Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation.

High dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission in multiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8(+)T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1(+)CD8(+)T-cells and of PD-1-expressing CD19(+) B-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis.

Autologous haematopoietic stem-cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to 'reboot' the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify, through a robust and unbiased transcriptomic analysis, any changes of gene expression in T-cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T-cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T-cells of MS patients at 2 years post-transplantation, aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy, we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T-cell subsets at all time points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data, a number of significant changes in both the CD4+ and CD8+ T-cells subsets from MS post-transplant. Notably, CD8+ T-cells revealed more extensive changes in the expression of genes involved in effector immune responses.

Cyclosporine level: difference between blood samples collected through peripheral and central venous access.

AIMS AND OBJECTIVES: To identify differences in cyclosporine levels between blood samples collected from a peripheral venous access, catheter line used for drug infusion and catheter line not used for drug infusion in adult patients receiving allogeneic haematopoietic stem cell transplantation. Background. Cyclosporine is an immunosuppressant that prevents graft-versus-host disease, has a narrow therapeutic window and causes nephrotoxicity. For cyclosporine infusion, a tunnelled central venous access device is used; however, because of the lipophilic properties of the drug, it can adsorb to the catheter surface and falsely raise cyclosporine concentrations in blood specimens. DESIGN: Prospective observational study. METHODS: The study collected 135 blood samples from 16 patients. In 13 subjects, samples were obtained from the three lines at three time points (1, 7 and 14 days after the start of cyclosporine infusion), and for three subjects, samples were only obtained at 1 and 7 days after the start of infusion. The 5-ml blood discard method was used for samples collected from the catheter. Using this procedure, the catheter line was washed with saline solution, 5 ml of blood and saline solution were aspirated from the catheter line and discarded, and then sample blood used for the test was collected. The paired t-test with the Bonferroni correction was used to analyse the differences in cyclosporine serum levels. RESULTS: Significant differences were observed when the drug serum levels obtained in the line used for drug infusion were compared with the levels obtained in the line not used for infusion or the peripheral venous line. No differences in drug levels were identified in blood collected from the peripheral venous line and the line not used for drug infusion. CONCLUSION: Drug adsorption occurs in the line used for infusion. Therefore, the blood sample collected from the line not used for cyclosporine infusion can be considered reliable for drug concentration determination. RELEVANCE TO CLINICAL PRACTICE: Nurses should standardise one line of the tunnelled central venous access device for cyclosporine infusion, which avoids the need for evasive procedures and provides patients with more comfort.

Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-κB signalling.

Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T cells into regulatory T cells in vitro. The marker CD69 is a target of canonical nuclear factor kappa-B (NF-κB) signalling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3(+) T cells were activated and cultured in the presence or absence of MSCs. CD4(+) cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 (BAY) and a siRNA against v-rel reticuloendotheliosis viral oncogene homolog B (RELB) were used to explore the differential roles of canonical and non-canonical NF-κB signalling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69(+) cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69(+) cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signalling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signalling on the third day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signalling.

Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial.

PURPOSE: To evaluate the short-term (10 months) safety of a single intravitreal injection of autologous bone marrow-derived mononuclear cells in patients with retinitis pigmentosa or cone-rod dystrophy. METHODS: A prospective, Phase I, nonrandomized, open-label study including 3 patients with retinitis pigmentosa and 2 patients with cone-rod dystrophy and an Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/200 or worse. Evaluations including best-corrected visual acuity, full-field electroretinography, kinetic visual field (Goldman), fluorescein and indocyanine green angiography, and optical coherence tomography were performed at baseline and 1, 7, 13, 18, 22, and 40 weeks after intravitreal injection of 10 × 10(6) autologous bone marrow-derived mononuclear cells (0.1 mL) into 1 study eye of each patient. RESULTS: No adverse event associated with the injection was observed. A 1-line improvement in best-corrected visual acuity was measured in 4 patients 1 week after injection and was maintained throughout follow-up. Three patients showed undetectable electroretinography responses at all study visits, while 1 patient demonstrated residual responses for dark-adapted standard flash stimulus (a wave amplitude approximately 35 µV), which remained recordable throughout follow-up, and 1 patient showed a small response (a wave amplitude approximately 20 µV) recordable only at Weeks 7, 13, 22, and 40. Visual fields showed no reduction (with a Goldman Standard V5e stimulus) for any patient at any visit. No other changes were observed on optical coherence tomography or fluorescein and indocyanine green angiograms. CONCLUSION: Intravitreal injection of autologous bone marrow-derived mononuclear cells in eyes with advanced retinitis pigmentosa or cone-rod dystrophy was associated with no detectable structural or functional toxicity over a period of 10 months. Further studies are required to investigate the role, if any, of autologous bone marrow-derived mononuclear cell therapy in the management of retinal dystrophies.

Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study.

BACKGROUND: Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta. METHODS: Eligible patients had relapsing-remitting MS, attended Northwestern Memorial Hospital, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse. Peripheral blood haemopoietic stem cells were mobilised with 2 g per m2 cyclophosphamide and 10 microg per kg per day filgrastim. The conditioning regimen for the haemopoietic stem cells was 200 mg per kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg per kg rabbit antithymocyte globulin. Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation. We also sought to investigate the safety and tolerability of autologous non-myeloablative haemopoietic stem cell transplantation. FINDINGS: Between January, 2003, and February, 2005, 21 patients were treated. Engraftment of white blood cells and platelets was on median day 9 (range day 8-11) and patients were discharged from hospital on mean day 11 (range day 8-13). One patient had diarrhoea due to Clostridium difficile and two patients had dermatomal zoster. Two of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy. 17 of 21 patients (81%) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and five patients (24%) relapsed but achieved remission after further immunosuppression. After a mean of 37 months (range 24-48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses. Significant improvements were noted in neurological disability, as determined by EDSS score (p<0.0001), neurological rating scale score (p=0.0001), paced auditory serial addition test (p=0.014), 25-foot walk (p<0.0001), and quality of life, as measured with the short form-36 (SF-36) questionnaire (p<0.0001). INTERPRETATION: Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial.

C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus.

CONTEXT: In 2007, the effects of the autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in 15 patients with type 1 diabetes mellitus (DM) were reported. Most patients became insulin free with normal levels of glycated hemoglobin A(1c) (HbA(1c)) during a mean 18.8-month follow-up. To investigate if this effect was due to preservation of beta-cell mass, continued monitoring was performed of C-peptide levels after stem cell transplantation in the 15 original and 8 additional patients. OBJECTIVE: To determine C-peptide levels after autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM during a longer follow-up. DESIGN, SETTING, AND PARTICIPANTS: A prospective phase 1/2 study of 23 patients with type 1 DM (aged 13-31 years) diagnosed in the previous 6 weeks by clinical findings with hyperglycemia and confirmed by measurement of serum levels of anti-glutamic acid decarboxylase antibodies. Enrollment was November 2003-April 2008, with follow-up until December 2008 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil. Hematopoietic stem cells were mobilized via the 2007 protocol. MAIN OUTCOME MEASURES: C-peptide levels measured during the mixed-meal tolerance test, before, and at different times following HSCT. Secondary end points included morbidity and mortality from transplantation, temporal changes in exogenous insulin requirements, and serum levels of HbA(1c). RESULTS: During a 7- to 58-month follow-up (mean, 29.8 months; median, 30 months), 20 patients without previous ketoacidosis and not receiving corticosteroids during the preparative regimen became insulin free. Twelve patients maintained this status for a mean 31 months (range, 14-52 months) and 8 patients relapsed and resumed insulin use at low dose (0.1-0.3 IU/kg). In the continuous insulin-independent group, HbA(1c) levels were less than 7.0% and mean (SE) area under the curve (AUC) of C-peptide levels increased significantly from 225.0 (75.2) ng/mL per 2 hours pretransplantation to 785.4 (90.3) ng/mL per 2 hours at 24 months posttransplantation (P < .001) and to 728.1 (144.4) ng/mL per 2 hours at 36 months (P = .001). In the transient insulin-independent group, mean (SE) AUC of C-peptide levels also increased from 148.9 (75.2) ng/mL per 2 hours pretransplantation to 546.8 (96.9) ng/mL per 2 hours at 36 months (P = .001), which was sustained at 48 months. In this group, 2 patients regained insulin independence after treatment with sitagliptin, which was associated with increase in C-peptide levels. Two patients developed bilateral nosocomial pneumonia, 3 patients developed late endocrine dysfunction, and 9 patients developed oligospermia. There was no mortality. CONCLUSION: After a mean follow-up of 29.8 months following autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00315133.

Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus.

CONTEXT: Type 1 diabetes mellitus (DM) results from a cell-mediated autoimmune attack against pancreatic beta cells. Previous animal and clinical studies suggest that moderate immunosuppression in newly diagnosed type 1 DM can prevent further loss of insulin production and can reduce insulin needs. OBJECTIVE: To determine the safety and metabolic effects of high-dose immunosuppression followed by autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in newly diagnosed type 1 DM. DESIGN, SETTING, AND PARTICIPANTS: A prospective phase 1/2 study of 15 patients with type 1 DM (aged 14-31 years) diagnosed within the previous 6 weeks by clinical findings and hyperglycemia and confirmed with positive antibodies against glutamic acid decarboxylase. Enrollment was November 2003-July 2006 with observation until February 2007 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil. Patients with previous diabetic ketoacidosis were excluded after the first patient with diabetic ketoacidosis failed to benefit from AHST. Hematopoietic stem cells were mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (10 microg/kg per day) and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg). MAIN OUTCOME MEASURES: Morbidity and mortality from transplantation and temporal changes in exogenous insulin requirements (daily dose and duration of usage). Secondary end points: serum levels of hemoglobin A1c, C-peptide levels during the mixed-meal tolerance test, and anti-glutamic acid decarboxylase antibody titers measured before and at different times following AHST. RESULTS: During a 7- to 36-month follow-up (mean 18.8), 14 patients became insulin-free (1 for 35 months, 4 for at least 21 months, 7 for at least 6 months; and 2 with late response were insulin-free for 1 and 5 months, respectively). Among those, 1 patient resumed insulin use 1 year after AHST. At 6 months after AHST, mean total area under the C-peptide response curve was significantly greater than the pretreatment values, and at 12 and 24 months it did not change. Anti-glutamic acid decarboxylase antibody levels decreased after 6 months and stabilized at 12 and 24 months. Serum levels of hemoglobin A(1c) were maintained at less than 7% in 13 of 14 patients. The only acute severe adverse effect was culture-negative bilateral pneumonia in 1 patient and late endocrine dysfunction (hypothyroidism or hypogonadism) in 2 others. There was no mortality. CONCLUSIONS: High-dose immunosuppression and AHST were performed with acceptable toxicity in a small number of patients with newly diagnosed type 1 DM. With AHST, beta cell function was increased in all but 1 patient and induced prolonged insulin independence in the majority of the patients.

Immunological Balance Is Associated with Clinical Outcome after Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes.

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.

Transcriptional profiling reveals intrinsic mRNA alterations in multipotent mesenchymal stromal cells isolated from bone marrow of newly-diagnosed type 1 diabetes patients.

BACKGROUND: Bone marrow multipotent mesenchymal stromal cells (MSCs) are a diverse subset of precursors that contribute to the homeostasis of the hematopoietic niche. MSCs can be isolated and expanded in vitro and have unique immunomodulatory and regenerative properties that make them attractive for the treatment of autoimmune diseases, including type 1 diabetes (T1D). Whether autologous or allogeneic MSCs are more suitable for therapeutic purposes has not yet been established. While autologous MSCs may present abnormal function, allogeneic cells may be recognized and rejected by the host immune system. Thus, studies that investigate biological characteristics of MSCs isolated from T1D patients are essential to guide future clinical applications. METHODS: Bone marrow-derived MSCs from recently diagnosed type 1 diabetes patients (T1D-MSCs) were compared with those from healthy individuals (C-MSCs) for morphological and immunophenotypic characteristics and for differentiation potential. Bioinformatics approaches allowed us to match absolute and differential gene expression of several adhesion molecules, immune mediators, growth factors, and their receptors involved with hematopoietic support and immunomodulatory properties of MSCs. Finally, the differentially expressed genes were collated for functional pathway enrichment analysis. RESULTS: T1D-MSCs and C-MSCs were similar for morphology, immunophenotype, and differentiation potential. Our absolute gene expression results supported previous literature reports, while also detecting new potential molecules related to bone marrow-derived MSC functions. T1D-MSCs showed intrinsic abnormalities in mRNA expression, including the immunomodulatory molecules VCAM-1, CXCL12, HGF, and CCL2. Pathway analyses revealed activation of sympathetic nervous system and JAK STAT signaling in T1D-MSCs. CONCLUSIONS: Collectively, our results indicate that MSCs isolated from T1D patients present intrinsic transcriptional alterations that may affect their therapeutic potential. However, the implications of these abnormalities in T1D development as well as in the therapeutic efficacy of autologous MSCs require further investigation.

Myosin-V colocalizes with MHC class II in blood mononuclear cells and is up-regulated by T-lymphocyte activation.

Myosin-V is involved in organelle and vesicle trafficking in Saccharomyces cerevisiae and in other eukaryotic cells from yeast to human. In the present study, we determined by FACS that the major subpopulations of the peripheral blood mononuclear cells express myosin-V with similar fluorescence intensity. Confocal microscopy showed intense labeling for myosin-V at the centrosomal region and a punctate staining throughout the cytoplasm, frequently associated with the central microtubule arrays and the actin-rich cortex. Some degree of overlap with an endolysosomal marker and dynein light-chain 8 k was found at the cell center. Striking colocalization was observed with the major histocompatibility complex (MHC) class II molecules near the cell surface. Treatment with phytohemagglutinin, which induces T-lymphocyte activation, associated with MHC class II expression, increased the levels of myosin-V protein and mRNA for the three members of class V myosins. These data suggest that class V myosins might be involved in relevant functions in the immune response.

Fusarium infection in hematopoietic stem cell transplant recipients.

To characterize the epidemiology and prognostic factors of invasive fusariosis in hematopoietic stem cell transplant (HSCT) recipients, the records of HSCT recipients from 9 hospitals (7 in Brazil and 2 in the United States) were retrospectively reviewed. Sixty-one cases were identified: 54 in allogeneic HSCT recipients and 7 in autologous HSCT recipients. The incidence of fusariosis among allogeneic HSCT recipients varied between a range of 4.21-5.0 cases per 1000 in human leukocyte antigen (HLA)--matched related transplant recipients to 20.19 cases per 1000 in HLA-mismatched transplant recipients. The median time period between transplantation and diagnosis of fusariosis was 48 days. Among allogeneic HSCT recipients, a trimodal distribution was observed: a first peak before engraftment, a second peak at a median of 62 days after transplantation, and a third peak >1 year after transplantation. The actuarial survival was 13% (median, 13 days). Persistent neutropenia was the single prognostic factor for death identified by multivariate analysis.

Immunological evaluation of patients with recurrent abortion.

In a prospective study, we performed immunological tests in patients with recurrent abortion. Nine couples with two or more fetal losses of no apparent cause were selected as the patient group, and nine volunteer couples with at least two children and without a history of abortion were used as controls. The frequency of major histocompatibility complex (human leukocyte antigens, HLA) antigen sharing was determined by serological methods, antipaternal antibodies by microlymphocytotoxicity, lymphocyte phenotypes (CD4, CD8, CD19, CD16, CD56 and HLA-DR positive cells) by flow cytometry and natural killer (NK) cytotoxicity by (51)Cr release. NK activity was correlated to the degree of HLA-C sharing and to the percentage of CD16+ and CD56+ cells and to progesterone levels measured by radioimmunoassay. No difference in class I or class II HLA antigen sharing was detected between couples with and without recurrent abortion. Antipaternal antibodies were not found in the serum of any woman of the study. A higher absolute number of CD8+ cells (P=0.01) and a trend to increased CD19+ cells (P=0.05) were observed among patients. NK activity did not differ between the two groups when expressed as specific cytotoxicity and it was reduced among patients with recurrent abortion when expressed as lytic units/10(7) cells (P=0.04). There was correlation between NK activity and the percentage of CD16+ and CD56+ cells but not with progesterone levels in patients with recurrent abortion. Our data suggest that an increased NK activity may not play a role in the occurrence of repeated abortion. On the other hand, an increase in circulating CD8+ T cells was observed in patients suggesting that antifetal cytotoxicity in recurrent abortion may be mediated by T cells and not by NK cells.

Immunological aspects in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron death, leading to muscle atrophy, paralysis, and death usually within 3 to 5 years after diagnosis. Most cases are sporadic, with still undefined etiopathogenesis. Both the innate and adaptive immune systems are involved in ALS, with special participation of T lymphocytes and microglia. Inflammation plays a dual role in the disease, protective and T regulatory cell rich in the early stages and deleterious as disease progresses. Attempts to modulate immune/inflammatory system response are reported in the literature, and while beneficial effects are achieved in ALS animal models, results of most clinical trials have been disappointing. The impaired blood-brain barrier is an important feature in the pathogenesis of ALS and likely affects the immune system response. The present review describes the role of the immune system in ALS pathogenesis and the tight coupling of immunity and central nervous system barrier function.

Neurovascular aspects of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated and poorly understood pathogenesis. Strong evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models. The present review provides an updated analysis of the microvascular pathology and impaired BBB/BSCB in ALS. Based on experimental and clinical ALS studies, the roles of cellular components, cell interactions, tight junctions, transport systems, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption are discussed. The impact of BBB/BSCB damage in ALS pathogenesis is a novel research topic, and this review will reveal some aspects of microvascular pathology involved in the disease and hopefully engender new therapeutic approaches.

Stem cell therapy for diabetes mellitus.

In this review, we present (1) a brief discussion of hematopoietic stem cell transplantation (HSCT) for severe and refractory autoimmune diseases (AIDs) from its beginning in 1996 through recently initiated prospective randomized clinical trials; (2) an update (up to July 2009) of clinical and laboratory outcomes of 23 patients with newly diagnosed type 1 diabetes mellitus (T1DM), who underwent autologous HSCT at the Bone Marrow Transplantation Unit of the Ribeirão Preto Medical School, University of São Paulo, Brazil; (3) a discussion of possible mechanisms of action of HSCT in AIDs, including preliminary laboratory data obtained from our patients; and (4) a discussion of future perspectives of stem cell therapy for T1DM and type 2 DM, including the use of stem cell sources other than adult bone marrow and the combination of cell therapy with regenerative compounds.

Autologous hematopoietic stem cell transplantation for childhood autoimmune disease.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used in the management of patients with autoimmune disorders. Experience gained in adults has helped to better define the conditioning regimens required and appropriate selection of patients who are most likely to benefit from autologous HSCT. The field has been shifting toward the use of safer and less intense nonmyeloablative regimens used earlier in the disease course before patients accumulate extensive irreversible organ damage. This article reviews the experience of using autologous HSCT in treating the most common childhood autoimmune and rheumatic diseases, primarily juvenile idiopathic arthritis, systemic lupus erythematosus, and diabetes mellitus.

Stem cell transplantation for type 1 diabetes mellitus.

BACKGROUND: The use of stem cells to treat type 1 diabetes mellitus has been proposed for many years, both to downregulate the immune system and to provide beta cell regeneration. CONCLUSION: High dose immunosuppression followed by autologous hematopoietic stem cell transplantation is able to induce complete remission (insulin independence) in most patients with early onset type 1 diabetes mellitus.

Autologous hematopoietic stem cell transplantation for type 1 diabetes.

In this review, we present (1) the scientific basis for the use of high-dose immunosuppression followed by autologous peripheral blood hematopoietic stem cell transplantation for newly diagnosed type 1 diabetes (T1D); (2) an update of the clinical and laboratory outcome of 20 patients transplanted at the University Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil, and followed up to January/2008, including 4 relapses among 19 patients without previous ketoacidosis; (3) a commentary on criticisms to our article that appeared in four articles from the scientific literature; and (4) a discussion of the prospectives for cellular therapy for T1D.