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Biomedical subjects

R K Burt

Publications and source records attributed to R K Burt.

At least 19 recordsLinked to original sources
PubMed2006

Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis.

We have investigated the influence of different hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), Flt-3 ligand (Flt-3L) and thrombopoietin (TPO), on the course of relapsing experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Disease course and central nervous system histology were evaluated in all groups. When given after immunization but before either disease onset or during remission, Flt-3L, SCF and G-CSF exacerbated disease severity whereas TPO had no effect compared to non-cytokine-treated controls. When compared to controls, TPO did not exacerbate disease. We conclude that autoimmune disease severity may be affected by hematopoietic growth factors currently being employed in hematopoietic stem cell transplantation of patients with autoimmune disease. The mechanism of their effects remains unknown: it may be related to both T helper (Th) 1/Th2 skewing and/or homing of inflammatory cells to the disease-affected organ.

Animals↗
PubMed2004

The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns over the use of total-body irradiation in systemic sclerosis.

Hematopoietic stem cell transplantation (HSCT) is becoming an increasingly recognized indication for treatment of autoimmune diseases and severe immune-mediated disorders. However, multicenter registry data have demonstrated higher than anticipated early toxicity, approximately 10% for autoimmune diseases in general, and 20-27% for diffuse systemic sclerosis (scleroderma). If uncorrected, this high treatment-related mortality will hinder development of stem cell therapy for immune-mediated diseases. In order to develop safer regimens, we address some pitfalls and concepts involved in design and selection of conditioning regimens for autoimmune diseases in general, and because it is associated with the highest regimen-related toxicity, scleroderma in specific.

Autoimmune Diseases↗
PubMed2003

The promise of hematopoietic stem cell transplantation for autoimmune diseases.

Hematopoietic stem cell transplantation (HSCT) is being increasingly utilized for the treatment of a whole spectrum of severe autoimmune diseases refractory to conventional therapy. Although allogeneic HSCT has been followed by durable complete remission in a restricted number of patients with coincidental disease, the autologous procedure is generally preferred because of its lesser toxicity. Most autoimmune diseases are the consequence of a multistep process, mainly originating from the interplay of genetic, environmental, and hormonal factors. It has been postulated that if immunosuppressive regimens can eliminate or effectively reduce the level of autoreactive T and B cells, then regeneration of de novo immunity even in the autologous setting may bypass the initial breakdown of self-tolerance and ensure prolonged disease remission. As mentioned in a recent review of this field, protocol design including conditioning regimen, patient selection, stem cell source and final outcome are likely to be disease-specific. The following is a summary of the 2002 International Bone Marrow Transplantation Registry/American Society of Blood and Bone Marrow Transplantation (IBMTR/ASBMT) satellite symposium in Orlando, Florida on 24 February 2002 on 'Expanding the Promise of Hematopoietic Stem Cell Transplantation in Autoimmune Diseases'.

Autoimmune Diseases↗
PubMed2003

Stem cell therapy for autoimmune disease: overview of concepts from the Snowbird 2002 tolerance and tissue regeneration meeting.

Hematopoietic stem cell transplantation as a treatment for autoimmune disease began in 1996 and has subsequently spread worldwide. In Europe phase III trials have opened, while in America phase III trials are being designed and funded by the National Institutes of Health. On 6 June 2002, clinicians and scientists from around the world met at Snowbird, Utah to discuss the results and future directions of stem cell therapy for autoimmune diseases. What follows are general concepts from chairpersons of this meeting.

Autoimmune Diseases↗
PubMed2003

Hematopoietic stem cell transplantation for multiple sclerosis: finding equipoise.

Hematopoietic stem cell transplantation of multiple sclerosis is rapidly expanding. Success for this approach requires an understanding of the pathophysiology of multiple sclerosis and design of trials that select patients with active inflammatory disease, low disability scores, and avoidance of conditioning agents that may damage neural stem cell compartments or further compromise already injured axons.

Clinical Protocols↗
PubMed2003

Hematopoietic stem cell transplantation for severe Crohn's disease.

It is clear that some patients with severe Crohn's disease (CD) fail to respond favorably to the standard treatment, including antibody to Tumor Necrosis Factor alpha (TNFalpha), We have embarked on a unique therapy for this group of patients, intense immune suppression followed by autologous hematopoietic stem cell transplantation (HSCT). The response to this approach in our first four patients has been excellent, with there being no significant untoward event from the transplantation and with each patient entering clinical remission in terms of the Crohn's Disease Activity Index off all therapy for CD and no diarrhea or abdominal pain. However, some evidence of minor laboratory abnormalities and slight inflammation of the colon on colonoscopic evaluation persist up to 1 year post-transplant. It is suggested that HSCT should be considered a reasonable option for patients who have failed standard CD therapy, although long-term follow-up will be necessary to confirm the duration of the induced clinical remission.

Abdominal Pain↗
PubMed2003

Allogeneic stem cell transplantation for autoimmune diseases: nonmyeloablative conditioning regimens.

Hematopoietic stem cell transplantation (HSCT) for autoimmune diseases have been, because of safety reasons, overwhelmingly autologous. Results are, in general, encouraging with improvement in quality of life, a remission of up to several years, and perhaps in some diseases improved survival. This indicates that further study of autologous HSCT especially under phase III design is warranted. However, the ultimate goal of HSCT is cure of otherwise incurable autoimmune diseases. For this reason, allogeneic HSCT in carefully selected high-risk patients with autoimmune diseases using strategies to minimize both regimen-related toxicity and graft-versus-host disease (GVHD) is ongoing at Northwestern University and will be reviewed briefly.

Arthritis, Rheumatoid↗
PubMed2003

Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores: is neoangiogenesis occurring?

Systemic sclerosis (SSc) is presumed to be an immune-mediated vasculopathy of unknown etiology. SSc is unresponsive to most immune-modulating therapies except for intravenous cyclophosphamide, which is reported to demonstrate some benefit. We, therefore, dose-escalated cyclophosphamide to 200 mg/kg and added rabbit ATG 7.5 mg/kg along with infusion of unselected hematopoietic stem cells to minimize the cytopenic interval. Engraftment occurred rapidly (day 8) with minimal unexpected toxicity, no infections, and unexpectedly rapid improvement in the modified Rodnan Skin Score.

Antilymphocyte Serum↗
PubMed2003

Transduction of hematopoietic stem cells with a retroviral vector expressing the neomycin phosphotransferase gene.

Transduction of stem cells with a marking gene holds promise to determine if tissue repair or regeneration is derived from the adult hematopoietic stem cell and if relapse of an autoimmune disease should occur whether relapse arises from the stem cell compartment or from lymphocytes surviving the conditioning regimen. New safety concerns about gene-modified stem cell would entail new safety testing such as documentation of the insertional site prior to release.

Antigens, CD↗
PubMed2002

Engraftment syndrome: a common cause for rash and fever following autologous hematopoietic stem cell transplantation for multiple sclerosis.

Autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated as a therapy for patients with progressive multiple sclerosis (MS) at risk of debilitating neurological impairment. While preliminary results from a few studies have been reported, little is known about toxicities or outcome of HSCT for MS. We report a relatively frequent triad of non-infectious fever, rash and fatigue or lassitude that may also be associated with pruritus, pulmonary symptoms, and eosinophilia and frequently occurs around engraftment. This syndrome occurred in 26% of our series of patients (5/19) undergoing HSCT for multiple sclerosis. The engraftment syndrome is usually self-limited but may require intervention with systemic corticosteroids.

Adult↗
PubMed2001

Collection of hematopoietic stem cells from patients with autoimmune diseases.

We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow harvests and 174 peripheral blood stem cell mobilizations were performed on 187 patients. Disease indications were multiple sclerosis (76 patients), rheumatoid arthritis (37 patients), scleroderma (26 patients), systemic lupus erythematosus (19 patients), juvenile chronic arthritis (13 patients), idiopathic autoimmune thrombocytopenia (8 patients), Behcet's disease (3 patients), undifferentiated vasculitis (3 patients), polychondritis (1 patient) and polymyositis (1 patient). Bone marrow harvests were used in the Peoples Republic of China and preferred worldwide for children. PBSC mobilization was the preferred technique for adult stem cell collection in America, Australia, and Europe. Methods of PBSC mobilization included G-CSF (5, 10, or 16 microg/kg/day) or cyclophosphamide (2 or 4 g/m2) with either G-CSF (5 or 10 microg/kg/day) or GM-CSF (5 microg/kg/day). Bone marrow harvests were without complications and did not affect disease activity. A combination of cyclophosphamide and G-CSF was more likely to ameliorate disease activity than G-CSF alone (P < 0.001). g-csf alone was more likely to cause disease exacerbation than the combination of cyclophosphamide and g-csf (P = 0.003). Three patients died as a result of cyclophosphamide-based stem cell collection (2.6% of patients mobilized with cyclophosphamide). When corrected for patient weight and apheresis volume, progenitor cell yields tended to vary by underlying disease, prior medication history and mobilization regimen. Trends in the approaches to, and results of, progenitor cell mobilization are suggested by this survey. While cytokine-based mobilization appears less toxic, it is more likely to result in disease reactivation. Optimization with regard to cell yields and safety are likely to be disease-specific and prospective disease-specific studies of mobilization procedures appear warranted.

Adolescent↗
PubMed2001

Allogeneic stem cell transplantation for Evans syndrome.

Evans syndrome is a rare disorder characterized by combined autoimmune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Standard treatments consist of transfusions, corticosteroids, splenectomy, IVIG, anabolic steroids, vincristine, alkylating agents, or cyclosporine. In a patient with refractory disease, an allogeneic hematopoietic stem cell transplant (HSCT) resulted in complete clinical and serologic remission for more than 30 months. Allogeneic HSCT may be the only current curative therapy for Evans syndrome but may also be complicated by significant toxicities.

Adrenal Cortex Hormones↗
PubMed2001

Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis.

There is little information about the clinical course of patients with rheumatoid arthritis (RA) who relapse after autologous blood stem cell transplantation (ASCT). We describe 6 patients with severe RA who received ASCT in 3 US centers. Duration of followup was between 24 and 42 months posttransplant. Five patients achieved major responses but relapsed 3-22 months posttransplant. Two patients with relapse improved remarkably after restarting disease modifying antirheumatic drugs (DMARD). Two patients developed a mild RA flare at 3 and 5 months posttransplant and improved spontaneously. All 4 patients who improved after an initial disease flare remained highly functional at 14-22 months posttransplant. All patients in this study were anti-tumor necrosis factor (TNF) drug naive; all received a TNF blocker as a second line posttransplant salvage therapy, but only 3 responded. Future ASCT strategies need to focus on improving the durability of the early posttransplant responses.

Adult↗
PubMed2001

Future strategies in hematopoietic stem cell transplantation for rheumatoid arthritis.

Patients with coincidental rheumatoid arthritis (RA) treated by allogeneic hematopoietic stem cell transplantation (HSCT) for drug induced aplastic anemia have been fortuitously cured of RA. Other than these examples with allogeneic HSCT, there is no known curative therapy for RA. Despite its potential to cure, allogeneic transplantation is not being offered to patients with RA due to transplant related mortality. Advances in HSCT conditioning regimens and better prevention of graft-versus-host disease should allow consideration of allogeneic HSCT as therapy for severe RA. We propose a new, well tolerated, nonmyeloablative allogeneic stem cell transplant regimen as treatment for RA.

Arthritis, Rheumatoid↗
PubMed2000

Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide, represent a subset of patients at high risk of early death. We investigated the safety and efficacy of immune suppression and autologous haemopoietic stem-cell infusion to treat such patients. METHODS: From 1996, we selected patients with persistent SLE despite use of cyclophosphamide. Patients underwent dose-intense immune suppression and autologous haemopoietic stem-cell (CD34) infusion. Peripheral blood lymphocytes were analysed by flow cytometry, ELISA, and T-cell-receptor spectratyping before and after transplantation. We mobilised autologous haemopoietic stem cells with 2.0 g/m2 cyclophosphamide and 10 microg/kg granulocyte colony stimulating factor daily, enriched with CD34-positive selection, and reinfused after immunosuppression with 200 mg/kg cyclophosphamide, 1 g methylprednisolone, and 90 mg/kg equine antithymocyte globulin. RESULTS: Nine patients underwent stem-cell mobilisation but two were excluded before transplantation because of infection. The remaining seven received high-dose chemotherapy and stem-cell infusion. Median time to an absolute neutrophil count higher than 0.5x10(9)/L and nontransfused platelet count higher than 20x10(9)/L was 9 days (range 8-11) and 11 days (10-13), respectively. At a median follow-up of 25 months (12-40), all patients were free from signs of active lupus. Renal, cardiac, pulmonary, and serological markers, and T cell phenotype and repertoire had normalised. INTERPRETATION: Patients remained free from active lupus and improved continuously after transplantation, with no immunosuppressive medication or small residual doses of prednisone. T-cell repertoire diversity and responsiveness was restored. Durability of remission remains to be established.

Adolescent↗
PubMed2000

Intense immune suppression for systemic lupus--the role of hematopoietic stem cells.

The treatment of severe autoimmune diseases has been recently revitalized by the introduction of intense immune suppression with immune ablative intent followed by three different procedures. These are allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT (using either marrow or peripheral blood), and intense immune suppression without stem cell support. Current trials suggest that high dose immune suppressive therapy with or without autologous hematopoietic stem cell support can induce remission of previously refractory disease. Follow-up is too brief to determine if intense immune suppression, and more specifically autologous HSCT, will ultimately cure SLE. It is conceivable that an allogeneic source of stem cells from a normal donor (e.g. HLA matched sibling) will be required to achieve a cure. It is also possible that autologous HSCT, even if not curative, may prolong the life of patients with otherwise high-risk features. In carefully selected patients, the potential benefits of this procedure may outweigh the risks.

Animals↗