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.

CCUMULATED CLINICAL EXPErience indicates that there is an inverse association between beta-cell function and chronic complications of type 1 diabetes mellitus (DM)-the higher the Cpeptide levels (an indirect measure of viable beta-cell function), the lower the incidence of microvascular complications of type 1 DM. 1 Since the establishment of the autoimmune etiology of type 1 DM in the late 1970s, many clinical trials analyzing the effects of different types of immune interventions demonstrated that beta-cell preservation is an achievable target in different degrees. 2,3 Based on the theory of possible reconstitution of immune tolerance after "immunologic reset" with autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT), 4 in 2007, we reported a phase 1/2 trial evaluating the safety and metabolic effects of autologous nonmyeloablative HSCT in 15 patients with newly diagnosed type 1 DM. 5 The majority of pa-Author Affiliations are listed at the end of this article.

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.

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.

BackgroundType 1 diabetes mellitus (T1D) is characterized by autoimmune responses resulting in destruction of insulin-producing pancreatic beta cells. Multipotent mesenchymal stromal cells (MSCs) exhibit immunomodulatory potential, migratory capacity to injured areas and may contribute to tissue regeneration by the secretion of bioactive factors. Therefore, MSCs are considered as a promising approach to treat patients with different autoimmune diseases (AID), including T1D patients. Phenotypical and functional alterations have been reported in MSCs derived from patients with different AID. However, little is known about the properties of MSCs derived from patients with T1D. Since autoimmunity and the diabetic microenvironment may affect the biology of MSCs, it becomes important to investigate whether these cells are suitable for autologous transplantation. Thus, the aim of the present study was to evaluate the in vitro properties and the in vivo therapeutic efficacy of MSCs isolated from bone marrow of newly diagnosed T1D patients (T1D-MSCs) and to compare them with MSCs from healthy individuals (C-MSCs).MethodsT1D-MSCs and C-MSCs were isolated and cultured until third passage. Then, morphology, cell diameter, expression of surface markers, differentiation potential, global microarray analyses and immunosuppressive capacity were in vitro analyzed. T1D-MSCs and C-MSCs therapeutic potential were evaluated using a murine experimental model of streptozotocin (STZ)-induced diabetes.ResultsT1D-MSCs and C-MSCs presented similar morphology, immunophenotype, differentiation potential, gene expression of immunomodulatory molecules and in vitro immunosuppressive capacity. When administered into diabetic mice, both T1D-MSCs and C-MSCs were able to reverse hyperglycemia, improve beta cell function and modulate pancreatic cytokine levels.ConclusionsThus, bone marrow MSCs isolated from T1D patients recently after diagnosis are not phenotypically or functionally impaired by harmful inflammatory and metabolic diabetic conditions. Our results provide support for the use of autologous MSCs for treatment of newly diagnosed T1D patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0261-4) contains supplementary material, which is available to authorized users.

BackgroundSince its first description, Mönckeberg's sclerosis has only been related to arterial media calcification, being listed among the primary diseases of the vessels.Case presentationWe report here a clinically and histologically confirmed case of Mönckeberg's sclerosis in which the patient presented with massive areas of soft tissue calcifications in the pharynx and larynx. Polysomnographic parameters showed severe obstructive apnea refractory to nasal continuous positive airway pressure. Clinical and laboratory findings excluded concomitant endocrine or rheumatological diseases.ConclusionOur data provide a new insight about Mönckeberg's sclerosis, i.e., the fact that the etiopathogenic process involved in the phenomenon of calcification may not be restricted only to the arteries, but may occur in the entire organism. Further studies of the etiopathogenesis of this disease are needed.

Care for diabetes patients using the Staged Diabetes Management protocol: an experience report RESUMOO trabalho em equipe multiprofissional de saúde tem sido reconhecido como importante para a educação do paciente diabético. Este estudo objetivou descrever a implementação de um programa de atendimento utilizando-se o protocolo Staged Diabetes Management e caracterizar as atividades desenvolvidas pela equipe multiprofissional de saúde do Centro Educativo de Enfermagem para Adultos e Idosos, de Ribeirão Preto, a pacientes com diabetes. O trabalho foi desenvolvido no período de abril de 2004 a abril de 2005, mediante encontros semanais, combinando atividades individuais e em grupo, coordenadas por enfermeiros, médicos, nutricionistas, psicólogos e educadores físicos. Os resultados mostraram que a utilização do protocolo SDM contribuiu para melhorar o controle metabólico do paciente diabético e conseqüentemente, a cobertura medicamentosa para diabetes mellitus, hipertensão arterial e dislipidemia; também aumentou a adesão ao plano alimentar, à atividade física e o conhecimento acerca da doença, e ainda, reduziu os sinais e sintomas referidos pelos pacientes. Esta experiência indicou a viabilidade da implementação do referido protocolo. Acredita-se que a divulgação de trabalhos desta natureza pode contribuir com as diretrizes preconizadas pela Organização Mundial da Saúde para o atendimento de pessoas diabéticas, especialmente, o automanejo da doença. Descritores: Diabetes mellitus; Educação; Educação em enfermagem; Equipe de assistência ao paciente.

Summary Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell‐mediated destruction of pancreatic β cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis‐related gene expression in T1D patients was evaluated before and after treatment with high‐dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI‐AHSCT). We also correlated gene expression results with clinical response to HDI‐AHSCT. We observed a decreased expression of bad, bax and fasL pro‐apoptotic genes and an increased expression of a1, bcl‐xL and cIAP‐2 anti‐apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI‐AHSCT, we found an up‐regulation of fas and fasL and a down‐regulation of anti‐apoptotic bcl‐xL genes expression in post‐HDI‐AHSCT periods compared to pre‐transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl‐xL and cIAP‐1 genes expression were found similar to controls 2 years after HDI‐AHSCT. Furthermore, over‐expression of pro‐apoptotic noxa at 540 days post‐HDI‐AHSCT correlated positively with insulin‐free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis‐related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI‐AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI‐AHSCT therapy.