40 results on '"Burt, RK"'
Search Results
2. Heterogeneous pattern of improvement in right ventricular mechanics following hematopoietic stem cell transplant in patients with systemic sclerosis
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Chen, C, primary, Nishtala, A, additional, Groenendyk, JW, additional, Schultz, WM, additional, Li, E, additional, Shah, SJ, additional, Burt, RK, additional, and Freed, BH, additional
- Published
- 2021
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3. Immune Profile of Severe Refractory Crohn’s Disease Patients Candidates to Autologous Hematopoietic Stem Cell Transplantation
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Bueno, Ruiz Ma, and Burt Rk
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Crohn's disease ,Immune system ,Refractory ,business.industry ,medicine.medical_treatment ,Immunology ,medicine ,Hematopoietic stem cell transplantation ,medicine.disease ,business - Published
- 2020
4. Hematopoietic stem cell transplantation for severe and refractory lupus: analysis after five years and fifteen patients.
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Traynor AE, Barr WG, Rosa RM, Rodriguez J, Oyama Y, Baker S, Brush M, and Burt RK
- Published
- 2002
5. Paediatric rheumatology workshop/series editor: P Woo. Haematopoietic stem cell transplantation for active systemic lupus erythematosus.
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Traynor, A and Burt, RK
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- 1999
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6. Autologous hematopoietic stem cell transplantation in refractory rheumatoid arthritis: sustained response in two of four patients.
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Burt RK, Georganas C, Schroeder J, Traynor A, Stefka J, Schuening F, Graziano F, Mineishi S, Brush M, Fishman M, Welles C, Rosen S, and Pope R
- Published
- 1999
7. The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP.
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Burt RK, Tappenden P, Balabanov R, Han X, Quigley K, Snowden JA, and Sharrack B
- Abstract
Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327-277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Burt, Tappenden, Balabanov, Han, Quigley, Snowden and Sharrack.)
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- 2021
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8. Medical, ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn's disease in Brazil.
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Ruiz MA, Junior RLK, Piron-Ruiz L, Saran PS, Castiglioni L, de Quadros LG, Pinho TS, and Burt RK
- Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. The etiology of CD is unknown; however, genetic, epigenetic, environmental, and lifestyle factors could play an essential role in the onset and establishment of the disease. CD results from immune dysregulation due to loss of the healthy symbiotic relationship between host and intestinal flora and or its antigens. It affects both sexes equally with a male to female ratio of 1.0, and its onset can occur at any age, but the diagnosis is most commonly observed in the range of 20 to 40 years of age. CD diminishes quality of life, interferes with social activities, traumatizes due to the stigma of incontinence, fistulae, strictures, and colostomies, and in severe cases, affects survival when compared to the general population. Symptoms fluctuate between periods of remission and activity in which complications such as fistulas, strictures, and the need for bowel resection, surgery, and colostomy implantation make up the most severe aspects of the disease. CD can be progressive and the complications recurrent despite treatment with anti-inflammatory drugs, corticosteroids, immunosuppressants, and biological agents. However, over time many patients become refractory without treatment alternatives, and in this scenario, hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment option. The rationale for the use of HSCT for CD is anchored in animal studies and human clinical trials where HSCT could reset a patient's immune system by eliminating disease-causing effector cells and upon immune recovery increase regulatory and suppressive immune cells. Autologous HSCT using a non-myeloablative regimen of cyclophosphamide and anti-thymocyte globulin without CD34+ selection has been to date the most common transplant conditioning regimen adopted. In this review we will address the current situation regarding CD treatment with HSCT and emphasize the medical, ethical, and legal aspects that permeate the procedure in Brazil., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)
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- 2020
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9. Low toxicity and favorable clinical and quality of life impact after non-myeloablative autologous hematopoietic stem cell transplant in Crohn's disease.
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Ruiz MA, Kaiser RL Jr, de Quadros LG, Piron-Ruiz L, Peña-Arciniegas T, Faria MAG, Siqueira RC, Pirozzi FF, Kaiser FSL, and Burt RK
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- Adult, Crohn Disease complications, Female, Humans, Male, Middle Aged, Transplantation, Autologous, Young Adult, Crohn Disease therapy, Hematopoietic Stem Cell Transplantation adverse effects, Quality of Life
- Abstract
Objective: The incidence of adverse events in myeloablative transplant protocols is high in refractory Crohn's disease; this study used low doses of cyclophosphamide. Fourteen patients were submitted to non-myeloablative autologous hematopoietic stem cell transplantation., Results: The average number of days of anemia (hemoglobin < 10 g/dL) was 5.4 ± 4.2 and 14 ± 2.4 in the mobilization and conditioning phases, respectively. The mean number of days of neutropenia (neutrophils < 0.5 × 10
9 /L) in the mobilization phase was 1.7 ± 1.5 while it was 7.6 ± 1.4 in the conditioning phase. When comparing the conditioning and mobilization phases, there was an increased number days of leukopenia (white blood cells < 1.0 × 109 /L), lymphocytopenia (lymphocytes < 0.5 × 109 /L) and thrombocytopenia (platelets < 25 × 109 /L). Crohn's Disease Activity Index values before the transplant ranged from 155 to 450.5 (mean 281.2 ± 79.0) and at 30 days after the procedures they ranged from 45.4 to 177 (mean 95.8 ± 35.4). Moreover, the procedure improved in overall quality of life of patients. Non-myeloablative autologous hematopoietic stem cell transplantation with lower doses of cyclophosphamide leads to lower rates of hematological toxicity and adverse events compared to protocols described in the literature. Trial registration NCT 03000296: Date 9 December 2016.- Published
- 2017
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10. Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes.
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Malmegrim KC, de Azevedo JT, Arruda LC, Abreu JR, Couri CE, de Oliveira GL, Palma PV, Scortegagna GT, Stracieri AB, Moraes DA, Dias JB, Pieroni F, Cunha R, Guilherme L, Santos NM, Foss MC, Covas DT, Burt RK, Simões BP, Voltarelli JC, Roep BO, and Oliveira MC
- Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) increases C-peptide levels and induces insulin independence in patients with type 1 diabetes. This study aimed to investigate how clinical outcomes may associate with the immunological status, especially concerning the balance between immunoregulation and autoreactivity. Twenty-one type 1 diabetes patients were monitored after AHSCT and assessed every 6 months for duration of insulin independence, C-peptide levels, frequencies of islet-specific autoreactive CD8
+ T cells (CTL), regulatory lymphocyte subsets, thymic function, and T-cell repertoire diversity. In median follow-up of 78 (range 15-106) months, all patients became insulin-independent, resuming insulin after median of 43 (range 6-100) months. Patients were retrospectively divided into short- or prolonged-remission groups, according to duration of insulin independence. For the entire follow-up, CD3+ CD4+ T-cell numbers remained lower than baseline in both groups, whereas CD3+ CD8+ T-cell levels did not change, resulting in a CD4/CD8 ratio inversion. Memory CTL comprehended most of T cells detected on long-term follow-up of patients after AHSCT. B cells reconstituted to baseline levels at 2-3 months post-AHSCT in both patient groups. In the prolonged-remission-group, baseline islet-specific T-cell autoreactivity persisted after transplantation, but regulatory T cell counts increased. Patients with lower frequencies of autoreactive islet-specific T cells remained insulin-free longer and presented greater C-peptide levels than those with lower frequencies of these cells. Therefore, immune monitoring identified a subgroup of patients with superior clinical outcome of AHSCT. Our study shows that improved immunoregulation may balance autoreactivity endorsing better metabolic outcomes in patients with lower frequencies of islet-specific T cells. Development of new strategies of AHSCT is necessary to increase frequency and function of T and B regulatory cells and decrease efficiently autoreactive islet-specific T and B memory cells in type 1 diabetes patients undergoing transplantation.- Published
- 2017
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11. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis.
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Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, Carassiti D, Reynolds R, Salvetti M, Calabresi PA, Coles AJ, Battistini L, Martin R, Burt RK, and Muraro PA
- Subjects
- Adult, Analysis of Variance, Brain metabolism, Brain pathology, Cyclophosphamide therapeutic use, Cytokines metabolism, Female, Flow Cytometry, Granzymes metabolism, Humans, Immunosuppressive Agents therapeutic use, Ki-67 Antigen metabolism, Longitudinal Studies, Lymphocyte Count, Male, Middle Aged, Mucous Membrane metabolism, Mucous Membrane pathology, Multiple Sclerosis drug therapy, Perforin metabolism, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes, Regulatory classification, Young Adult, Hematopoietic Stem Cell Transplantation methods, Interleukin-17 metabolism, Multiple Sclerosis pathology, Multiple Sclerosis surgery, T-Lymphocytes, Regulatory immunology
- Abstract
Autologous haematopoietic stem cell transplantation has been tried as one experimental strategy for the treatment of patients with aggressive multiple sclerosis refractory to other immunotherapies. The procedure is aimed at ablating and repopulating the immune repertoire by sequentially mobilizing and harvesting haematopoietic stem cells, administering an immunosuppressive conditioning regimen, and re-infusing the autologous haematopoietic cell product. 'Non-myeloablative' conditioning regimens to achieve lymphocytic ablation without marrow suppression have been proposed to improve safety and tolerability. One trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and inflammatory stabilization in treated patients with highly active multiple sclerosis. The aim of the present study was to understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action. Peripheral blood was obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and longitudinally followed for 2 years. We examined the phenotype and function of peripheral blood lymphocytes by cell surface or intracellular staining and multi-colour fluorescence activated cell sorting alone or in combination with proliferation assays. During immune reconstitution post-transplantation we observed significant though transient increases in the proportion of CD4+ FoxP3+ T cells and CD56(high) natural killer cell subsets, which are cell subsets associated with immunoregulatory function. CD8+ CD57+ cytotoxic T cells were persistently increased after therapy and were able to suppress CD4+ T cell proliferation with variable potency. In contrast, a CD161(high) proinflammatory CD8+ T cell subset was depleted at all time-points post-transplantation. Phenotypic characterization revealed that the CD161(high)CD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut mucosa but expressing the central nervous system-homing receptor CCR6. Detection of mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions confirmed their involvement in the disease pathology. Intracellular cytokine staining demonstrated interferon γ and interleukin 17 production and lack of interleukin 10 production, a pro-inflammatory profile. Mucosal-associated invariant T cell frequency did not change in patients treated with interferon β; and was more depleted after autologous haematopoietic stem cell transplantation than in patients who had received high-dose cyclophosphamide (n = 7) or alemtuzumab (n = 21) treatment alone, suggesting an additive or synergistic effect of the conditioning regime components. We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide and alemtuzumab.
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- 2013
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12. MOVING TOWARDS A DETENTE IN THE STEM CELL DEBATE.
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Burt RK, Anversa P, and Ricordi C
- Published
- 2013
13. Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction: a preclinical study.
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Burt RK, Chen YH, Verda L, Lucena C, Navale S, Johnson J, Han X, Lomasney J, Baker JM, Ngai KL, Kino A, Carr J, Kajstura J, and Anversa P
- Subjects
- Animals, Blood Pressure physiology, Cell Culture Techniques methods, Cell Proliferation, Cells, Cultured, Coculture Techniques, Embryonic Stem Cells physiology, Embryonic Stem Cells radiation effects, Female, Fibroblasts cytology, Fibroblasts physiology, Graft Survival physiology, Humans, Macaca mulatta, Mice, Mice, Inbred ICR, Mice, Inbred NOD, Mice, SCID, Myocardial Contraction physiology, Myocardial Infarction physiopathology, Myocytes, Cardiac physiology, Transcriptome, Transplantation, Heterologous, Embryonic Stem Cells cytology, Myocardial Infarction pathology, Myocardial Infarction therapy, Myocardium pathology, Myocytes, Cardiac cytology, Stem Cell Transplantation methods
- Abstract
Rationale: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown., Objective: To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences., Methods and Results: After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls., Conclusions: As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
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- 2012
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14. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up.
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Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, Testori A, Halverson A, Verda L, de Villiers WJ, Jovanovic B, and Oyama Y
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- Adalimumab, Adolescent, Adult, Animals, Antibodies, Monoclonal, Humanized, Female, Follow-Up Studies, Hematopoietic Stem Cell Mobilization, Humans, Male, Middle Aged, Rabbits, Remission Induction, Survival Rate, Time Factors, Transplantation Conditioning, Transplantation, Autologous, Treatment Outcome, Young Adult, Antibodies, Monoclonal therapeutic use, Crohn Disease therapy, Drug Resistance, Hematopoietic Stem Cell Transplantation, Myeloablative Agonists therapeutic use, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 μg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.
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- 2010
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15. Risks of immune system treatments.
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Burt RK, Abinun M, Farge-Bancel D, Fassas A, Hiepe F, Havrdová E, Ikehara S, Loh Y, Marmont du Haut Champ A, Voltarelli JC, Snowden J, and Slavin S
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- Humans, Immune System physiology, Infertility etiology, Risk, Transplantation Conditioning adverse effects, Transplantation Conditioning methods, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation adverse effects
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- 2010
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16. A case of autoimmune-related retinopathy and optic neuropathy syndrome treated by autologous nonmyeloablative hematopoietic stem cell transplantation.
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Oyama Y, Burt RK, Thirkill C, Hanna E, Merrill K, and Keltner J
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- Autoantibodies blood, Autoantigens immunology, Autoimmune Diseases immunology, Blotting, Western, Electroretinography, Eye Proteins immunology, Female, Hearing Disorders etiology, Hearing Disorders therapy, Humans, Middle Aged, Optic Nerve Diseases immunology, Retinal Diseases immunology, Syndrome, Transplantation, Autologous, Vision Disorders etiology, Vision Disorders therapy, Visual Acuity, Visual Field Tests, Visual Fields, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation, Optic Nerve Diseases therapy, Retinal Diseases therapy
- Abstract
Autoimmune-related retinopathy and optic neuropathy (ARRON) syndrome is characterized by visual loss and often the presence of antibodies against retinal or optic nerve antigens in the absence of cancer. Limited success has been reported in treatment of ARRON syndrome with medications that suppress the immune system. In many patients, current strategies are insufficient to control the disease. A 47-year-old woman with progressive visual and hearing loss attributed to ARRON syndrome that was resistant to conventional therapies underwent autologous hematopoietic stem cell transplantation (HSCT). Clinical manifestations appeared to stabilize. This report suggests that autologous HSCT may have a therapeutic role in ARRON syndrome.
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- 2009
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17. Resolution of SLE-related soft-tissue calcification following haematopoietic stem cell transplantation.
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Mandelbrot DA, Santos PW, Burt RK, Oyama Y, Block GA, Ahya SN, Rosa RM, and Traynor AE
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- Adolescent, Adult, Arm, Calcinosis pathology, Calciphylaxis etiology, Calciphylaxis pathology, Calciphylaxis therapy, Connective Tissue Diseases pathology, Female, Humans, Leg, Lupus Erythematosus, Systemic pathology, Skin Ulcer etiology, Skin Ulcer pathology, Skin Ulcer therapy, Calcinosis etiology, Calcinosis therapy, Connective Tissue Diseases etiology, Connective Tissue Diseases therapy, Hematopoietic Stem Cell Transplantation, Lupus Erythematosus, Systemic complications, Lupus Erythematosus, Systemic therapy
- Abstract
Background: Calciphylaxis and calcinosis can both cause severe morbidity and mortality in patients with systemic lupus erythematosus (SLE). Haematopoietic stem cell transplantation (HSCT) has been successfully used to treat patients with refractory SLE. It was hypothesized that in calciphylaxis and calcinosis, ongoing inflammatory activity contributes to the calcium deposition in the media of small arteries, as well as perivascular and periarticular tissues. We report three patients whose soft-tissue calcification syndromes dramatically resolved after undergoing HSCT., Methods: Three patients referred for refractory SLE underwent HSCT at a tertiary care medical center. SLE serologies and clinical features before and after HSCT were recorded., Results: Despite receiving >6 months of intravenous cyclophosphamide (CYC), three SLE patients showed signs of persistent lupus activity, including severe soft-tissue calcification. The first patient was on haemodialysis and developed severe calciphylaxis with large ulcers and tissue necrosis. The second patient had calcinosis, with palpable crystals extruding from ulcers. The third patient had calcinosis characterized by subcutaneous nodules and plaques. Because prior conventional therapies had failed, the three were treated with high-dose CYC, anti-thymocyte globulin and HSCT. They have been followed post-HSCT for 26-38 months, with excellent clinical responses, including sustained resolution of skin abnormalities., Conclusions: The successful treatment of advanced calcium deposition by aggressive immune ablation underscores the contribution of SLE-mediated inflammation to soft-tissue calcification syndromes.
- Published
- 2008
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18. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.
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Verda L, Kim DA, Ikehara S, Statkute L, Bronesky D, Petrenko Y, Oyama Y, He X, Link C, Vahanian NN, and Burt RK
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- Animals, Autoimmunity, Cell Line, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 pathology, Embryonic Stem Cells immunology, Female, Immune Tolerance, Islets of Langerhans immunology, Islets of Langerhans pathology, Lymphocyte Culture Test, Mixed, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Radiation Chimera immunology, T-Lymphocytes immunology, Transplantation, Homologous, Diabetes Mellitus, Type 1 prevention & control, Embryonic Stem Cells transplantation, Hematopoietic Stem Cell Transplantation
- Abstract
Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.
- Published
- 2008
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19. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used.
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Loh Y, Oyama Y, Statkute L, Quigley K, Yaung K, Gonda E, Barr W, Jovanovic B, Craig R, Stefoski D, Cohen B, and Burt RK
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- Adult, Autoimmune Diseases metabolism, Factor VIII antagonists & inhibitors, Factor VIII metabolism, Female, Humans, Male, Middle Aged, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Hematopoietic Stem Cell Transplantation, Transplantation Conditioning methods
- Abstract
Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.
- Published
- 2007
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20. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens.
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Burt RK, Marmont A, Oyama Y, Slavin S, Arnold R, Hiepe F, Fassas A, Snowden J, Schuening F, Myint H, Patel DD, Collier D, Heslop H, Krance R, Statkute L, Verda L, Traynor A, Kozak T, Hintzen RQ, Rose JW, Voltarelli J, Loh Y, Territo M, Cohen BA, Craig RM, Varga J, and Barr WG
- Subjects
- Autoimmune Diseases mortality, Humans, Immunosuppressive Agents therapeutic use, Lymphocytes drug effects, Myeloablative Agonists therapeutic use, Survival Rate, Transplantation, Autologous, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation methods, Randomized Controlled Trials as Topic, Transplantation Conditioning methods
- Published
- 2006
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21. Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation.
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Statkute L, Traynor A, Oyama Y, Yaung K, Verda L, Krosnjar N, and Burt RK
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- Adolescent, Adult, Antiphospholipid Syndrome immunology, Antiphospholipid Syndrome pathology, Female, Follow-Up Studies, Humans, Immunoglobulin M immunology, Lupus Erythematosus, Systemic immunology, Lupus Erythematosus, Systemic pathology, Lupus Erythematosus, Systemic surgery, Male, Middle Aged, Thrombosis complications, Treatment Outcome, Antiphospholipid Syndrome complications, Antiphospholipid Syndrome surgery, Hematopoietic Stem Cell Transplantation adverse effects, Lupus Erythematosus, Systemic complications
- Abstract
Systemic lupus erythematosus (SLE) is the most common disease associated with antiphospholipid syndrome (APS). We, therefore, evaluated 46 patients with refractory SLE treated by autologous hematopoietic stem cell transplantation (HSCT) for a history of APS prior to transplantation. The prevalence of SLE-related APS in our patient population was 61% (28 of 46 patients with refractory SLE). Nineteen of 28 patients with APS had lupus anticoagulant (LA) or high titers of anticardiolipin antibodies (ACLAs), either immunoglobulin (Ig)G or IgM, when evaluated at study entry. Six of 8 evaluable LA+ patients became and remained LA-; 5 of 7 initially ACLA IgG+ patients and 9 of 11 ACLA IgM+ patients demonstrated normalization of ACLA titers when followed after HSCT. Eighteen of 22 patients refractory to chronic anticoagulation discontinued anticoagulation therapy a median of 4 months after transplantation; 78% of them remained free of thrombotic events and in complete SLE remission for up to 78 months (median, 15 months) after HSCT. There was no treatment-related mortality. Autologous HSCT may be performed safely in patients with APS and appears to be effective therapy for eliminating ALPAs and preventing thrombotic complications in patients with SLE.
- Published
- 2005
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22. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients.
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Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, Gress RE, McFarland HF, Burt RK, and Martin R
- Subjects
- Adult, Amino Acid Sequence, Antigens, CD34 metabolism, Female, Follow-Up Studies, Humans, Immunologic Memory immunology, Leukocytes immunology, Leukocytes pathology, Male, Middle Aged, Molecular Sequence Data, Multiple Sclerosis pathology, Phenotype, Receptors, Antigen, T-Cell chemistry, T-Lymphocytes immunology, T-Lymphocytes pathology, Thymus Gland cytology, Transplantation, Autologous, Treatment Outcome, Multiple Sclerosis immunology, Multiple Sclerosis therapy, Receptors, Antigen, T-Cell immunology, Stem Cell Transplantation, Thymus Gland immunology
- Abstract
Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.
- Published
- 2005
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23. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.
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Oyama Y, Craig RM, Traynor AE, Quigley K, Statkute L, Halverson A, Brush M, Verda L, Kowalska B, Krosnjar N, Kletzel M, Whitington PF, and Burt RK
- Subjects
- Adolescent, Adult, Crohn Disease physiopathology, Female, Humans, Male, Pilot Projects, Recurrence, Remission Induction, Survival Analysis, Treatment Outcome, Crohn Disease therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Background & Aims: Crohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. Due to a high morbidity and/or an increase in mortality in refractory cases, a new treatment approach is needed. In theory, maximum immune ablation by autologous hematopoietic stem cell transplantation (HSCT) can induce a remission., Methods: We conducted a phase 1 HSCT study in 12 patients with refractory CD. Candidates were younger than 60 years of age with a Crohn's Disease Activity Index (CDAI) of 250-400 despite conventional therapies including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34 + enriched. The immune ablative (conditioning) regimen consisted of 200 mg/kg cyclophosphamide and 90 mg/kg equine antithymocyte globulin., Results: The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, and vomiting. The median days for neutrophil and platelet engraftment were 9.5 (range, 8-11) and 9 (range, 9-18), respectively. The initial median CDAI was 291 (range, 250-358). Symptoms and CDAI improved before hospital discharge, whereas radiographic and colonoscopy findings improved gradually over months to years following HSCT. Eleven of 12 patients entered a sustained remission defined by a CDAI < or =150. After a median follow-up of 18.5 months (range, 7-37 months), only one patient has developed a recurrence of active CD, which occurred 15 months after HSCT., Conclusions: Autologous HSCT may be performed safely and has a marked salutary effect on CD activity. A randomized study will be needed to confirm the efficacy of this therapy.
- Published
- 2005
- Full Text
- View/download PDF
24. Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism.
- Author
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Burt RK, Oyama Y, Verda L, Quigley K, Brush M, Yaung K, Statkute L, Traynor A, and Barr WG
- Subjects
- Alemtuzumab, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antibodies, Neoplasm therapeutic use, Antigens, CD analysis, Antigens, Differentiation, Myelomonocytic analysis, Antirheumatic Agents therapeutic use, CD3 Complex analysis, Cyclophosphamide therapeutic use, Female, Humans, Immunosuppressive Agents therapeutic use, Middle Aged, Sialic Acid Binding Ig-like Lectin 3, Vidarabine therapeutic use, Arthritis, Rheumatoid therapy, Hematopoietic Stem Cell Transplantation, Transplantation Chimera, Vidarabine analogs & derivatives
- Abstract
This report describes the first allogeneic hematopoietic stem cell transplantation (HSCT) performed for the indication of rheumatoid arthritis (RA). We used nonmyeloablative allogeneic HSCT to treat a 52-year-old woman who had treatment-refractory RA and a poor prognosis (24 swollen and 38 involved joints). She was treated with fludarabine, cyclophosphamide, CAMPATH-1H, and CD34-selected HSCT (8 million CD34+ donor cells/kg); the donor was the patient's HLA-matched, rheumatoid factor-negative sister. One year post-HSCT, the patient has had no infection except dermatomal varicella-zoster virus infection and no acute or chronic graft-versus-host disease (GVHD). Her RA has remained in remission with no immunosuppressive or immunomodulatory medications. The patient is a mixed chimera, with 55% donor T (CD3+) cells and 70% donor myeloid (CD33+) cells. This is the first published report of allogeneic HSCT performed for the indication of RA. Mixed chimerism has resulted in marked amelioration of RA, without GVHD.
- Published
- 2004
- Full Text
- View/download PDF
25. Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease.
- Author
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Burt RK, Verda L, Kim DA, Oyama Y, Luo K, and Link C
- Subjects
- Animals, Cell Differentiation drug effects, Cell Line, Chimera, Colony-Forming Units Assay, Cytokines pharmacology, Female, Graft vs Host Disease prevention & control, Hematopoiesis drug effects, Immune Tolerance, Immunocompetence, In Vitro Techniques, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes cytology, T-Lymphocytes immunology, Hematopoietic Stem Cell Transplantation, Stem Cell Transplantation, Totipotent Stem Cells
- Abstract
A single embryonic stem cell (ESC) line can be repetitively cryopreserved, thawed, expanded, and differentiated into various cellular components serving as a potentially renewable and well-characterized stem cell source. Therefore, we determined whether ESCs could be used to reconstitute marrow and blood in major histocompatibility complex (MHC)-mismatched mice. To induce differentiation toward hematopoietic stem cells (HSCs) in vitro, ESCs were cultured in methylcellulose with stem cell factor, interleukin (IL)-3, and IL-6. ESC-derived, cytokine-induced HSCs (c-kit+/CD45+) were isolated by flow cytometry and injected either intra bone marrow or intravenously into lethally irradiated MHC-mismatched recipient mice. From 2 wk to 6 mo after injection, the peripheral blood demonstrated increasing ESC-derived mononuclear cells that included donor-derived T and B lymphocytes, monocytes, and granulocytes without clinical or histologic evidence of graft-versus-host disease (GVHD). Mixed lymphocyte culture assays demonstrated T cell tolerance to both recipient and donor but intact third party proliferative responses and interferon gamma production. ESCs might be used as a renewable alternate marrow donor source that reconstitutes hematopoiesis with intact immune responsiveness without GVHD despite crossing MHC barriers.
- Published
- 2004
- Full Text
- View/download PDF
26. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.
- Author
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Burt RK, Cohen BA, Russell E, Spero K, Joshi A, Oyama Y, Karpus WJ, Luo K, Jovanovic B, Traynor A, Karlin K, Stefoski D, and Burns WH
- Subjects
- Adult, Combined Modality Therapy, Disease Progression, Female, Humans, Immunosuppressive Agents administration & dosage, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive pathology, Treatment Failure, Whole-Body Irradiation, Disability Evaluation, Hematopoietic Stem Cell Transplantation adverse effects, Multiple Sclerosis, Chronic Progressive therapy
- Abstract
There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.
- Published
- 2003
- Full Text
- View/download PDF
27. Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions.
- Author
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Burt RK, Drobyski WR, Seregina T, Traynor A, Oyama Y, Keever-Taylor C, Stefka J, Kuzel TM, Brush M, Rodriquez J, Burns W, Tennant L, and Link C
- Subjects
- Graft vs Host Disease etiology, Graft vs Leukemia Effect, Humans, Lymphocytes metabolism, Polymerase Chain Reaction, Tissue Donors, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Lymphocyte Transfusion, Simplexvirus enzymology, Thymidine Kinase genetics, Transduction, Genetic
- Abstract
Objective: Donor lymphocytes mediate both a beneficial graft-vs-leukemia/lymphoma (GVL) effect as well as graft-vs-host disease (GVHD), the most dreaded complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transduction of donor lymphocytes with a herpes simplex thymidine kinase (HSVtk) gene prior to infusion confers lethal sensitivity to the anti-herpes drug, ganciclovir (GCV). HSVtk-transduced donor lymphocyte infusions (DLI) have already been used and significant problems have limited the clinical experience to very few patients. To this end, we also report on a study of whether HSVtk-DLI induces GVHD/GVL and if infusion of GCV allows abrogation of GVHD by selective killing of donor lymphocytes., Materials and Methods: Nine patients with relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were infused with HSVtk gene-modified donor lymphocytes. In brief, transgeneic lymphocytes were prepared by 3 days of activation, 1 day of transduction, 6 days of selection with G418, and 2 to 4 weeks of expansion., Results: From 5.0 to 199 x 10(6) CD3(+) DLI were infused. There were no toxicities and no correlation between CD3(+) cell dose and either GVHD or GVL was observed. Only one patient who had cutaneous T-cell lymphoma (CTCL) developed GVHD and that same patient is the only patient to have an anti-tumor response. The patient was infused with 23 x 10(6) CD4(+) and 9.7 x 10(6) CD8(+) HSVtk DLI. Following discontinuation of immune suppression and infusion of GCV, GVHD promptly resolved. Although the CTCL relapsed, it has been easily controlled with intermittent topical therapy. One patient with acute myelogenous leukemia (AML) had a remission inversion of undetermined significance. Two patients with AML, one patient with lymphoma, and four patients with chronic myelogenous leukemia (CML) did not respond., Conclusion: HSVtk-DLI may provide an anti-tumor effect in vivo and may induce GVHD that is abrogated by GCV treatment. While technical aspects to improve response need to be perfected, HSVtk-DLI infusion to induce a transient GVL/GVHD may become an effective future therapy to minimize complications of allogeneic HSCT.
- Published
- 2003
- Full Text
- View/download PDF
28. High-dose immune suppression and autologous hematopoietic stem cell transplantation in refractory Crohn disease.
- Author
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Burt RK, Traynor A, Oyama Y, and Craig R
- Subjects
- Adolescent, Adult, Anti-Infective Agents therapeutic use, Antilymphocyte Serum, Autoimmune Diseases drug therapy, Autoimmune Diseases immunology, Combined Modality Therapy, Crohn Disease drug therapy, Crohn Disease immunology, Cyclophosphamide pharmacology, Female, Granulocyte Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cell Mobilization, Humans, Immune Tolerance, Immunosuppressive Agents administration & dosage, Infection Control, Male, Neutropenia etiology, Remission Induction, Salvage Therapy, Severity of Illness Index, T-Lymphocytes, Transplantation Conditioning, Transplantation, Autologous immunology, Autoimmune Diseases therapy, Crohn Disease therapy, Immunosuppressive Agents therapeutic use, Peripheral Blood Stem Cell Transplantation
- Abstract
Two patients with severe Crohn disease, defined by a Crohn Disease Activity Index (CDAI) higher than 250 despite anti-tumor necrosis factor alpha (TNF-alpha), were treated by intense immune suppression and autologous hematopoietic stem cell transplantation (HSCT). Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (G-CSF; 5 micro g/kg/d), enriched ex vivo by CD34+ selection, and reinfused after immune conditioning with cyclophosphamide (200 mg/kg) and equine anti-thymocyte globulin (ATG; 90 mg/kg). Patients have remained in remission (CDAI < 100) for 1 year since HSCT. We conclude that further HSCT studies for severe Crohn disease appear warranted.
- Published
- 2003
- Full Text
- View/download PDF
29. SLE - hematopoietic stem cell transplantation for systemic lupus erythematosus.
- Author
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Burt RK and Traynor AE
- Subjects
- Humans, Hematopoietic Stem Cell Transplantation methods, Lupus Erythematosus, Systemic therapy
- Abstract
Hematopoietic stem cell transplantation was first reported for patients with systemic lupus erythematosus in 1997. The procedure has since been performed worldwide including in Europe, in Brazil, and in China. A National Institutes of Health-funded phase III clinical trial of hematopoietic stem cell transplantation for refractory systemic lupus erythematosus is anticipated to begin in 2003. Encouraging responses are raising new hope about the role of adult hematopoietic stem cells in systemic lupus erythematosus.
- Published
- 2003
- Full Text
- View/download PDF
30. Plasticity of hematopoietic stem cells: enough to induce tolerance and repair tissue?
- Author
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Burt RK, Traynor AE, Oyama Y, and Barr WG
- Subjects
- Animals, Humans, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells immunology, Immune Tolerance immunology
- Published
- 2002
- Full Text
- View/download PDF
31. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure?
- Author
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Burt RK, Slavin S, Burns WH, and Marmont AM
- Subjects
- Animals, Autoimmune Diseases etiology, Autoimmune Diseases immunology, Humans, Transplantation, Autologous, Transplantation, Homologous, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation methods, Immune Tolerance
- Abstract
Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.
- Published
- 2002
- Full Text
- View/download PDF
32. Cellular suicide therapy of malignant disease.
- Author
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Link CJ, Seregina T, Traynor A, and Burt RK
- Subjects
- Animals, Female, Humans, Leukemia surgery, Ovarian Neoplasms surgery, Apoptosis physiology, Cell Transplantation, Neoplasms surgery, Transplantation, Heterologous methods, Transplantation, Homologous methods
- Abstract
Adoptive cellular therapy is developing as a supplement or alternative to chemotherapy and/or radiation for malignant disease. Our focus is two ongoing clinical studies with transgeneic (genetically altered) cellular therapy; one uses allogeneic (from another person) lymphocytes to treat leukemia, and the second uses xenogeneic (from another species) fibroblast cells genetically altered to contain a toxin-producing suicide gene to treat ovarian cancer. Allogeneic donor lymphocyte infusions (DLI) are known to induce remission of hematologic malignancies. However, the toxicity associated with DLI is related to graft-versus-host-disease, which is due to donor lymphocytes attacking normal tissue in the recipient. Therefore, we have taken the approach of infusing DLI that have been modified to contain a latent suicide gene to treat leukemia. To treat ovarian cancer, we used xenogeneic nonimmune fibroblast-derived cells to deliver a tumor-directed cytotoxic gene to carcinoma cells. These cells release HStk transgene retroviruses that in turn transduce replicating tumor cells but not quiescent epithelium, rendering the tumor selectively susceptible to ganciclovir-mediated killing. These initial trials summarize the early stage of allogeneic/xenogeneic adoptive cellular therapy for cancer, and although the data are limited, it is encouraging to see some patients with evidence of antitumor responses. Advances in our understanding of the basic science of these treatments, together with improvements in the technology of vector design, will be required to streamline these methodologies into broader application.
- Published
- 2000
- Full Text
- View/download PDF
33. Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murine encephalomyelitis virus-induced demyelinating disease.
- Author
-
Burt RK, Padilla J, Dal Canto MC, and Miller SD
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmune Diseases virology, Cardiovirus Infections immunology, Cardiovirus Infections virology, Contraindications, Cytokines biosynthesis, Cytopathogenic Effect, Viral, Demyelinating Diseases immunology, Demyelinating Diseases virology, Disease Models, Animal, Disease Progression, Female, Genetic Predisposition to Disease, Humans, Immunocompromised Host, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred Strains, Myelin Sheath immunology, Spinal Cord metabolism, Spinal Cord virology, T-Lymphocytes, Cytotoxic immunology, Theilovirus immunology, Theilovirus isolation & purification, Virus Latency, Virus Replication, Whole-Body Irradiation, Autoimmune Diseases therapy, Cardiovirus Infections therapy, Central Nervous System virology, Demyelinating Diseases therapy, Hematopoietic Stem Cell Transplantation adverse effects, Lymphocyte Depletion adverse effects, Multiple Sclerosis therapy, Theilovirus physiology
- Abstract
Theiler's murine encephalomyelitis virus (TMEV) establishes a persistent infection in the central nervous system (CNS) leading to an inflammatory demyelinating disease of the CNS in which the histology and clinical course is similar to multiple sclerosis (MS). Disease pathogenesis is primarily due to T-cell-mediated destruction of myelin, which has been attributed to cytopathic effects of the virus, but immune-mediated destruction of myelin mediated via both virus-specific and myelin-specific T cells appear to play the major role. To determine if bone marrow transplantation would be an effective therapy for a virus-initiated autoimmune disease and to better separate viral cytopathic effects from immune-mediated demyelination, we ablated the immune system of TMEV-infected animals with 1,100 cGy total body irradiation, and then the animal's immunity was reconstituted by transplantation of disease-susceptible SJL/J mice with syngeneic marrow or disease-susceptible DBA/2J with marrow from disease-resistant (C57Bl/6 x DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed after onset of disease resulted in 42% mortality in SJL/J syngeneic transplants, 47% mortality in diseased DBA2 recipients restored with marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients receiving marrow from B6D2 donors previously infected with TMEV. Delayed type hypersensitivity (DTH) to both virion and myelin proteins was decreased in surviving mice that underwent transplantation; however, CNS viral titers were significantly elevated compared with nontransplanted controls. We conclude that a functional immune system with appropriate T-cell responses are important in prevention of lethal cytopathic CNS effects from TMEV. Relevant to the clinical use of bone marrow transplantation, attempts to ablate the immune system in viral-mediated immune diseases or virus-initiated autoimmune disease may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively depleted of lymphocytes.
- Published
- 1999
34. Haematopoietic stem cell transplantation for active systemic lupus erythematosus.
- Author
-
Traynor A and Burt RK
- Subjects
- Adult, Female, Follow-Up Studies, Humans, Lupus Erythematosus, Systemic diagnosis, Nephritis diagnosis, Nephritis pathology, Nephritis therapy, Transplantation, Autologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Lupus Erythematosus, Systemic therapy
- Abstract
Objective: For patients with systemic lupus erythematosus (SLE) who are at risk of disease-related mortality, we have initiated a protocol of intensive immunosuppression and haematopoietic stem cell support. The first patient enrolled in this study was in the midst of a lupus flare manifest by nephritis and rapidly declining renal function, uncontrolled hypertension, immune-mediated cytopenias, and serositis characterized by a large pericardial effusion and abdominal pain. Antinuclear antibody (ANA), anti-double-stranded (ds) DNA and complement were abnormal. This patient is now more than 1 yr post-stem cell transplant and is taking no immunosuppressive medication. Her serologies are normal, effusions have resolved, blood pressure is normal and renal function is markedly improved. The clinical and serological course of this patient is summarized here., Methods: Autologous haematopoietic stem cells (HSC) were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (G-CSF) (10 microg/kg/day). Stem cells were enriched ex vivo using CD34-positive immunoselection and reinfused after immunosuppression with cyclophosphamide (200 mg/kg) and antithymocyte globulin (ATG) (90 mg/kg)., Results: White blood cell engraftment with an absolute neutrophil count (ANC) of >500/microl (0.5 x 10(9)/l) and platelet engraftment with a non-transfused platelet count of >20000/microl (20 x 10(9)/l) occurred on day 10 and 14, respectively. Therapy was complicated by a cell lysis-like effect with hyperphosphataemia, hyperuricaemia, normal anion gap metabolic acidosis and transient exacerbation of renal insufficiency., Conclusion: This is the first autologous T-cell-depleted haematopoietic stem cell transplantation performed to treat lupus in an active flare. This patient has, for the first time since discase onset (13 yr ago), entered a complete clinical and serological remission which persists at >1 yr of follow-up. The durability of this remission is unknown.
- Published
- 1999
- Full Text
- View/download PDF
35. Clinical utility in maximizing CD34+ cell count in stem cell grafts.
- Author
-
Burt RK
- Subjects
- Graft vs Host Disease prevention & control, Hematopoiesis, Humans, Prognosis, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Antigens, CD34 analysis, Hematopoietic Stem Cell Transplantation
- Published
- 1999
36. Hematopoietic stem cell transplantation: a new therapy for autoimmune disease.
- Author
-
Burt RK and Traynor AE
- Subjects
- Adolescent, Adult, Female, Humans, Lupus Erythematosus, Systemic complications, Pneumonia etiology, Pneumonia therapy, Hematopoietic Stem Cell Transplantation, Lupus Erythematosus, Systemic therapy, Multiple Sclerosis therapy
- Published
- 1999
- Full Text
- View/download PDF
37. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation.
- Author
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Burt RK, Traynor AE, Pope R, Schroeder J, Cohen B, Karlin KH, Lobeck L, Goolsby C, Rowlings P, Davis FA, Stefoski D, Terry C, Keever-Taylor C, Rosen S, Vesole D, Fishman M, Brush M, Mujias S, Villa M, and Burns WH
- Subjects
- Activities of Daily Living, Adult, Antigens, CD34 analysis, Antilymphocyte Serum therapeutic use, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid therapy, Autoimmune Diseases drug therapy, Combined Modality Therapy, Cyclophosphamide therapeutic use, Female, Granulocyte Colony-Stimulating Factor therapeutic use, Hematopoietic Stem Cell Mobilization, Humans, Immune Tolerance, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic therapy, Methylprednisolone therapeutic use, Middle Aged, Multiple Sclerosis drug therapy, Multiple Sclerosis therapy, Transplantation, Autologous, Treatment Outcome, Whole-Body Irradiation, Autoimmune Diseases therapy, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents therapeutic use, Transplantation Conditioning
- Abstract
Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis are immune-mediated diseases that are responsive to suppression or modulation of the immune system. For patients with severe disease, immunosuppression may be intensified to the point of myelosuppression or hematopoietic ablation. Hematopoiesis and immunity may then be rapidly reconstituted by reinfusion of CD34(+) progenitor cells. In 10 patients with these autoimmune diseases, autologous hematopoietic stem cells were collected from bone marrow or mobilized from peripheral blood with either granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF. Stem cells were enriched ex vivo using CD34(+) selection and reinfused after either myelosuppressive conditioning with cyclophosphamide (200 mg/kg), methylprednisolone (4 g) and antithymocyte globulin (ATG; 90 mg/kg) or myeloablative conditioning with total body irradiation (1,200 cGy), methylprednisolone (4 g), and cyclophosphamide (120 mg/kg). Six patients with multiple sclerosis, 2 with systemic lupus erythematosus, and 2 with rheumatoid arthritis have undergone hematopoietic stem cell transplantation. Mean time to engraftment of an absolute neutrophil count greater than 500/microL (0.5 x 10(9)/L) and a nontransfused platelet count greater than 20,000/microL (20 x 10(9)/L) occurred on day 10 and 14, respectively. Regimen-related nonhematopoietic toxicity was minimal. All patients improved and/or had stabilization of disease with a follow-up of 5 to 17 months (median, 11 months). We conclude that intense immunosuppressive conditioning and autologous T-cell-depleted hematopoietic transplantation was safely used to treat these 10 patients with severe autoimmune disease. Although durability of response is as yet unknown, all patients have demonstrated stabilization or improvement.
- Published
- 1998
38. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis.
- Author
-
Burt RK, Padilla J, Begolka WS, Canto MC, and Miller SD
- Subjects
- Animals, Encephalomyelitis, Autoimmune, Experimental pathology, Encephalomyelitis, Autoimmune, Experimental physiopathology, Female, Mice, Recurrence, Transplantation, Isogeneic, Treatment Outcome, Bone Marrow Transplantation, Encephalomyelitis, Autoimmune, Experimental therapy
- Abstract
Relapsing experimental autoimmune encephalomyelitis (R-EAE) is an immune-mediated demyelinating central nervous system (CNS) disease. Myeloablation and syngeneic bone marrow transplantation (SBMT), when performed at the peak of acute disease (day 14), prevented glial scarring and ameliorated the disease severity. In contrast, when syngeneic BMT was performed late in chronic phase (day 78), significant glial scarring remained and the clinical severity did not differ significantly from that of the controls. After SBMT in either the acute or chronic phase of disease, the posttransplant immune system remained responsive to myelin epitopes as determined by in vitro proliferation and interferon-gamma (IFN-gamma) production. However, in mice undergoing SBMT, in vivo delayed-type hypersensitivity (DTH) responses were significantly decreased while IFN-gamma RNA levels and inflammatory infiltrates within the CNS were slightly improved. We conclude that failure of SBMT to improve the clinical disease when performed in chronic phase may be due to preexisting glial scarring. We also conclude that in the absence of glial scarring and irreversible neuronal injury, in vivo DTH responses and histology are better predictors of clinical improvement than in vitro proliferation or IFN-gamma cytokine production.
- Published
- 1998
39. Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.
- Author
-
Link CJ Jr, Burt RK, Traynor AE, Drobyski WR, Seregina T, Levy JP, Gordon L, Rosen ST, Burns WH, Camitta B, Casper J, Horowitz M, Juckett M, Lawton C, Margolis D, Pietryga D, Rowlings P, Taylor C, Furtado M, Stefka J, Gupta-Burt S, Kaiser H, and Vesole DH
- Subjects
- Evaluation Studies as Topic, Genetic Vectors, Humans, Immunotherapy, Adoptive adverse effects, Lymphocytes cytology, Lymphocytes metabolism, Patient Selection, Remission Induction methods, Simplexvirus enzymology, Thymidine Kinase metabolism, Clinical Protocols, Immunotherapy, Adoptive methods, Leukemia, Lymphoid therapy, Thymidine Kinase genetics
- Abstract
This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.
- Published
- 1998
- Full Text
- View/download PDF
40. Antineoplastic drug resistance and DNA repair.
- Author
-
Burt RK, Poirier MC, Link CJ Jr, and Bohr VA
- Subjects
- DNA, Neoplasm genetics, DNA-Directed DNA Polymerase genetics, Humans, In Vitro Techniques, Neoplasms genetics, Neoplasms pathology, Pyrimidine Dimers genetics, Antineoplastic Agents therapeutic use, DNA Repair drug effects, DNA, Neoplasm drug effects, Drug Resistance genetics, Genes, Regulator genetics, Neoplasms drug therapy
- Abstract
Important aspects of the DNA repair mechanisms in mammalian, and especially human, cells are reviewed. The DNA repair processes are essential in the maintenance of the integrity of the DNA and in the defense against cancer. It has recently been discovered that the DNA repair efficiency differs in different regions of the genome and that active genes are preferentially repaired. There is mounting evidence that DNA repair processes play a role in the development of drug resistance by tumor cells. We will discuss such data as well as further approaches to clarify the relationship between DNA repair and antineoplastic drug resistance. Specifically, there is an increasing need to investigate the intragenomic heterogeneity of DNA repair and correlate the repair efficiency in specific genes to aspects of drug resistance. We also discuss the therapeutic potential of inhibiting the DNA repair processes and thereby possibly overcoming drug resistance.
- Published
- 1991
- Full Text
- View/download PDF
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