first CR (NTD-Haplo, 70% vs. SUCBT, 77% p = 0.14); median interval from diagnosis to transplant was also similar (176 vs. 194 days; p = 0.09). Cytogenetic risk groups were alike between the Haplo and SUCBT groups (p = 0.76), with intermediate risk being most prevalent (36% vs. 41%, respectively). Haplo transplantations were per- formed in more recent years (median year of transplant- ation was 2014 vs. 2011; p < 0.001). As expected, anti-thymocyteglobulin (ATG) was mostly used in SUCBT (91% vs. 29% in NTD-Haplo; p < 0.001). For SUCBT, the median dose of total nucleated cells at col- lection was 3.3 × 10 7 /kg (range, 1.7–8.4), and 80% of the patients received ≥ 2.5 × 10 7 /kg. Cord blood units were HLA matched with the recipient at a level of at least 4/6 in 68% of the cases. Among NTD-Haplo patients, 80% received bone marrow as stem cell source, and post-transplant cyclophosphamide (PTCY) was adminis- trated in 71% of the cases (Additional file 1: Table S1). Further details about transplant procedures and GvHD prophylaxis are provided in (Additional file 1: Tables S2, S3). The median follow-up was 22 (range, 1–96) and 24 (range, 1–83) months for NTD-Haplo and SUCBT, respectively.
Over the last decade, the success rate of intraportal human islet allotransplantation in nonuremic type 1 diabetic patients has significantly improved, but graft function cannot be maintained in the majority of recipients [90,93,113,151,245,256,257, 300]. The cessation of immunosuppression in recipients with failing implants has been found to result in development of human leukocyte antigen (HLA) antibodies [45,46,193]. Allosensitization was noticed in most patients in the Edmonton protocol, who received fresh or shortly incubated islet grafts prepared from one to three donors under immune therapy consisting of induction with daclizumab at each islet graft injection and maintenance therapy with sirolimus with low-dose tacrolimus. A recent report from the Collaborative Islet Transplant Registry including 303 islet graft recipients also found a significant increase in HLA class I sensitization . The present study examines whether this is also the case in our protocol in which long- term cultured islet cell grafts were prepared from 2 to 11 donors and characterized and standardized for their cellular composition. Our immunosuppression protocol consisted of anti-thymocyteglobulin (ATG) induction and maintenance therapy with mycophenolate mofetil (MMF) and calcineurin inhibitors (CNI; n=28) or sirolimus with (n=3) or without (n=4) CNI. Both the standard complement-dependent cytotoxicity (CDC) assay and a solid-phase flow-based method (Luminex) were used to detect and identify HLA antibodies. Their appearance was analyzed against characteristics of patients, grafts, and immunosuppression.
Allogeneic stem cell transplantation (SCT) remains a powerful therapeutic modality for patients with acute myeloid leukemia (AML) [1 – 8]. The superior clinical out- comes of allogeneic SCT versus chemotherapy alone as post-remission treatment could be related to the graft- versus-leukemia (GVL) effects of recovered donor T cells. Over the last 10 years, T-cell-replete haploidentical SCT (haplo-SCT), especially unmanipulated haplo-SCT with anti-thymocyteglobulin (ATG) [3, 9, 10] or with post- cyclophosphamide (PT/Cy) , is widely accepted as a viable alternative for patients without HLA-identical donors, and its outcomes may be comparable to those of HLA-identical sibling donor transplantation (MSDT) or unrelated donor transplantation (MUDT) [4, 9]. However, it remains unclear whether haplo-SCT have different anti- leukemia effects than other allografts .