Selective T-cell Research Articles

CD28 Blockade Ex Vivo Induces Alloantigen-Specific Immune Tolerance but Preserves T-Cell Pathogen Reactivity.

Donor T-cells contribute to reconstitution of protective immunity after allogeneic hematopoietic stem cell transplantation (HSCT) but must acquire specific tolerance against recipient alloantigens to avoid life-threatening graft-versus-host disease (GvHD). Systemic immunosuppressive drugs may abrogate severe GvHD, but this also impedes memory responses to invading pathogens. Here, we tested whether ex vivo blockade of CD28 co-stimulation can enable selective T-cell tolerization to alloantigens by facilitating CD80/86-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling. Treatment of human allogeneic dendritic cell/T-cell co-cultures with a human CD28 blocking antibody fragment (α-huCD28) significantly abrogated subsequent allospecific immune responses, seen by decreased T-cell proliferation and of type 1 cytokine (IFN-γ and IL-2) expression. Allo-tolerization persisted after discontinuation of CD28 blockade and secondary alloantigen stimulation, as confirmed by enhanced CTLA-4 and PD-1 immune checkpoint signaling. However, T-cells retained reactivity to pathogens, supported by clonotyping of neo-primed and cross-reactive T-cells specific for Candida albicans or third-party antigens using deep sequencing analysis. In an MHC-mismatched murine model, we tolerized C57BL/6 T-cells by ex vivo exposure to a murine single chain Fv specific for CD28 (α-muCD28). Infusion of these cells, after α-muCD28 washout, into bone marrow-transplanted BALB/c mice caused allo-tolerance and did not induce GvHD-associated hepatic pathology. We conclude that selective CD28 blockade ex vivo can allow the generation of stably allo-tolerized T-cells that in turn do not induce graft-versus-host reactions while maintaining pathogen reactivity. Hence, CD28 co-stimulation blockade of donor T-cells may be a useful therapeutic approach to support the immune system after HSCT.

Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation

T cells undergo metabolic reprogramming with major changes in cellular energy metabolism during activation. In patients with mitochondrial disease, clinical data were marked by frequent infections and immunodeficiency, prompting us to explore the consequences of oxidative phosphorylation dysfunction in Tcells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, we created a mouse model with isolated dysfunction in Tcells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation invitro and immunodeficiency invivo. Select Tcell effector subsets were particularly affected; this could be traced to their bioenergetic requirements. In summary, the findings presented herein emphasize the role of COX particularly in Tcells as a metabolic checkpoint for cell fate decisions following Tcell activation, with heterogeneous effects in Tcell subsets. In addition, our studies highlight theutility of translational models that recapitulate human mitochondrial disease for understanding immunometabolism.

Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis

ObjectivesTo assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA).MethodsThis study randomised patients (1:1) with active PsA (~60%...

Fulminant Myocarditis with Combination Immune Checkpoint Blockade

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell–driven drug reaction. (Funded by Vanderbilt–Ingram Cancer Center Ambassadors and others.)

Immune Modulation in Children. A South African Perspective

Immune deficiencies in South Africa can be divided into two categories, i.e. primary immune deficiencies or secondary due to illnesses such as malignancies or infection e.g. the human immune virus (HIV). In the private pediatric clinical setting, children of-ten present with illnesses that can be traced to selective secondary immune deficiencies. Although highly effective, not all children are eligible for intravenous immunoglobulin therapy, either due to costs or non-IgG related immune deficiencies such as selective IgA or T-cell deficiencies. Intramuscular and subdermal immunoglobulin options are equally expensive and uncomfortable. The use of oral immune modulators, such as the erythromycin derivatives, has raised some concern, mainly because of the potential risk of bacterial resistance. Other so called immune boosters, e.g. Echinacea’s, are being advertised as potential solutions but have yet to prove to be efficient. In addition to this, the interaction between the gut micro-biome and the immune system is complex, but critical in maintaining and optimizing the immune system. Under certain disease entities such as inflammatory bowel disease, resulting in a leaky gut, the immune system becomes compromised because of the interaction between certain inflammatory signals and the lymphoid and bone marrow tissue specifically the naive and memory T-cell populations, such as CD4 and CD8 lymphocytes. An overview to immune modulation will be presented that has a direct beneficial effect on the health outcome of the children and new therapeutic modalities will be evaluated in terms of their response and restoration of the T-cell populations.

Partial T-Cell Depletion By Low-Dose Anti-Thymocyte Globulin to Reduce Severe Acute and Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Background: T cells from a stem cell source are inevitably contaminated, and over 5.0×104/kg T cells are thought to induce graft-versus-host disease (GVHD) in HLA-mismatched or haplo-identical stem cell transplantations (SCTs) [4]. To suppress GVHD reactions, a procedure for T-cell depletion (TCD) was developed over the past several decades, especially for HLA-mismatched and haplo-identical SCTs, which are at high risk for GVHD. To reduce the incidence of GVHD, a potentially effective agent is anti-thymocyte globulin (ATG), which is generally administered at a dose of ≥ 5-10 mg/kg. Based on data regarding the use of ATG for the treatment of aplastic anemia, we hypothesized that ATG might accommodate engraftment and inhibit GVHD. We attempted to use a lower dose of ATG to decrease non-relapse mortality (NRM) in Japanese patients undergoing an HLA-matched SCT.Patients and method: We treated patients with hematological diseases who underwent an allogeneic SCT after March 2010 without or with 2.5 mg/kg ATG. The inclusion criteria for underlying disease included both hematological malignancies and bone marrow failures. All consecutive patients transplanted from an allogeneic related or unrelated donor were included. Cord blood transplantations were omitted from this analysis. The patients who underwent an SCT before February 2010 (n=20) were examined as the control group without ATG treatment. ATG was administered 1 day prior to the transplantation day at 2.5 mg/kg with 500 mg/body methylpredonisolone as a preconditioning procedure. GVHD prophylaxis, tacrolimus 0.03 mg/kg and short-term MTX (10-7-7 mg/m2) was adapted for both the ATG group and the control group.Results: Thirty-nine (21 male, 18 female) recipients were recruited (median age 49 yrs, range 19-64 yrs). Their underlying diseases were acute myeloid leukemia (n=14), acute lymphoblastic leukemia (n=10), myelodysplastic syndrome (n=5), lymphoma (n=7), and myeloma, aplastic anemia, and other malignancy (n=1 each). Preparation regimens were myeloablative for 17 patients (14 cyclophosphamide [CY]/total body irradiation [TBI], two busulfan [BU]/CY, and another) and non-myeloablative for the other 22 patients (14 fludarabine/melphalan [Flu/Mel] and eight Flu/BU). All but one patient achieved engraftment, and one secondary graft failure was observed. The overall incidences of acute and chronic GVHD were 63.2% and 15.8% for the ATG-treated patients (40.0% and 25.0% for the control cohort), respectively. Acute GVHD (grades II to IV and III to IV) in the recipients who received ATG occurred in 21.1% and 0.0% (control cohort, 10.0% and 5.0%), respectively. The estimated probability of overall survival (OS) 2.5 yrs after transplantation was 77.8% for the ATG group (controls, 57.1%). The relapse rate 2.5 yrs after transplantation was 21.1% and 20.0% in the ATG and control groups, respectively. The NRM rate was decreased after ATG treatment: 25.0% vs. 10.5% (not significant). The causes of mortality with or without ATG were recurrent diseases (n=1 and 2), infection (n=1 and 0), and adverse events caused by transplant-related complication (n=1 and 5), respectively. No deaths due to acute or chronic GVHD occurred.Discussion: Low-dose ATG could suppress the incidence of severe acute GVHD and chronic GVHD without increasing the NRM, although our study design did not have enough power to make a conclusion about the efficacy of low-dose ATG. However, partial T-cell depletion may be effective for HLA-matched SCT recipients. Our results show that ATG at 2.5 mg/kg can be used safely for the Japanese transplant population of HLA-matched donors. Low-dose ATG is a potential treatment to partially disempower T cells from a stem cell source, which are inevitably contaminated. Recent developments in the prophylaxis for GVHD, such as selective cytotoxic T-cell depletion by using a post-transplant CY regimen, are promising strategies to fully suppress T cells as the GVHD enhancer. Previous studies revealed the clinical efficacy of GVHD prophylaxis but did not clarify the significance of its survival benefit. Likewise, our present findings indicated a lack of survival benefit by ATG treatment in this small study. However, the low-dose ATG contributed to a reduction of severe GVHD. Although early mortality after transplantation is decreasing, late-onset comorbidity including chronic GVHD remains a significant problem. DisclosuresNo relevant conflicts of interest to declare.

Children with Acute Leukemia Given Hematopoietic Stem Cell Transplantation (HSCT) from an HLA-Compatible Sibling, or an Unrelated Donor (UD) or an HLA-Haploidentical Relative after Alpha/Beta T-Cell Depletion Have a Comparable Outcome

Background: Allogeneic HSCT is a widely used treatment for children with acute leukemia (AL) either relapsed or at high risk of treatment failure. However, an HLA-identical sibling is available for only 20-25% of patients and an UD can be located in a suitable time only for a portion of the remaining population. HSCT from an HLA-haploidentical relative (haplo-HSCT) is now considered an alternative option, especially in view of the recent insights in graft manipulation. We recently developed a novel method of more selective T-cell depletion based on physical elimination of α/β T cells (ClinicalTrial.gov identifier: NCT01810120), shown to be effective for both preventing graft-versus-host disease (GvHD) and for conferring improved protection against infections in comparison to haplo-HSCT performed through the infusion of positively selected CD34+ cells. The initial results on 40 patients with AL were reported at the ASH Meeting in 2013 (Bertaina et al). We now present the comparison of the outcome of 80 children with AL given haplo-HSCT after α/β T-cell depletion (group 1) with that of patients transplanted from an HLA-identical sibling (group 2) or an UD (group 3) in the same time period.Patients and methods: All patients with AL were transplanted at the Bambino Gesù Children's Hospital in Rome, Italy, between December 2010 and September 2014; 80 patients were included in group 1, 41 in group 2 and 51 in group 3. Patients were offered α/β T-cell-depleted haplo-HSCT in the absence of suitable conventional donor (HLA identical sibling or 10/10 UD evaluated using high resolution typing) or if affected by rapidly progressive disease not permitting time to identify an UD. Clinical characteristics of patients assigned to the 3 groups and those of their donor are shown in Table1. All children were given a fully myeloablative regimen. No group 1 patient was given any post-transplantation GvHD prophylaxis, while patients of group 2 and 3 were given Cyclosporine-A and short-term methotrexate. Group 1 and 3 patients received ATG Fresenius® (4 mg/Kg/day) from day -5 to -3 for preventing both graft rejection and GvHD.Results: All group 2 and 3 patients had sustained engraftment of donor cells, while 1 of the 80 patients included in group 1 experienced primary graft failure and was rescued by haplo-HSCT from the other parent. The cumulative incidence (CI) of acute GvHD was 30%, 41% and 42%, respectively. Remarkably, all children of the group 1 who developed acute GvHD had a skin-only involvement, while 17% and 16.3% of those of group 2 and 3 had either gut or liver involvement (p<0.001). The CI of chronic GvHD was significantly lower in group 1 children than in those of groups 2 and 3 (p=0.02, see also Figure 1-Panel A). None of the 4 group 1 patients experiencing chronic GvHD had the extensive form of the disease, while the CI of extensive chronic GvHD of group 2 and 3 was 8% and 14%, respectively (p=0.01). Four, 1 and 6 children of patients assigned in group 1, 2 and 3, respectively, died for transplant-related causes; the CI of transplantation-related mortality (TRM) in the 3 groups is shown in Figure 1-Panel B. Relapse was the main cause of treatment failure and occurred at a comparable CI in all the 3 groups (see also Panel C of Figure 1). The 3-year probability of Event-Free Survival (EFS) was comparable in the 3 groups (Figure 1 - Panel D). In multivariate analysis, a Total Body Irradiation (TBI)-containing regimen was the only variable favourably influencing EFS of group 1 children (hazard ratio 2.93, 95% Confidence Interval 1.24-6.95). No variable influenced EFS of group 2 and 3 patients.Conclusions: Overall, these data indicate that haplo-HSCT after α/β T-cell depletion is associated with a risk of TRM and leukemia recurrence comparable to that of transplantation from an HLA-identical sibling or an UD, this translating in a similar probability of EFS. In view of the low incidence of chronic GvHD, this transplant option has to be considered a competitive alternative for children with AL in need of an allograft.TableSibling (n=41)MUD (n=51)Haplo (n=80)Sexp=0.77M273255F141925Age at Transplantation (years)10.69.49.7p=0.20Diseasep=0.23ALL343556AML71624Disease status at Transplantationp=0.13CR1203030CR2212047≥CR3013CMV serology (Donor/Recipient)p=0.001neg/neg856neg/pos8217pos/neg1411pos/pos242156Source of Stem Cellsp<0.0001BM40400PBSC11180Conditioning regimensp=0.10TBI-based262960non TBI-based152220 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

BPX-501 Cells (donor T cells transduced with iC9 suicide gene) Are Able to Clear Life-Threatening Viral Infections in Children with Primary Immune Deficiencies Given Alpha/Beta T-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT)

Background: T-cell depleted haplo-HSCT is an established treatment for children with primary immune deficiencies (PID). However, children given this type of allograft are exposed to the risk of fatal events due to viral infections because of the prolonged impairment of adaptive immunity. We recently developed a novel method of selective T-cell depletion based on physical elimination of α/β T cells (ClinicalTrial.gov identifier: NCT01810120), which was shown to be safe and more effective than transplantation of positively-selected CD34+ cells for preventing life-threatening infections. However, we recorded some severe and even fatal viral infections, which prompted us to explore innovative approaches to accelerate the recovery of adaptive immunity. For this purpose, we designed an ongoing phase I/II trial aimed at testing the safety and the efficacy of post-transplant infusion of BPX-501 cells in children with malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). We report 3 cases of children with either severe combined immune deficiency (SCID) or Wiskott-Aldrich syndrome (WAS), who were enrolled in the dose escalation phase of the study and who cleared cytomegalovirus (CMV) or Adenovirus (AdV) infections likely due to the contribution of the BPX-501 cells.Patients and methods: Patient #1, affected by SCID, was transplanted from the HLA-haploidentical father. Before transplantation she had CMV-DNAemia which was treated with ganciclovir until donor stem cell infusion. She was given 2.5 x 105/kg BPX-501 cells on day 17 after transplantation. Patient #2, also affected by SCID, was transplanted from the HLA-haploidentical mother. Before transplantation she had AdV-DNAemia and high load of the virus in stools. She was given 5 x 105/kg BPX-501 cells on day 15 after transplantation. Patient #3 was affected by WAS and referred to the transplant unit; in the months preceding haplo-HSCT the child had developed CMV retinitis and hepatitis with high levels of CMV-DNAemia. This patient was transplanted from the father and received 1 x 106/kg BPX-501 cells on day 15 after haplo-HSCT. Basic phenotype of circulating lymphocytes was assessed by flow cytometry on fresh heparinized peripheral blood samples at 10, 20, 30, 60, 90, 120 and 150 days post haplo-HSCT, respectively. Since BPX-501 cells are CD3+/CD19+, it was easy to track the presence of these genetically modified cells. CMV specific reconstitution was also monitored through the INF gamma ELISPOT assay. In particular, peripheral blood mononuclear cells were stimulated for 16hrs in the presence of peptide libraries derived from pp65, IE1 and IE2 CMV-specific antigens.Results: The increase in the number of both CD3+ T lymphocytes and BPX-501 cells over time after transplantation together with the modifications of DNAemia of both CMV and AdV in the 3 patients are reported in Panel A, B and C, respectively, of Figure 1. In all of these patients, the pre-existing viral infection was progressively cleared once the BPX-501 cells were infused. These cells expanded in vivo and are still persisting, contributing to the recovery of adoptive immunity. The median time to reach an absolute number of α/β CD3+ cells greater than 0.5x109/L was 90, 90 and 30 days, respectively. None of these patients experienced either acute or chronic Graft-versus-Host Disease (GvHD) and no organ inflammatory-related toxicity was recorded. All children are alive and disease free, without infections, at day +200, +180 and +160, respectively. The 2 patients with CMV infection showed a specific response for at least one CMV-derived antigen; indeed, one patient showed a prevalence in pp65 response, whereas in the second one, we observed a specific anti-CMV response against all three tested antigens (Figure 1 - Panel D).Conclusions: Infusion of BPX-501 cells is able to accelerate the recovery of adaptive T-cell immunity in children with PID given haplo-HSCT after depletion of α/β T cells, thus rendering the procedure safer even in children with active infections at time of transplantation. These cells, once infused, expand in vivo and persist over time, contributing to the clearance of viral infections, without inducing GvHD. [Display omitted] DisclosuresMoseley:Bellicum Pharmaceuticals: Employment, Equity Ownership.

PP-107 CYTOMEGALOVIRUS REACTIVATION RATES AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION: SINGLE CENTER EXPERIENCE

Hemopoietic stem cell transplantation (HSCT) is a standard procedure for treatment of malignant and non-malignant hematological diseases. HSCT donors include HLA-identical siblings, matched or mismatched unrelated donors and haploidentical related donors. Graft-versus-host disease (GvHD), mediated by donor alloreactive T-cells in the graft, can be triggered by minor histocompatibility antigens in HLA-identical pairs, by alleles at loci not considered for MUD-matching or by the mismatched haplotype in haplo-HSCT. Therefore, removal of donor T-cells, that contain the alloreactive precursors, is required, but T-cell depletion associates with opportunistic infections and with reduced graft-versus-leukemia effect. Selective T-cell depletion strategies have been introduced, like removal of αβ T-lymphocytes and of naive T-cells, two subsets including the alloreactive precursors, but the ultimate goal is specific removal of alloreactive T-cells. Here we review the different approaches to deplete alloreactive T-cells only and discuss pros and cons, specificity, efficiency and efficacy. Combinations of different methods and innovative approaches are also proposed for depleting specific alloreactive T-cells with high efficiency.

Histological Evidence of Recurrent Type 1 DM or De-Novo Type 2 DM in Whole Pancreas Transplants With Late Loss of Function: Report of 4 Cases.

The most common indication for pancreas transplantation is Type 1 diabetes mellitus(DM). Recurrence of this disorder with selective T-cell mediated destruction of β cells has been reported. Changes consistent with Type 2 DM (amyloid deposition) have occurred in rare cases of islet transplantation. A proportion of recipients develop hyperglycemia despite receiving a technically successful graft. Occasionally progressive hyperglycemia develops after several years of excellent graft function. Management of pancreas allografts is based mostly on clinical findings (and renal biopsy in SPKs) with histological evaluation of the pancreas itself done only rarely. Thus, histological correlates of hyperglycemia and overall graft failure, are often unavailable. We retrospectively performed Congo red stain for amyloid, and Insulin and Glucagon stains for β and α islet cells, respectively in samples from patients with hyperglycemia received between 2000 and 2013 (152 pancreas biopsies and 33 pancreatectomies). Islet pathology that could explain the graft failure (independent of acute or chronic rejection) was identified in 2 biopsies and 2 pancreatectomies from 4 patients summarized in table 1. There was no fibrosis/parenchymal atrophy.Table: No Caption available.Primary islet disease may represent the main cause of graft loss in pancreas transplantation. The incidence of recurrent Type 1 DM is considered to be low but this has not been studied systematically. Similarly, the occurrence of de-novo Type 2 DM changes, described here for the first time in whole pancreas transplants has not been studied. Systematic evaluation of histological samples is necessary for accurate determination of the cause of graft loss in pancreas transplants.

Advances in subcutaneous immunotherapy

Current limitations in subcutaneous immunotherapy (SCIT) include the length of time required to achieve tolerance as well as the potential for systemic side-effects. Advances in allergen immunotherapy include targeted therapies to B-cell and T-cell pathways that can lead to more rapid desensitization and potentially the prevention of allergic disease. Novel molecularly engineered compounds and delivery vehicles allow for rapid and efficient desensitization. Combination with immune modifiers, treatment with epitope-based compounds, and hypoallergenic recombinant vaccines have the potential to improve immunogenicity while limiting systemic side-effects. Advances in SCIT create new therapeutic opportunities for patients to improve safety, efficacy, and compliance. Concepts using epitope-based immunotherapy and carrier-fusion peptides have the potential to induce tolerance quickly via selective B-cell and T-cell pathways.

The Pharmacokinetics and Pharmacodynamics of TOL101, a Murine IgM Anti-Human αβ T Cell Receptor Antibody, in Renal Transplant Patients

TOL101 is a highly selective murine anti-αβ Tcell receptor (TCR) IgM antibody and has recently completed phaseII testing in primary renal transplant patients. This study was undertaken to determine the pharmacokinetic, pharmacodynamic, and immunogenic profile of TOL101. Nine cohorts of two to six patients received at least five daily doses (of, or combination of, 0.28, 1.4, 7, 14, 28, or 42mg) of TOL-101 administered at successively higher doses. Semi-logarithmic graphs of serum TOL101 concentration versus time supported the use of a one-compartment intravenous infusion pharmacokinetic model. The model was parameterized in terms of serum clearance (CL) and volume of distribution (V d). There was a trend toward a decrease in serum CL as the dose increased from 1.4 to 28mg. However, the mean values for CL and V d were consistent across the cohorts that received 28, 32, and 42mg. The mean±standard deviation half-lives for these five cohorts ranged from 15.1±7.35 to 28.6±8.46h, with an overall mean of 23.8h, supporting both daily as well as fixed (i.e., not based on weight) dosing. Using CD3+ ≤25cells/mm(3) as the primary pharmacodynamic marker, all non-responders were in the 0.28, 1.4, or 7mg cohorts, suggesting that starting doses above 14mg are required. Finally, one patient out of 36 was found to have anti-drug antibody. Together, the data show that while TOL101 is a highly potent anti-TCR antibody, its pharmacological profile is somewhat versatile, allowing for daily dosing without immunogenicity concerns.

Naïve subset develops the most important alloreactive response among human CD4+T lymphocytes in Human Leukocyte Antigen‐identical related setting

In longitudinal clinical studies, receiving a high percentage of allogeneic donor-derived CD4(+) CCR7(+) T cells, which include naïve and central memory subsets have been correlated with increased incidence and severity of acute GVHD. Whether naïve and central memory CD4(+) T-cell subsets contribute more or equally to alloimmune responses are still unclear in human. The aim of this study was to investigate in vitro the alloreactive response of purified naïve, central memory, and effector memory CD4(+) T-cell subsets in HLA identical setting. By coculturing monocyte-derived dendritic cells and purified CD4(+) T-cell subsets, from healthy HLA-identical male and female sibling pairs, we found that naïve CD4(+) CCR7(+) CD45RA(+) T cells developed the highest proliferative response upon stimulation by minor histocompatibility antigens and were progressively driven to produce high levels of interferon-γ, tumor necrosis factor, and interleukin-6. Comparatively, the central memory CD4(+) CCR7(+) CD45RA(neg) subset proliferated to a lower extent and produced very low amounts of pro-inflammatory cytokines while the CCR7(neg) effector memory CD4(+) subset was unresponsive. This study demonstrates the superior capacity of naïve CD4(+) T cells to mount a primary alloreactive response as compared to central memory T cells. Their proliferative response associated with a pro-inflammatory differentiation makes them potentially acute GVHD inducers. These in vitro results in line with what we have observed in clinical studies and may also lend support to approaches of partial selective T-cell depletion for GVHD prevention.

アザプロペランおよびスピロ環骨格を有する(&amp;minus;)-Actumineの全合成

(−)-Actumine A is a tetracyclic alkaloid isolated from the roots of Sinomenium acutum. (−)-Actumine A possesses selective T-cell cytotoxicity, antiamnesic activity, and characteristic aza-propellane core and spirocycle structure. In this review, total syntheses of (−)-actumine A are described, focusing on the construction of above-mentioned structure.

Mesangial immunoglobulin (Ig)A glomerulonephritis in a patient with rheumatoid arthritis treated with abatacept

We report observations of a 47-year-old seropositive woman with rheumatoid arthritis (RA) suffering from mesangial immunoglobulin (Ig)A glomerulonephritis (GN) after initiation of abatacept, a selective T-cell co-stimulation modulator cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig. She was initially treated by corticosteroids, followed by methotrexate associated with a TNF inhibitor (adalimumab then switched to etanercept), finally switched to abatacept monotherapy, after secondary failure of these two forms of TNF inhibitors. Due to a progressively increased hematuria and proteinuria after abatacept therapy initiation, a renal biopsy was performed highlighting GN with mesangial IgA deposits, with necrosis and extracapillary crescent formations. IgA GN as a possible adverse event to abatacept was considered. Abatacept was stopped and a treatment by corticosteroids was initiated. Proteinuria decreased a couple of months after abatacept interruption. The short term between abatacept induction and IgA GN onset, as well as GN improvement since abatacept discontinuation, lend weight to the argument that CTLA4-Ig may play a crucial role in IgA GN pathogenesis. The possibility of a drug postponed adverse event justifies a long-term renal surveillance in RA patients treated by abatacept.

AB0553 Switching from SC to IV abatacept: Pharmacokinetic simulations to support dose regimen

BackgroundAbatacept (ABA) is a selective T-cell co-stimulation modulator approved in the US for RA, available in both IV and SC formulations. There is a need to establish a safe and...

Incidence of posttransplantation lymphoproliferative disorder (PTLD) following allogeneic blood or marrow transplantation (alloBMT) using post-transplantation cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis.

7009 Background: Immunosuppression to prevent graft rejection and GVHD is associated with an increased incidence of PTLD in the first year after alloBMT. AlloBMTs using partially HLA-mismatched or unrelated donor grafts, particularly when coupled with selective T-cell depletion approaches and/or anti-thymocyte globulin therapy, are associated with PTLD rates of 4-8%. The incidence of PTLD after umbilical cord blood alloBMT ranges from 2-7%. We evaluated the incidence of PTLD associated with the use of PT-Cy as GVHD prophylaxis at Johns Hopkins Hospital. Methods: After IRB approval, the Blood and Marrow Transplant Research database was queried for adult patients (age &gt; 18) who received PT-Cy as GVHD prophylaxis. Medical records from the first year after alloBMT, including clinical notes, pathology reports, and laboratory assays for Epstein-Barr virus (EBV), were reviewed. Results: From 2000-2011, 765 alloBMT patients received PT-Cy (50 mg/kg/day on days 3 and 4 after alloBMT) as GVHD prophylaxis. Of these, 734 patients had 1-year follow-up or death. In patients receiving myeloablative conditioning and HLA-matched grafts (n=289, 117 unrelated donors), PT-Cy was the sole GVHD prophylaxis. Other patients undergoing alloBMT received mycophenolate mofetil and tacrolimus in addition to PT-Cy. These included recipients of HLA-matched (n=63) or haploidentical (n=352) grafts who were conditioned with reduced intensity regimens, as well as recipients of HLA-haploidentical grafts who received myeloablative regimens (n=30). Forty-one patients with CD20(+) tumors received rituximab after alloBMT as part of a clinical protocol. There were no cases of PTLD. Conclusions: The absence of PTLD in this series, even among high-risk recipients of haploidentical or unrelated donor grafts, suggests that PT-Cy is less associated with PTLD than other GVHD prophylaxis strategies. We hypothesize that multiple mechanisms may account for the lack of PTLD with PT-Cy, including destruction of B cells that harbor EBV, sparing of EBV-specific memory T cells, and rapid immune reconstitution.

Actualités thérapeutiques : l’abiratérone, le bélatacept, le vandétanib et la fidaxomycine

Among the 35 new molecular entities approved by the FDA in 2011, 17 were particularly notable for their significant contributions to the health of patients, including abiraterone acetate, vandetanib, belatacept and fidaxomicin. Thus, abiraterone acetate, namely Zytiga®, was included as the first in a new class of drugs to treat late-stage prostate cancer. The ability of Zytiga® to prolong survival in these patients was considered as significant because they have few other treatments options and the benefits of Zytiga® outweighed the risks of reported side-effects. Vandetanib, namely Caprelsa®, was also considered as a relevant drug since it represents the first drug approved to treat particularly aggressive medullary thyroid cancer, an orphan disease. Despite huge progress in transplantation, renal transplantation remains a serious problem since patients treated with the calcineurin inhibitors cyclosporine and tacrolimus are at high risk of developing renal injury. With longer follow-up, the novel immunosuppressant belatacept continued to show better renal function compared with a cyclosporine-based regimen, as well as a consistent safety profile and comparable efficacy. It was approved by the Food and Drug Administration in June 2011 for the prophylaxis of organ rejection in adult recipients of a kidney transplant acting by a selective T-cell costimulation blocker given as an infusion. Clostridium difficile is currently the most important cause of infectious diarrhea in the United States. Fidaxomicin, a macrolide antibiotic, was recently approved for treatment of these infections (CDIs). It could be an alternative treatment for infection with C. difficile, with similar efficacy and safety to vancomycin. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile.

Abatacept Use After Failure of Multiple Biologic Agents in Patients With Severe Rheumatoid Arthritis

Abatacept (CTLA4-Ig) is a fully humanized soluble selective T-cell costimulatory inhibitor. Randomized controlled trials (RCTs) of abatacept have demonstrated its efficacy in patients with rheumatoid arthritis (RA) who either are methotrexatenaive 1 or have had an inadequate response to methotrexate 2,3 or antiYtumor necrosis factor (anti-TNF) therapy. 4 Data on the effectiveness and safety of abatacept in patients who have failed multiple biologics with different mechanisms of action, however, are limited. In the RCT of abatacept in TNF-failure patient cohorts, the majority of patients had failed only 1 anti-TNF agent, and no patients had previously received rituximab (RTX). 4 Observational data on the effectiveness in daily clinical practice are also scarce 5 but important, because they provide realworld effectiveness and safety data in patients who often differ from patients included in RCTs. 6 In this study, we describe our experience with abatacept in treating patients with severe RA after failure of anti-TNF therapy and after failure of both anti-TNF therapy and RTX. Our hypothesis was that abatacept was an effective and safe agent in patients with RA refractory to multiple therapeutic agents.

Belatacept for Kidney Transplant Recipients: A Systematic Review and Meta-Analysis

Background: Cardiovascular morbidity and mortality associated with calcineurin-inhibitor (CNI) based immunosuppression regimens present the biggest challenge for medium to long-term patient and graft outcomes. Belatacept, a selective T-cell co-stimulation blocker offers the potential for effective CNI-free maintenance. Objectives: To systematically review the benefit and harms of Belatacept versus CNI-based regimens. Search Strategy: We searched databases and conference proceedings to December 2011. Selection Criteria: Randomised controlled trials of Belatacept versus CNIs in kidney transplant recipients. Data Collection and Analysis: Two investigators independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean difference (MD) at 1 year, both with 95% confidence intervals (CI). Stratified analyses and meta-regression were used to investigate potential heterogeneity. Results: We included 4 trials (1516 recipients): 3 studies (1427 participants) compared Belatacept versus Cyclosporine; 1 study (89 participants) compared Belatacept versus Tacrolimus. Co-interventions varied: Basiliximab (3 studies, 1427 participants); Anti-Thymocyte Globulin (1 study, 89 participants); Mycophenolate Mofetil (4 studies, 1490 participants); and Sirolimus (1 study, 26 participants). Belatacept compared to CNI (figure 1) did not increase risk of mortality (RR0.62, CI0.31-1.25), death-censored graft loss (RR0.78, CI0.5-1.22) or acute rejection (RR1.49, CI0.76-2.93). Incidence of new-onset diabetes after transplant (NODAT, RR0.35, CI0.14-0.86), chronic allograft nephropathy (CAN, RR0.72, CI0.55-0.94) and use of multiple anti-hypertensives (RR0.79, CI0.68-0.91) were reduced. There was no difference in incidence of malignancy (RR0.98, CI0.31-3.13).[Fig 1 Belatacept v CNI:Main Outcomes, 1year]Considering dosage; high-dose Belatacept compared to CNI did not increase risk of mortality (RR0.85, CI0.44-1.64), death-censored graft loss (RR0.85, CI0.51-1.42) or acute rejection (RR1.69, CI0.88-3.27). NODAT (RR0.51, CI0.28-0.92) and CAN (RR0.71, CI0.52-0.96) were reduced, with no difference in use of multiple anti-hypertensives (RR0.88, CI0.71-1.09) or malignancy (RR0.92, CI0.24-3.55). Low-dose Belatacept compared to CNI did not increase mortality (RR0.48, CI0.21-1.08), death-censored graft loss (RR0.85, CI0.52-1.39), or acute rejection (RR1.46, CI0.8-2.66). NODAT (RR0.47, 95% CI0.26-0.87), CAN (RR0.72, 95% CI0.55-0.94) and use of multiple anti-hypertensives (RR0.79, 95% CI0.68-0.91) were reduced. Risk of malignancy (RR0.48, CI0.21-1.08) was not different. Comparing high versus low-dose Belatacept, we observed no significant difference in any outcome. Conclusions: For outcomes measured at 1 year, recipient and graft survival are no different, but Belatacept-treated patients use fewer anti-hypertensive agents and have less NODAT. Considerable uncertainty remains about relative effects over the medium term and longer, particularly whether these translate into improved cardiovascular outcomes. Longer-term trial data could better instruct Belatacept's therapeutic application.