Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation.

Nephrotic syndrome (NS) is an extremely rare complication of myeloablative allogeneic haematopoietic cell transplantation (HCT) that usually occurs in association with chronic graft-versus-host disease (C-GVHD). We observed an unexpectedly high incidence of NS in a cohort of 163 consecutive patients undergoing non-myeloablative HCT from a related human leucocyte antigen-compatible donor. Seven patients developed NS at a median 318 d post-transplant (range 119-1203 d; cumulative incidence 6.

Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia.

Eighty patients with chronic myeloid leukemia (CML) underwent T cell-depleted stem cell transplantation from an HLA-identical sibling, with add-back of donor T cells on days 30 to 45 and days 60 to 100 in patients in whom grade 2 or greater acute graft-versus-host disease (GVHD) developed. The outcomes for 54 patients with chronic-phase (CP) and 26 with advanced-phase (AP) disease were as follows: overall survival, 85% +/- 5% versus 36% +/- 10%; transplantation-related mortality (TRM), 13% +/- 5% versus 43% +/- 11%; and current leukemia-free survival, 76% +/- 6% versus 34% +/- 9%. The day-30 lymphocyte count (LC30) was strongly associated with outcome.

Lineage-specific engraftment and outcomes after T-cell-depleted peripheral blood stem cell transplant with Flu/Cy/TBI conditioning.

Sixty patients with haematological malignancies received a myeloablative regimen of total body irradiation, cyclophosphamide and fludarabine followed by a T-cell-depleted peripheral blood stem cell transplant from a human leucocyte antigen identical sibling. To improve donor immune function, 1 x 10(7) CD3+ cells/kg were added-back between d 45 and 100. T-cell and myeloid chimaerism were monitored regularly to evaluate the effect of T-cell chimaerism on outcome.

Improved outcome for peripheral blood stem cell transplantation for advanced primary myelodysplastic syndrome.

Stem cell transplantation for myelodysplastic syndrome (MDS) is characterized by high transplant-related mortality (TRM), especially in older patients and those with more advanced disease. Outcome after peripheral blood stem cell transplantation (PBSCT) may be superior to earlier results with bone marrow transplantation. Forty-three patients (aged 12-73 years; median, 49 years) received an HLA-identical sibling donor PBSCT.

Biological properties of photocrosslinked alginate microcapsules.

An alternative form of gene therapy using recombinant cell lines delivering therapeutic products encapsulated in alginate hydrogel has proven effective in treating many murine models. The lack of long-term capsule stability has led to a new strategy to reinforce the microcapsules with a photopolymerized interpenetrating covalent network of N-vinylpyrrolidone (NVP) and sodium acrylate. Here the properties for potential application in gene therapy are reported.

Quantitative chemical mapping of sodium acrylate- and N-vinylpyrrolidone-enhanced alginate microcapsules.

Alginate microcapsules enclosing recombinant cells secreting therapeutic products have been used successfully to treat several murine models of human diseases. The mechanical and chemical properties of these alginate capsules can be improved by the addition and in situ photo-polymerization of sodium acrylate and N-vinylpyrrolidone in the alginate capsule. The purpose of this modification was to form additional covalent cross-links.

Allogeneic hematopoietic cell transplantation as immunotherapy for solid tumors: current status and future directions.

Although myeloablative conditioning can cytoreduce or debulk malignancies, the curative antitumor effects of allogeneic hematopoietic stem cell transplantation (HCT) are mostly mediated by transplanted donor immune cells. A heightened awareness and appreciation of the immune-mediated anticancer effects that occur after allogeneic transplantation has led to the increasing use of reduced-intensity stem cell transplantation (RIST) approaches to treat advanced malignancies. The graft-versus-leukemia effects that occur against hematologic cancers after RIST have recently attracted oncologists to explore the therapeutic potential of allogeneic HCT for treatment-refractory solid tumors.

Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival.

Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor.

Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation.

We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients (median age, 65 years [range, 51-73 years]), with advanced hematologic malignancies underwent transplantation following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n = 5), melphalan (n = 5), or busulfan (n = 6).

A novel method to enhance the stability of alginate-poly-L-lysine-alginate microcapsules.

Implantation of microencapsulated recombinant cells is an alternative approach to gene therapy. These genetically-engineered cells enclosed in microcapsules to deliver therapeutic recombinant products have been effective in treating several murine models of human diseases. However, the most commonly used microcapsules fabricated from alginate ionically cross-linked with calcium suffer from loss of long-term mechanical stability.

Prediction and prevention of transplant-related mortality from pulmonary causes after total body irradiation and allogeneic stem cell transplantation.

Between July 1997 and August 2004, 146 consecutive patients with hematologic malignancies received a T cell-depleted peripheral blood stem cell transplant from an HLA-identical sibling by using total body irradiation (TBI) and cyclophosphamide conditioning regimens. Eighty-five patients received 13.6 Gy of TBI with no lung shielding, and 61 received lung shielding (total lung dose, 6-12 Gy).

Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation.

Delayed donor erythropoiesis and pure red-cell aplasia (PRCA) complicate major-ABO mismatched non-myeloablative allogeneic stem-cell transplantation. To characterize these events, we analysed red-cell serology and chimaerism in lymphohaematopoietic lineages, including plasma cells and B cells, in 12 consecutive major-ABO incompatible transplants following cyclophosphamide/fludarabine-based conditioning. Donor erythropoiesis was delayed to more than 100 days in nine (75%) patients including six (50%) who developed PRCA.

Allogeneic hematopoietic cell transplantation for metastatic renal cell carcinoma after nonmyeloablative conditioning: toxicity, clinical response, and immunological response to minor histocompatibility antigens.

Purpose: This phase I trial assessed the safety, efficacy, and immunologic responses to minor histocompatibility antigens following nonmyeloablative allogeneic hematopoietic cell transplantation as treatment for metastatic renal cell carcinoma.

Experimental Design: Eight patients received conditioning with fludarabine and low-dose total body irradiation followed by hematopoietic cell transplantation from an HLA-matched sibling donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression.

Nonmyeloablative transplantation for solid tumors: a new frontier for allogeneic immunotherapy.

The failure of conventional chemotherapy to improve survival in a large percentage of patients with advanced solid tumors has prompted the development of alternative anticancer approaches. Conventional allogeneic hematopoietic stem cell transplantation (HSCT) relies on myeloablative conditioning to eradicate the underlying disease, as well as suppress the patient's immune response, allowing engraftment of the donor's lymphohematopoietic system. Such preparative regimens are frequently associated with serious hematologic and nonhematologic toxicities, resulting in substantial morbidity and mortality.

Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been explored as a method to enhance the efficacy of chemotherapy for advanced solid tumors. The failure of autologous hematopoietic stem cell transplantation to prolong survival in patients with metastatic solid tumors has sparked interest recently in studies exploring the potential of allogeneic hematopoietic stem cell transplantation for such patients. Allogeneic hematopoietic stem cell transplantation is widely accepted as a potent form of immunotherapy capable of curing patients with chemotherapy-refractory hematologic malignancies.

Identification of a low affinity mannose 6-phosphate-binding site in domain 5 of the cation-independent mannose 6-phosphate receptor.

The 300-kDa cation-independent mannose 6-phosphate receptor (CI-MPR) and the 46-kDa cation-dependent MPR (CD-MPR) are type I integral membrane glycoproteins that play a critical role in the intracellular delivery of newly synthesized mannose 6-phosphate (Man-6-P)-containing acid hydrolases to the lysosome. The extracytoplasmic region of the CI-MPR contains 15 contiguous domains, and the two high affinity ( approximately 1 nm) Man-6-P-binding sites have been mapped to domains 1-3 and 9, with essential residues localized to domains 3 and 9. Domain 5 of the CI-MPR exhibits significant sequence homology to domains 3 and 9 as well as to the CD-MPR.

Green fluorescent protein expression in dendritic cells enhances their immunogenicity and elicits specific cytotoxic T-cell responses in humans.

Objective: Green fluorescent protein (GFP) has been used to monitor and select cells transduced with vectors encoding other transgenes of interest. We investigated the immunogenic nature of GFP in humans and further explored whether this xenoprotein could be used as a functional adjuvant to enhance T-cell immunity to the melanoma tumor antigen MART1.

Methods: Peripheral blood lymphocytes from healthy donors were stimulated by autologous dendritic cells expressing GFP, then cloned by limiting dilution and tested for antigen specificity following coculture with GFP-expressing or GFP-negative targets.

Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease.

A retrospective chart review was performed on seven patients treated with topical ocular corticosteroid therapy for progressive cicatricial conjunctivitis associated with chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A clinical grading criteria for conjunctival GVHD based on the degree of cicatrization was developed and patients graded prior to therapy. During the treatment course, the dose and frequency of topical corticosteroids and clinical outcomes were recorded.

Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells.

Cellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell-mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts.