Abstract Despite having demonstrated noninferior efficacy against atazanavir/ritonavir plus coformulated tenofovir/emtricitabine (cTDF/FTC), the combination of nevirapine plus cTDF/FTC is not included among preferred regimens in some international guidelines. This combination is frequently used in Spain. We analyzed its effectiveness and safety as first-line therapy in a routine clinical practice. A ...

Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered ...

Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR) genes is an attractive strategy to direct autologous T-cell immunity against tumor-associated antigens. However, clinical effectiveness has been hampered by limited in vivo persistence. We investigated whether the use of major histocompatibility complex-mismatched T cells would prolong ...

Graft-versus-host disease (GVHD) is mediated by mature donor T cells contained in the hematopoietic stem cell graft. During the development of GVHD, signaling through a variety of costimulatory receptors plays an important role in allogeneic T cell responses. Even though delivery of costimulatory signals is a prerequisite for full activation ...

BACKGROUND: Chronic graft-versus-host disease (CGVHD) is a serious and increasingly common complication after allogeneic (allo) hematopoietic stem-cell transplantation, but currently available therapies have demonstrated limited efficacy. Furthermore, the statins have been reported to be effective in various immune-mediated disease models, but their therapeutic potentials versus CGVHD have not been determined. ...

BACKGROUND: Acute graft-versus-host disease (GVHD) is a critical obstacle to bone marrow transplantation. Although numerous studies have described immunosuppression protocols to mitigate acute GVHD, the need still exists for a more efficient immunosuppressant with fewer side effects. Here, we evaluated the protective effect of CP-690550, a newly developed Janus kinase ...

Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, the ability of donor T cells to respond to recipient antigens is coopted to generate graft-versus-tumor (GVT) responses. The major reason for treatment failure is tumor recurrence, which is ...

Haploidentical hematopoietic cell transplantation (HHCT) using CD34 selected grafts is complicated by slow engraftment and immune reconstitution. Engraftment and immune reconstitution might be improved using CD3/CD19-depleted grafts and reduced intensity conditioning (RIC). We report on 28 patients after HHCT with CD3/CD19-depleted grafts using RIC, which were prospectively evaluated for engraftment ...

Graft-versus-host disease (GVHD) is initiated and maintained by antigen-presenting cells (APCs) that prime alloreactive donor T cells. APCs are therefore attractive targets for GVHD prevention and treatment. APCs are diverse in phenotype and function, making understanding how APC subsets contribute to GVHD necessary for the development of APC-targeted therapies. Langerhans ...

Allogeneic hematopoietic cell transplantation (AHCT) is an efficient therapy for different malignant and nonmalignant hematological diseases. However, the use of this therapeutic approach is still limited by some severe toxic side effects, mainly graft-versus-host disease (GvHD). Today, the risk of fatal GvHD restrains the wider application of AHCT to many ...

Interleukin-17A is a hallmark of a subset of CD4+ lymphocytes called T(H)17. Allogeneic hematopoietic stem cell transplantation (HSCT) induces an immune response that facilitates graft acceptance, but if clinically apparent as acute graft-versus-host disease (aGvHD), it may adversely affect transplantation outcomes. TH17 cells are involved in the inflammatory processes associated ...

Because of the necessary immunodepletion prior to cord blood transplantation as well as the immaturity of cord blood immune cells, recipients experience a high incidence of viral infection in addition to complications observed after hematopoietic stem cell transplantation, such as relapse and graft-versus-host disease. We describe current immunotherapeutic approaches to ...

Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling ...

Previous studies suggest regulatory T cells (Tregs) inhibit graft-versus-host disease (GVHD) in mouse and human hematopoietic cell transplant (HCT) recipients. As the gastrointestinal tract represents one of the most common and severe sites of GVHD-related tissue damage, we sought to determine whether a deficit in circulating or gastric mucosal Treg ...

Studies in mice have shown that proinflammatory Th17 cells can cause acute graft-versus-host disease (aGVHD) related tissue damage; however, whether they play a role in human aGVHD remains unclear. In a prospective study, we measured the proportion of Th17 cells in the blood and skin of patients at the onset ...

Prolonged thrombocytopenia is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, its pathogenesis has remained obscure. In the present study, we used flow cytometry to determine the frequency of bone marrow megakaryocytes (MKs) and MK ploidy distributions in allo-HSCT recipients with or without prolonged thrombocytopenia (n = ...

We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40-directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis ...

Allogeneic bone marrow transplantation is an effective treatment for a number of malignant and nonmalignant diseases (Applebaum. 2001. Nature. 411: 385-389 and Copelan. 2006. N Engl J Med. 354: 1813-1826). However, the application of this therapeutic modality has been impeded by a number of confounding side effects, the most frequent ...

Myeloid-derived suppressor cells (MDSCs) are a well-defined population of cells that accumulate in the tissue of tumor-bearing animals and are known to inhibit immune responses. Within 4 days, bone marrow cells cultured in granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor resulted in the generation of CD11b(+)Ly6G(lo)Ly6C(+) MDSCs, the majority of ...

Allogeneic hematopoietic stem cell transplantation (HSCT) for leukemia can play a major role in reducing the risk of relapse by inducing a graft versus leukemia (GVL) effect. Here, we review the effectiveness of mismatching inhibitory killer-cell-immunoglobulin-like receptors (KIR) on donor natural killer (NK) cells as a mechanism for GVL. We ...

Attempts to treat congenital protein deficiencies using bone marrow-derived cells have been reported. These efforts have been based on the concepts of stem cell plasticity. However, it is considered more difficult to restore structural proteins than to restore secretory enzymes. This study aims to clarify whether bone marrow transplantation (BMT) ...

Graft-versus-host disease (GVHD) is a major risk factor for secondary malignancy after hematopoietic stem cell transplantation. Squamous cell carcinoma (SCC) of the skin and mucous membranes are especially frequent in this setting where aneuploidy and tetraploidy are associated with aggressive disease. The current study is directed at the mechanism of ...

Donor lymphocyte infusions (DLIs) are used for adoptive immunotherapy to prevent or treat relapse and infectious complications after allogeneic hematopoietic stem cell transplantation (HSCT). Unmanipulated DLIs are associated with a risk of graft-versus-host disease (GVHD), probably related to CD8(+) T cell activity. We investigated an automated clinical-scale human-CD4(+)-cell purification method ...

Alloreactive T cells are crucial for graft-versus-host disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report in this paper that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs, such ...

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow or hematopoietic stem cell transplantation. GVHD is thought to be primarily due to the response of mature T cells transferred along with the bone marrow graft to foreign histocompatibility antigens expressed on host tissues. Recent studies, however, have challenged ...

A 3-year-old girl with severe aplastic anemia (SAA) that was unresponsive to steroid, cyclosporine and filgrastim treatments received bone marrow (BM) mesenchymal stromal cells (MSC; 1.25 x 10(6)/kg), granulocyte colony-stimulating factor (G-CSF)-mobilized BM and peripheral blood stem cell grafts from her father. Prior to stem cell transplantation, she had experienced ...

The morbidity and mortality rates of invasive fungal infection in allogeneic stem cell recipients are still unacceptably high and have not been significantly improved by alternative antifungal strategies to date. Over the last few years, rapid methods for the clinical-scale generation of functionally active and well characterized antifungal T(H)1 cells ...

We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4(+) T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell ...

Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Despite significant advances in applicability, DLI has not been available for single-unit recipients of unrelated cord blood transplant. Ex vivo expansion of cord ...

Allogeneic hematopoietic stem cell transplantation (HSCT) is used effectively to treat a number of hematological malignancies. Its beneficial effects rely on donor-derived T cell-targeted leukemic cells, the so-called graft-versus-leukemia (GVL) effect. Induction of GVL is usually associated with concomitant development of graft-versus-host disease (GVHD), a major complication of allogeneic HSCT. ...

A 19-year-old girl with T-lymphoblastic lymphoma (T-LBL) was referred to our hospital because of refractory disease. After complete remission was achieved by the JALSG ALL-97 protocol, she received a bone marrow transplantation (BMT) from an unrelated, HLA-matched donor with myeloablative conditioning. Four months after BMT, T-LBL relapsed and donor lymphocyte ...

We have developed a dual bioluminescent reporter system allowing noninvasive, concomitant imaging of T-cell trafficking, expansion, and activation of nuclear factor of activated T cells (NFAT) in vivo. NFAT activation plays an important role in T-cell activation and T-cell development. Therefore we used this system to determine spatial-temporal activation patterns ...

Graft-versus-host disease (GvHD) is one of the major complications of allogeneic hematopoietic stem cell transplantation, an otherwise highly effective therapeutic modality for patients affected by hematological diseases. The main inducers of GvHD are alloreactive donor T cells, which recognize host antigens presented by recipient cells. The critical role of lymphocytes ...

Adoptive transfer of in vivo generated antigen-specific donor-derived T-cells is increasingly recognized as an effective approach for the treatment or prevention of EBV lymphomas and cytomegalovirus infections complicating allogeneic hematopoietic cell transplants. This review examines evidence from preclinical experiments and initial clinical trials to critically assess both the potential and ...

Murine T cells exposed to rapamycin maintain flexibility towards Th1/Tc1 differentiation, thereby indicating that rapamycin promotion of regulatory T cells (Tregs) is conditional. The degree to which rapamycin might inhibit human Th1/Tc1 differentiation has not been evaluated. In the presence of rapamycin, T cell costimulation and polarization with IL-12 or ...

Th17 cells have never been explored in human graft-versus-host disease (GVHD). We studied the correlation between the presence of Th17 cells with histologic and clinical parameters. We first analyzed a cohort of 40 patients with GVHD of the gastrointestinal tract. Tumor necrosis factor (TNF), TNF receptors, and Fas expression, and ...

T-cell-based adoptive immunotherapy is widely used to treat graft rejection and relapse after stem cell transplantation (SCT). However, this approach is hampered by a high risk of life-threatening graft-versus-host-disease (GvHD). Clinical trials have demonstrated the value of suicide genes to modify T cells for the effective control of GvHD. Herewith, ...

Allogeneic stem cell transplantation is associated with a powerful 'graft-versus-leukemia' effect that is generally considered to result from an alloreactive T-cell immune response. However, disease remission can also be observed after syngeneic transplantation and we investigated whether a T-cell immune response to cancer-testis antigens can be detected in patients in ...

The treatment of choice for severe combined immunodeficiency is bone marrow transplantation from an HLA-identical donor sibling without conditioning. However, this may result in low donor stem cell chimerism, leading to reduced long-term immune reconstitution. We compared engraftment, metabolic, and T-cell and B-cell immune reconstitution of HLA-identical sibling bone marrow ...

The target antigens of graft-versus-leukemia that are tumor associated are incompletely characterized. We examined responses developing against CML66, an immunogenic antigen preferentially expressed in myeloid progenitor cells identified from a patient with chronic myelogenous leukemia who attained long-lived remission following CD4+ donor lymphocyte infusion (DLI). From this patient, CML66-reactive CD8+ ...

Typical cases of severe combined immunodeficiency present at infancy (most frequently at 6 months of age) with repeated opportunistic infections; failure to thrive; and scarcity of lymphoid tissues, including undetectable lymph nodes and a small dysplastic thymus. Patients with profound T-cell dysfunction (PTD)/combined immunodeficiency (CID) have moderate to large numbers ...

Severe combined immunodeficiency (SCID) is a primary immunodeficiency disorder with heterogenous genetic etiologies. We describe a typical case in a 9-year-old boy that was masked by a clinically functional maternal T cell engraftment leading to late presentation with Pneumocystis jiroveci pneumonia and cytomegalovirus infection, probably following exhaustion of maternally engrafted ...

Suppressor of cytokine signaling-3 (SOCS3) is the main intracellular regulator of signaling by granulocyte colony-stimulating factor, an immune-modulatory cytokine used to mobilize stem cells for transplantation. We have therefore studied the contribution of SOCS3 to the spectrum of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Grafts from SOCS3(-/Deltavav) ...

Allogeneic hematopoietic stem-cell transplantation can cure some patients with high-risk B-cell malignancies, but disease relapse following transplantation remains a significant problem. One approach that could be used to augment the donor T-cell-mediated antitumor effect is the infusion of allogeneic donor-derived T cells expressing a chimeric antibody receptor (CAR) specific to ...

The aim of our study was to compare the results of unrelated donor (UD) peripheral blood stem cell transplantation versus UD bone marrow transplantation and to analyze the impact of infused CD34(+) and CD3(+) cell doses on survival and incidence of severe graft-versus-host disease (GVHD) in 187 children who underwent ...

Treatment of relapsed hematological malignancies after an allogeneic peripheral blood stem cell transplant (SCT) is challenging. Donor lymphocyte infusion (DLI) from the stem cell donor is an attractive clinical option to salvage this group of patients. We reviewed the important studies looking at donor lymphocyte infusion as a therapy for ...

Although bone marrow transplantation has resulted in life-saving T-cell reconstitution in infants with severe combined immunodeficiency (SCID), correction of B-cell function has been more problematic. This review examines B-cell reconstitution results presented in 19 reports from the United States and Europe on posttransplantation immune reconstitution in patients with SCID over ...

Liver allografts seem to be immunologically privileged; they are the only solid transplant that can protect cotransplanted organs from rejection. The mechanisms of this "hepatic tolerance" are poorly understood. The aim of this study was to examine the immunomodulatory effect of hepatic stellate cells (HSCs) in mixed lymphocyte reactions in ...

When bone marrow transplantation (BMT) is carried out, survival of the donor hematopoietic stem cells is crucial to maintain donor hematopoiesis in the recipients. We have shown that intra-bone marrow-bone marrow transplantation (IBM-BMT) can induce the rapid recovery of donor hematopoiesis and allow a reduction in radiation doses as a ...

Graft-versus-host disease (GVHD) is initiated when alloreactive donor T cells are primed by host APCs to undergo clonal expansion and maturation. Since there is a controversy regarding the role of nonhematopoietic cells in GVHD, we wanted to investigate the influence of MHC disparity on nonhematopoietic cells on the pathogenesis of ...