RESUMO
Uncontrolled activation of the innate immune system promotes the deterioration of neurons in different neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). T-cell vaccination (TCV) was developed by Irun Cohen and coworkers at the Weizmann Institute of Science (Israel) during the late 1970s and has been demonstrated to be an effective treatment for human autoimmune diseases and a regulator of macrophage activation in animal models. We treated seven ALS patients with this cell therapy and were able to slow or stop disease progression in the affected individuals. The median survival, which is 3.5 years, was extended to 6 years. They were also treated with autologous adult neural stem cells associated with effector T cells. The observed neurologic improvements after treatment lasted for at least 1 year. Clinical recovery in the treated ALS patients was confirmed by an independent, skilled neurologist using the ALS Functional Rating Scale-Revised (ALSFRS-R). TCV in conjunction with an autologous neural stem cell treatment might be a feasible, minimally invasive, safe, and effective approach to obtain enduring therapeutic effects in ALS patients.
Assuntos
Esclerose Lateral Amiotrófica/cirurgia , Esclerose Lateral Amiotrófica/terapia , Imunoterapia Adotiva/métodos , Células-Tronco Neurais/transplante , Linfócitos T/imunologia , Adulto , Idoso , Esclerose Lateral Amiotrófica/imunologia , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
OBJECTIVES: With the intention to ameliorate the clinical condition of patients with chronic spinal cord injury (SCI), a program that combines three cell therapies and an appropriate neurorehabilitation program were used to recreate and enhance the natural conditions of SCI repair. METHODS: Vascularization recovery is approached by selective artery infusion of BMMNCs (bone marrow mononuclear cells) to the disrupted area. Eighteen days later, with the aim to restore the specific inflammatory activity, an i.v. infusion of spinal cord specific ETCs (effector T cells) is carried out. With the intention of supplying cellular components for the process of repair, an infusion of autologous neural stem cells (NSCs) through selective feeding artery infusion is carried out, followed by an appropriate neurorehabilitation program. RESULTS: A total of eight ASIA (American Spinal Injury Association) A patients (five with jeopardized brachial plexus and three without) received the treatment. No severe adverse events was observed in any of the receptor patients: five patients evolved from ASIA A to ASIA D and regained the ability to stand up and, with varying effectiveness, to walk; two patients remained in the same condition, but exhibited motor and sensitive improvements; and one patient could not be evaluated. CONCLUSIONS: These reports suggest that the biological characteristics of acute SCI may be recreated in a comprehensive, safe and effective manner.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Traumatismos da Medula Espinal/terapia , Doença Crônica , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The degree of post-injury inflammation of the damaged area of a spinal cord is the main difference between the natural successful repair in inferior vertebrates and failure in superior vertebrates. The treatment of rats with anti-myelin lymphocytes after experimental spinal cord injury induces their functional recovery. On the other hand, mesenchymal stem cells (MSC) from adult BM implanted in injured areas recover the morphology and function of spinal cord in mammals. The purpose of this study was to determine whether there is a direct relationship between anti-nervous tissue T cells and MSC reparatory properties. METHODS: Circulating autoreactive lymphocytes of patients with spinal cord injuries and amyotrophic lateral sclerosis were isolated and activated in vitro. These cells were cocultured with autologous MSC for 2-15 days. Cocultures of non-selected lymphocytes were used as controls. RESULTS: After 48 h of coculture, MSC adopted a spindle shape with polarization of the cytoplasm that resembled bipolar neurons. Their nuclei diminished the nucleolus number and the chromatin lost its granular appearance. After 15 days of culture the cells developed the typical structure of a neural network. No morphologic changes were observed in control cultures. The differentiated cells reacted positively to tubuline III, GFAP and nestin. No differences were observed between the different patient cell sources. DISCUSSION: We observed that autoreactive cells may induce the transdifferentiation of MSC to neural stem cells. This T-cell-MSC interaction may be a common phenomenon during physiologic nerve tissue repair.
Assuntos
Autoimunidade/imunologia , Diferenciação Celular/fisiologia , Células-Tronco Mesenquimais/citologia , Neurônios/citologia , Células-Tronco/citologia , Linfócitos T/fisiologia , Esclerose Lateral Amiotrófica/imunologia , Antígenos CD/análise , Células da Medula Óssea/citologia , Complexo CD3/análise , Separação Celular/métodos , Forma Celular/fisiologia , Técnicas de Cocultura/métodos , Proteína Glial Fibrilar Ácida/análise , Humanos , Proteínas de Filamentos Intermediários/análise , Ativação Linfocitária/imunologia , Células-Tronco Mesenquimais/química , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/imunologia , Nestina , Neurônios/química , Hidrolisados de Proteína/imunologia , Receptores de Interleucina-2/análise , Traumatismos da Medula Espinal/imunologia , Células-Tronco/química , Linfócitos T/química , Linfócitos T/citologia , Tubulina (Proteína)/análiseRESUMO
BACKGROUND: This is a preliminary report on successful results obtained during treatment of two patients with chronic spinal cord injury. The therapeutic approach was based on the generation of controlled inflammatory activity at the injury site that induced a microenvironment for the subsequent administration of autologous, BM-driven transdifferentiated neural stem cells (NSC). METHODS: BM mesenchymal stem cells (MSC) were cocultured with the patient's autoimmune T (AT) cells to be transdifferentiated into NSC. Forty-eight hours prior to NSC implant, patients received an i.v. infusion of 5 x 10(8) to 1 x 10(9) AT cells. NSC were infused via a feeding artery of the lesion site. Safety evaluations were performed everyday, from the day of the first infusion until 96 h after the second infusion. After treatment, patients started a Vojta and Bobath neurorehabilitation program. RESULTS: At present two patients have been treated. Patient 1 was a 19-year-old man who presented paraplegia at the eight thoracic vertebra (T8) with his sensitive level corresponding to his sixth thoracic metamere (T6). He received two AT-NSC treatments and neurorehabilitation for 6 months. At present his motor level corresponds to his first sacral metamere (S1) and his sensitive level to the fourth sacral metamere (S4). Patient 2 was a 21-year-old woman who had a lesion that extended from her third to her fifth cervical vertebrae (C3-C5). Prior to her first therapeutic cycle she had severe quadriplegia and her sensitive level corresponded to her second cervical metamere (C2). After 3 months of treatment her motor and sensitive levels reached her first and second thoracic metameres (T1-T2). No adverse events were detected in either patient. DISCUSSION: The preliminary results lead us to think that this minimally invasive approach, which has minor adverse events, is effective for the repair of chronic spinal cord lesions.
Assuntos
Transplante de Células/métodos , Regeneração Nervosa , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/terapia , Transplante de Células-Tronco/métodos , Linfócitos T/transplante , Adulto , Esclerose Lateral Amiotrófica/imunologia , Antígenos CD/análise , Complexo CD3/análise , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Separação Celular/métodos , Transplante de Células/efeitos adversos , Técnicas de Cocultura , Potenciais Somatossensoriais Evocados/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Células-Tronco Mesenquimais/química , Células-Tronco Mesenquimais/citologia , Proteínas do Tecido Nervoso/imunologia , Neurônios/citologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Transplante de Células-Tronco/efeitos adversos , Células-Tronco/citologia , Linfócitos T/química , Linfócitos T/imunologia , Resultado do TratamentoRESUMO
To improve patient immune recognition of autologous tumor cells, we have developed a tumor B-cell lymphocyte hybridoma (TBH) autovaccination protocol. This approach is based on immunization of a cancer patient with a hybridoma cell suspension derived from the fusion of autologous activated B-cells and autologous cancer cells. This hybrid allows the host immune system to recognize and destroy oncocytes with low toxicity and high specificity. Of 21 treated patients with very advanced diseases, six complete responses and four partial responses were achieved. Overall, survival was prolonged. Side-effects and combination therapies with IL2, IL6 and gamma I/FN are discussed in this paper. Breast and colon cancer seem to be sensitive to this therapy.