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Biomedical subjects

James L M Ferrara

Publications and source records attributed to James L M Ferrara.

49 records · Page 3Linked to original sources
PubMed2002

Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation.

Acute graft-versus-host disease (GVHD) is thought to derive from direct T-cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as interleukin-1 (IL-1), tumor necrosis factor alpha, and interferon gamma may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T-cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double-blind, placebo-controlled randomized trial of recombinant human IL-1 receptor antagonist (IL-1Ra) in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day -4 to day +10. Randomization was stratified according to GVHD risk. The 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P =.88). There was no difference in hematologic recovery, transplantation-related toxicity, event-free survival, or overall survival. We conclude that blockade of IL-1 using IL-1Ra during conditioning and 10 days immediately after transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.

Acute Disease↗
PubMed2002

Graft-versus-host disease in the absence of the spleen after allogeneic bone marrow transplantation.

BACKGROUND: The spleen is considered to be an important secondary lymphoid organ where acute graft-versus-host disease (GVHD) is initiated by donor T cells that recognize host alloantigens after allogeneic bone-marrow transplantation (BMT). The influence of splenectomy on the development of GVHD prior to BMT has yet to be determined. METHODS: The mortality and severity of murine GVHD of unsplenectomized, splenectomized, and sham-operated recipients of allogeneic BMT were compared in a blinded fashion. Serum levels of interferon (IFN)-gamma were measured 7 days after BMT, as an index of systemic donor T-cell responses. RESULTS: Mortality and morbidity of acute GVHD were not significantly affected by splenectomy in a major histocompatibility complex (MHC)-mismatched, CD4-driven murine GVHD model and a minor histocompatibility antigen (MiHA)-mismatched, CD8-driven GVHD model. Serum levels of IFN-gamma also were not different between the groups. CONCLUSION: GVHD can readily develop after allogeneic BMT, even in the absence of the spleen, in these mouse models.

Animals↗
PubMed2002

Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma.

PURPOSE: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS: The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION: Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.

3-Iodobenzylguanidine↗
PubMed2002

Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease.

Recent evidence suggests that dendritic cells (DCs) can regulate and amplify immune responses. Flt3 ligand (FL)-derived DC function was tested as a stimulator of allogeneic lymphocytes in vitro and in vivo. Treatment of mice with FL dramatically expanded DC number, but DCs isolated from FL-treated mice (FL DCs) were poor stimulators of allogeneic T-cell responses in vitro. Further activation of FL DCs did not restore their stimulatory ability, and FL DCs did not suppress the stimulation of the allogeneic T cells by normal DCs. FL treatment significantly increased the CD8 alpha(+) DC subset, which appeared to be the reason for their poor stimulatory capacity. These observations were confirmed in vivo using a mouse model of acute graft-versus-host disease (GVHD) wherein host DCs play a critical role. FL treatment of recipients before allogeneic bone marrow transplantation dramatically suppressed donor T-cell responses to host antigens, thereby reducing GVHD mortality (P <.01). These data represent a novel strategy that alters host DCs and reduces acute GVHD.

Acute Disease↗
PubMed2002

Donor leukocyte infusion from immunized donors increases tumor vaccine efficacy after allogeneic bone marrow transplantation.

Donor T cells play a critical role in mediating both harmful graft-versus-host disease (GVHD) and beneficial graft-versus-tumor effect after allogeneic bone marrow transplantation (BMT). We have recently demonstrated a novel treatment strategy to stimulate specific antitumor activity with preservation of tolerance to host antigens after T cell-depleted allogeneic BMT by vaccination of recipients with irradiated B16 melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor. In this murine system, donor leukocyte infusion from a donor immunized with the recipient-derived B16 vaccines enhanced clinical activity of tumor vaccines without exacerbating GVHD. CD4(+) T cells are essential for this enhancement. In vitro analysis of splenocytes from donor leukocyte infusion donor mice demonstrated that immunization of donors with the recipient-derived B16 vaccines elicited potent T-cell proliferation and cytokine responses specific to B16 antigens. These results demonstrate that immunization of donors with recipient-derived tumor vaccines preferentially induces tumor-specific T-cell responses and that vaccination of both donors and recipients can generate potent antitumor immunity without exacerbating GVHD. This strategy has important implications to prevent recurrence of malignancies after BMT.

Animals↗
PubMed2002

Cellular and cytokine effectors of acute graft versus host disease.

Graft-versus-host-disease (GVHD) is the major complication of allogeneic Bone Marrow Transplant (BMT) and Older BMT recipients are at greater risk for acute graft-versus-host-disease. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older recipients. GVHD mortality and morbidity, as well as pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice. In a haploidential GVHD model, CD4+ donor T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2FI BM chimeras created with either old or young BM. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. We also evaluated whether alloantigen expression on host target epithelium is essential for tissue damage induced by GVHD in mouse models. In bone marrow chimeras recipients in which either MHC II or MHC I alloantigen was expressed only on APCs, we found that acute GVHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GVHD. These results suggest new strategies for the prevention and treatment of this toxic complication of BMT.

Acute Disease↗
PubMed2002

Acute graft-versus-host disease does not require alloantigen expression on host epithelium.

Alloantigen expression on host antigen-presenting cells (APCs) is essential to initiate graft-versus-host disease (GvHD); therefore, alloantigen expression on host target epithelium is also thought to be essential for tissue damage. We tested this hypothesis in mouse models of GvHD using bone-marrow chimeras in which either major histocompatibility complex class I or class II alloantigen was expressed only on APCs. We found that acute GvHD does not require alloantigen expression on host target epithelium and that neutralization of tumor necrosis factor-alpha and interleukin-1 prevents acute GvHD. These results pertain particularly to CD4-mediated GvHD but also apply, at least in part, to CD8-mediated GvHD. These results challenge current paradigms about the antigen specificity of GvHD effector mechanisms and confirm the central roles of both host APCs and inflammatory cytokines in acute GvHD.

Acute Disease↗
PubMed2002

Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation.

Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted.

Adolescent↗
PubMed2002

Understanding the alloresponse: new approaches to graft-versus-host disease prevention.

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). GVHD occurs when donor T cells react to host antigens on antigen-presenting cells (APCs) and attack host tissues, with sequential activation of donor T cells and monocytes/macrophages. The net effects of dysregulated cytokine production in this complex system are the severe inflammatory manifestations that we recognize as clinical acute GVHD. Long-term outcomes are also adversely affected by chronic GVHD, which has distinctive clinical and pathologic manifestations that mimic autoimmune disease, although its exact pathogenesis remains ambiguous. The ultimate goal for preventing GVHD is the induction of specific tolerance to host antigens, thereby maintaining favorable aspects of donor immunity. Tolerance may be achieved by costimulatory blockade, deletion of activated cells, suppression by regulatory T cells, and immune deviation. This report will focus on these mechanisms as they relate to the pathophysiology of acute GVHD.

Animals↗
PubMed2002

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease.

Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.

Aging↗
PubMed2002

The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease.

Allogeneic stem cell transplantation (SCT) is an important therapy for a number of malignant diseases, and acute graft versus host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes of this treatment strategy. The therapeutic potential of allogeneic SCT relies on the graft versus leukemia (GVL) effect, during which donor T lymphocytes eradicate residual malignant cells via immunological mechanisms. Unfortunately, beneficial GVL effects are closely associated with the toxicity of GVHD. The pathophysiology of GVHD is complex and fundamentally depends upon aspects of adaptive immunity and interactions between donor T cells and foreign host tissue antigens. Recent work has revealed that components of the innate immune response and the secretion of inflammatory cytokine effectors are also important. In this context, experimental studies have demonstrated that loss of gastrointestinal (GI) tract integrity plays a major role in the amplification of systemic GVHD. Specifically, translocation of endotoxin across a damaged GI tract and into the circulation promotes local and systemic cytokine release. This effect perpetuates further gut mucosal injury and endotoxin leak, thus establishing a positive feedback loop for progressive target organ injury and systemic inflammation. Data obtained using murine SCT models have shown that disruption of the cellular activating effects of lipopolysaccharide (LPS) significantly reduces cytokine secretion and GVHD severity without altering T-cell responses to host antigens. These findings support a critical role for LPS in the early inflammatory events responsible for GVHD and suggest that strategies which target the innate immune response and LPS receptor-ligand interactions may help prevent GVHD while preserving donor T-cell responses and GVL activity.

Animals↗
PubMed2002

Hematology grants workshop.

The process of writing an NIH grant application is complex and difficult. Understanding critical details of the review process is a key to success. In this article the authors analyze the NIH grant application process from the reviewer's perspective. They discuss NIH review criteria and highlight the characteristics of successful grant applications. They also suggest specific strategies to improve applications in terms of timeliness, clarity, focus, and independence and cover the key elements to revising an application that is not funded initially.

Financing, Organized↗