Various lines of evidence suggest that immune system dysregulation has a key role in autism spectrum disorder (ASD). Estes and McAllister review this evidence, covering genetic and maternal immune system-related risk factors, chronic immune system changes in individuals with ASD and in animal models, and potential pathophysiological mechanisms. Increasing evidence points to a central role for immune dysregulation in autism spectrum disorder (ASD). Several ASD risk genes encode components of the immune system and many maternal immune system-related risk factors — including autoimmunity, infection and fetal reactive antibodies — are associated with ASD. In addition, there is evidence of ongoing immune dysregulation in individuals with ASD and in animal models of this disorder. Recently, several molecular signalling pathways — including pathways downstream of cytokines, the receptor MET, major histocompatibility complex class I molecules, microglia and complement factors — have been identified that link immune activation to ASD phenotypes. Together, these findings indicate that the immune system is a point of convergence for multiple ASD-related genetic and environmental risk factors.

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Immune mediators in the brain and peripheral tissues in autism spectrum disorder

Objective We updated a prior systematic review of interventions for children (0–12 years) with autism spectrum disorder (ASD), focusing on recent studies of behavioral interventions. Data sources We searched the MEDLINE® (PubMed®), PsycInfo, and Educational Resources Information Clearinghouse (ERIC) databases as well as the reference lists of included studies and recent systematic reviews. We conducted the search in December 2013. Methods We included comparative studies (with treatment and comparison groups) of behavioral interventions with at least 10 participants with ASD in the update, and made our conclusions based on the cumulative comparative evidence across the original report and update. Two investigators independently screened studies against predetermined inclusion criteria and independently rated the quality of included studies. Results We included 65 unique studies comprising 48 randomized trials and 17 nonrandomized comparative studies (19 good, 39 fair, and 7 poor quality) published since the prior review. The quality of studies improved compared with that reported in the earlier review; however, our assessment of the strength of evidence (SOE), our confidence in the stability of effects of interventions in the face of future research, remains low for many intervention/outcome pairs. Early intervention based on high-intensity applied behavior analysis over extended timeframes was associated with improvement in cognitive functioning and language skills (moderate SOE for improvements in both outcomes) relative to community controls in some groups of young children. The magnitude of these effects varied across studies, potentially reflecting poorly understood modifying characteristics related to subgroups of children. Early intensive parent training programs modified parenting behaviors during interactions; however, data were more limited about their ability to improve developmental skills beyond language gains for some children (low SOE for positive effects on language). Social skills interventions varied in scope and intensity and showed some positive effects on social behaviors for older children in small studies (low SOE for positive effects on social skills). Studies of play/interaction-based approaches reported that joint attention interventions may demonstrate positive outcomes in preschool-age children with ASD when targeting joint attention skills (moderate SOE); data on the effects of such interventions in other areas were limited (low SOE for positive effects on play skills, language, social skills). Studies examining the effects of cognitive behavioral therapy on anxiety reported positive results in older children with IQs ≥70 (high SOE for improvements in anxiety in this population). Smaller short-term studies of other interventions reported some improvements in areas such as sleep and communication, but data were too sparse to assess their overall effectiveness. Conclusions A growing evidence base suggests that behavioral interventions can be associated with positive outcomes for children with ASD. Despite improvements in the quality of the included literature, a need remains for studies of interventions across settings and continued improvements in methodologic rigor. Substantial scientific advances are needed to enhance our understanding of which interventions are most effective for specific children with ASD and to isolate elements or components of interventions most associated with effects.

Therapies for Children With Autism Spectrum Disorder: Behavioral Interventions Update

Spinal cord injury (SCI) is the damage to the spinal cord that can lead to temporary or permanent loss of function due to injury to the nerve. The SCI patients are often associated with poor quality of life. This review discusses the current status of mesenchymal stem cell (MSC) therapy for SCI, criteria to considering for the application of MSC therapy and novel biological therapies that can be applied together with MSCs to enhance its efficacy. Bone marrow-derived MSCs (BMSCs), umbilical cord-derived MSCs (UC-MSCs) and adipose tissue-derived MSCs (ADSCs) have been trialed for the treatment of SCI. Application of MSCs may minimize secondary injury to the spinal cord and protect the neural elements that survived the initial mechanical insult by suppressing the inflammation. Additionally, MSCs have been shown to differentiate into neuron-like cells and stimulate neural stem cell proliferation to rebuild the damaged nerve tissue. These characteristics are crucial for the restoration of spinal cord function upon SCI as damaged cord has limited regenerative capacity and it is also something that cannot be achieved by pharmacological and physiotherapy interventions. New biological therapies including stem cell secretome therapy, immunotherapy and scaffolds can be combined with MSC therapy to enhance its therapeutic effects.

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Treatment of spinal cord injury with mesenchymal stem cells

Autism spectrum disorders (ASD) are characterized by social communication deficits, cognitive rigidity, and repetitive stereotyped behaviors. Mesenchymal stem cells (MSC) have a paracrine regenerative effect, and were speculated to be a potential therapy for ASD. The BTBR inbred mouse strain is a commonly used model of ASD as it demonstrates robust behavioral deficits consistent with the diagnostic criteria for ASD. BTBR mice also exhibit decreased brain-derived neurotrophic factor (BDNF) signaling and reduced hippocampal neurogenesis. In the current study, we evaluated the behavioral and molecular effects of intracerebroventricular MSC transplantation in BTBR mice. Transplantation of MSC resulted in a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice. This might indicate a possible mechanism underpinning the behavioral improvement. Our study suggests a novel therapeutic approach which may be translatable to ASD patients in the future.

Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice.

A systematic review of molecular imaging (PET and SPECT) in autism spectrum disorder: current state and future research opportunities

Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.

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Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Proof of Concept Study

Cerebral palsy is a nonprogressive heterogeneous group of neurological disorders with a growing rate of prevalence. Recently, cellular therapy is emerging as a potential novel treatment strategy for cerebral palsy. The various mechanisms by which cellular therapy works include neuroprotection, immunomodulation, neurorestoration, and neurogenesis. We conducted an open label, nonrandomized study on 40 cases of cerebral palsy with an aim of evaluating the benefit of cellular therapy in combination with rehabilitation. These cases were administered autologous bone marrow mononuclear cells intrathecally. The follow-up was carried out at 1 week, 3 months, and 6 months after the intervention. Adverse events of the treatment were also monitored in this duration. Overall, at six months, 95% of patients showed improvements. The study population was further divided into diplegic, quadriplegic, and miscellaneous group of cerebral palsy. On statistical analysis, a significant association was established between the symptomatic improvements and cell therapy in diplegic and quadriplegic cerebral palsy. PET-CT scan done in 6 patients showed metabolic improvements in areas of the brain correlating to clinical improvements. The results of this study demonstrate that cellular therapy may accelerate the development, reduce disability, and improve the quality of life of patients with cerebral palsy.

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A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier.

A clinical study shows safety and efficacy of autologous bone marrow mononuclear cell therapy to improve quality of life in muscular dystrophy patients.

Traumatic brain injury is an injury to the brain parenchyma resulting from external factors such as vehicular accidents, falls, or sports injuries. Its outcome involves primary insult followed by a cascade of secondary insult, resulting in diffuse axonal injury further causing white matter damage. Surgical intervention targets the primary damage, whereas only few treatment alternatives are available to treat the secondary damage. Cellular therapy could be one of the prospective therapeutic options, as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain. We conducted a pilot study on 14 cases who were administered with autologous bone marrow mononuclear cells, intrathecally. The follow up was done at 1 week, 3 months and 6 months after the intervention. The Functional Independence Measure scale, the SF-8 Health Survey Scoring and the disability rating scale were used as outcome measures. These scales showed a positive shift in scores at the end of 6 months. Improvements were observed in various symptoms, along with activities of daily living. Improvement in PET CT scan performed before and 6 months after the intervention in 3 patients corresponded to the clinical and functional improvements observed in these patients. The results of this study suggest that cell therapy may promote functional recovery leading to an improved quality of life in chronic TBI. Although the results are positive, the improvements after cell therapy are not optimal. Hence, additional multicenter, controlled studies are required to establish cell therapy as a standard therapeutic approach.

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Cell therapy attempted as a novel approach for chronic traumatic brain injury – a pilot study

Spinal cord injury often results into severe neurological deficits. Currently, there is no treatment available which can reverse the damage. Cell transplantation is a novel treatment strategy which has shown promising results in animal models of spinal cord injury. We administered fifty six chronic cervical spinal cord injury patients with autologous bone marrow mononuclear cells, intrathecally. As a part of the protocol, all the patients also underwent rehabilitation along with cell transplantation. On a mean follow up of 2 years ± 1 month, symptoms such as trunk stability, sitting balance, trunk muscle strength, upper limb strength, standing balance, deep touch sensation, bladder sensation, spasticity and walking balance demonstrated improvements. On performing McNemars test, a significant association was found between the improvements in these symptoms and the intervention. The improvement in Functional Independence Measure (FIM) scores was statistically significant using Wilcoxon Signed Rank test. A detailed analysis of factors such as age, cause of injury, chronicity of injury and rehabilitation before the intervention was performed. Here, we also compare this chronic cervical SCI group with chronic thoracolumbar SCI patients of our previous study. Though functional improvements were observed at greater extent in chronic thoracolumbar SCI group, the results in chronic cervical SCI group were also significant. Cell transplantation may promote neurofunctional recovery and improve the quality of life of the patients with chronic cervical spinal cord injury.

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Hema Biju

Papers

Autologous Bone Marrow Mononuclear Cell Therapy for Autism: An Open Label Proof of Concept Study

A clinical study of autologous bone marrow mononuclear cells for cerebral palsy patients: a new frontier.

A clinical study shows safety and efficacy of autologous bone marrow mononuclear cell therapy to improve quality of life in muscular dystrophy patients.

Cell therapy attempted as a novel approach for chronic traumatic brain injury – a pilot study

Role of Autologous Bone Marrow Mononuclear Cells in Chronic Cervical Spinal Cord Injury-A Longterm Follow Up Study