Allogeneic Stem Cell Therapy Research Articles

Abstract 18363: The Human Amniotic Mesenchymal Stem Cell -derived Ipscs Survive and Restore the Injured Hearts in an Immunocompetent Mouse Model of Myocardial Injury

Background: Stem cells are known to restore the injured myocardium. This capability may improve if there is enhanced in vivo survival of the transplanted stem cells. The hAMSCs are isolated from amniotic membrane underlying the chorion of a human placenta and are located in the fetal-maternal border, demonstrating unique immunomodulatory properties characterized by CD59 +, HLA-G +, and HLA-DR- to suppress the host immune response. A single polycistronic lentivirus reprograms the hAMSCs robustly to generate MiPSCs. Hypothesis: The MiPSCs retain the immunomodulatory properties of hAMSCs to attenuate immune rejection in an immunocompetent mouse to restore the injured myocardium. Methods and results: 250K MiPSCs were transplanted into the LAD ligated heart of FVB mice. 250K hAMSCs were injected into the hearts of LAD ligated immunodeficient SCID mice as control. In vivo bioluminescence (BLI) demonstrated robust viability signal in the luciferase-transduced MiPSCs for 2 weeks in FVB mice (Figure 1). When comparing the MiPSC-treated vs. the control (hAMSC-treated) mice during the 4-wk follow-up period, cardiac MRI demonstrated significantly improved LVEF (29.75 vs. 22.45%, p<0.05), decreased infarct % (21.47 vs. 31.06%, p<0.05), and increased viable myocardial volume (78.07 vs. 67.9 cm3, p<0.05). Notably, the MiPSCs did not form any teratoma. Conclusion: The MiPSCs exhibit unique immunomodulatory properties, which attenuate rejection by an immunocompetent mouse and significantly restore the injured heart. The MiPSCs may enable allogeneic cardiac stem cell therapy.

Human Amniotic Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells May Generate a Universal Source of Cardiac Cells

Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription-polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy.

Abstract 2818: Safety, Feasibility and Signal of Activity of Intra-carotid Allogenic Mesenchymal Stem Cell therapy in a Large Animal Stoke Model

INTRODUCTION: Promising pre-clinical data shows benefits of intra-carotid allogenic mesenchymal stem cell (MSCs) therapy in ischemic stroke (IS) in small animal stroke models. Intra-carotid (IC) delivery of MSCs may be superior to intravenous (IV) delivery. However, due to the large size (15-50 microns) of MSCs, there is a concern that they may cause microvascular occlusion during IC administration. There is a need for large animal experiments to confirm positive results in small animal models as has been recommended by STAIR and STEPS consortia. HYPOTHESIS: We tested the hypothesis that IC administration of allogeneic mesenchymal stem cells (MSCs) is feasible and safe in a large animal (canine) stroke model.. METHODS: We performed 1-3 hrs of reversible middle cerebral artery occlusion (rMCAo), in10 female mongrel dogs weighing 40-60 lbs, using an endovascular retrievable coil occlusion of the MCA with a transfemoral arterial approach. At 1 - 72 hrs after rMCAo, animals were assigned to the following treatment groups: A. IC saline placebo (saline) or B. IC allogeneic MSCs or C. IV allogeneic MSCs. Primary outcome measures were: development of angiographic occlusion post-IC MSC or saline infusion, change in MRI infarct volume or new ischemic lesions, and neurological deficit score (NDS) at 4 weeks. Dosing of MSCs was based on extrapolated maximum tolerated dose calculated in a rat study of IC MSCs in our laboratory. RESULTS: Successful IC administration of MSCs was possible in all animals assigned to the treatment group. Animals receiving IC MSCs at 1× 10^6 or 10 × 10^6 (n=6) there were no clinical adverse events or neurological worsening during or 4 weeks post treatment. There were no angiographic decreases in flow or occlusions during or after IC MSC delivery. In the two animals with additional TCD monitoring during IC MSC delivery there were no changes in flow velocity or HITS signals indicating emboli. There was no worsening in MRI infarct volume ( Fig 1 .) amongst the IC MSC groups. A dramatic decrease in infarct volume was noted, in 2 animals in the IC MSC group with minimal infarct related atrophy at one month. None of the animals in the IV MSC or IC saline groups (n=2 in each group) showed a significant change in MRI infarct volume, and major infarct related atrophy was noted. CONCLUSION: IC MSC administration in a large animal rMCAo model is feasible & safe. Fig1 : In vivo coronal MRI FLAIR sequences in IC delivery of MSCs in canine stroke model. There is a signal of biologic activity seen with IC MSC delivery. A. Baseline infarct at 48 hours after rMCAo. B. Infarct evolution at 29 days after IC administration of 10×10^6 MSCs.

Mucositis after Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation

Background: Therapyrelated mucositis is associated with considerable morbidity. This complication following allogeneic stem cell therapy (alloSCT) is less severe after reduced intense conditioning (RIC); however, even here it may be serious. Methods: 52 patients (male: n = 35 (67%), female: n = 17 (33%)) at a median age of 62 years (35–73 years) underwent alloSCT after RIC. Conditioning was either total body irradiation (TBI)_2Gy/±fludarabine (n = 33, 63.5%) or chemotherapy based. Graftversushost disease (GvHD) prophylaxis was carried out with cyclosporine A ± mycophenolate mofetil (MMF). 45 patients (87%) received shortcourse methotrexate (MTX). Mucositis was graded according to the Bearman and the World Health Organisation (WHO) scale. A variety of parameters were correlated with mucositis. Results: The Bearman and WHO scales showed excellent correlation. Mucositis was significantly more severe after chemotherapybased conditioning compared to conditioning with TBI_2Gy/±fludarabine (p < 0.002) as well as in cases with an increase in creatinine levels above the upper normal value (UNV) on day +1 after SCT (p < 0.05). Furthermore, the severity correlated with time to engraftment of leucocytes (correlation coefficient (cc) = 0.26, p < 0.02) and thrombocytes (cc = 0.38, p < 0.001). Conclusions: The conditioning regimen and increased creatinine levels at day +1 were identified as factors predicting the severity of mucositis after RICSCT. Creatinine levels on day +1 after SCT may help identify patients at risk for severe mucositis in the further course of transplantation.

Autologous and Allogeneic Limbal Stem Cell Therapy ‐ Where are the Limits?

AbstractAbstract not provided

Clinicopathologic findings following intra-articular injection of autologous and allogeneic placentally derived equine mesenchymal stem cells in horses

The development of an allogeneic mesenchymal stem cell (MSC) product to treat equine disorders would be useful; however, there are limited in vivo safety data for horses. We hypothesized that the injection of self (autologous) and non-self (related allogeneic or allogeneic) MSC would not elicit significant alterations in physical examination, gait or synovial fluid parameters when injected into the joints of healthy horses. Sixteen healthy horses were used in this study. Group 1 consisted of foals (n = 6), group 2 consisted of their dams (n = 5) and group 3 consisted of half-siblings (n = 5) to group 1 foals. Prior to injection, MSC were phenotyped. Placentally derived MSC were injected into contralateral joints and MSC diluent was injected into a separate joint (control). An examination, including lameness evaluation and synovial fluid analysis, was performed at 0, 24, 48 and 72 h post-injection. MSC were major histocompatibility complex (MHC) I positive, MHC II negative and CD86 negative. Injection of allogeneic MSC did not elicit a systemic response. Local responses such as joint swelling or lameness were minimal and variable. Intra-articular MSC injection elicited marked inflammation within the synovial fluid (as measured by nucleated cell count, neutrophil number and total protein concentration). However, there were no significant differences between the degree and type of inflammation elicited by self and non-self-MSC. The healthy equine joint responds similarly to a single intra-articular injection of autologous and allogeneic MSC. This pre-clinical safety study is an important first step in the development of equine allogeneic stem cell therapies.

Invited Commentary

Invited Commentary

Bone Marrow as a Source of Hematopoietic Stem Cells for Human Gene Therapy of β-Thalassemia

β-Thalassemia is a severe inherited anemia caused by insufficient production of β-globin chains. Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only cure, and is limited by donor availability and regimen-related toxicity and mortality. Gene therapy is a promising therapeutic tool for all thalassemic patients lacking a compatible donor and potentially provides transfusion independence in the absence of transplant-related complications, such as graft rejection and graft-versus-host disease. The issue of HSC procurement is critical in this setting because of the specific features of thalassemic syndromes, which include bone marrow (BM) expansion, ineffective erythropoiesis, and splenomegaly. Little is known about the efficiency of CD34(+) cell yield from steady-state BM harvests from thalassemic patients. We have collected data on safety and cell yield from 20 pediatric patients with β-thalassemia who underwent autologous BM harvest before allogeneic HSC transplantation, and from 49 age-matched sibling donors who also underwent BM harvest. The procedure was safe, as no significant adverse events occurred. In terms of cell yield, no difference was found between patients and normal donors in the number of CD34(+) cells and total nucleated cells harvested. Most importantly, no difference was found in the proportion of myeloid and erythroid progenitors, suggesting a similar repopulating capacity. On the basis of these results, we conclude that steady-state BM can be used as a safe and efficient source of HSC for gene therapy of β-thalassemia.

Company Profile: Athersys

Athersys (Nasdaq: ATHX) is a biopharmaceutical company engaged in the discovery and development of novel therapies designed to treat significant unmet medical needs. The company is heavily focused on the regenerative medicine area, with multiple clinical and preclinical stage programs. The most advanced programs at the company are focused on the development of MultiStem®, a clinical stage allogeneic stem cell therapy that has demonstrated potential for treating a range of conditions and is believed to have widespread application in the field of regenerative medicine. The company has internal programs applying MultiStem across multiple therapeutic areas including cardiovascular, neurological, immune dysfunction and other disease areas, and partnered programs with Pfizer (applying MultiStem to treat inflammatory bowel disease) and Angiotech Pharmaceuticals (acute myocardial infarction). Athersys has a broad network of collaborative relationships with leading research and clinical institutions and is committed to developing a pipeline of novel 'best-in-class' medicines.

Glial cell line‐derived neurotrophic factor–secreting genetically modified human bone marrow‐derived mesenchymal stem cells promote recovery in a rat model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal dopaminergic (DA) neurons. The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF), the most potent neurotrophic factor for DA neurons, has been demonstrated in many experimental models of PD. However, chronic delivery of GDNF to DA neurons in the brain remains an unmet challenge. Here, we report the effects of GDNF-releasing Notch-induced human bone marrow-derived mesenchymal stem cells (MSC) grafted into striatum of the 6-hydroxydopamine (6-OHDA) progressively lesioned rat model of PD. Human MSC, obtained from bone marrow aspirates of young, healthy adult volunteers, were transiently transfected with the intracellular domain of the Notch1 gene (NICD) to generate SB623 cells. SB623 cells expressing GDNF and/or humanized Renilla green fluorescent protein (hrGFP) following lentiviral transduction or nontransduced cells were stereotaxically placed into rat striatum 1 week after a unilateral partial 6-OHDA striatal lesion. At 4 weeks, rats that had received GDNF-transduced SB623 cells had significantly decreased amphetamine-induced rotation compared with control rats, although this effect was not observed in rats that received GFP-transduced or nontransduced SB623 cells. At 5 weeks, rejuvenated tyrosine hydroxylase-immunoreactive (TH-IR) fibers that appeared to be host DA axons were observed in and around grafts. This effect was more prominent in rats that received GDNF-secreting cells and was not observed in controls. These observations suggest that human bone-marrow derived MSC, genetically modified to secrete GDNF, hold potential as an allogeneic or autologous stem cell therapy for PD.

Immunosuppressive properties of human umbilical cord‐derived mesenchymal stem cells: role of B7‐H1 and IDO

Umbilical cord is a rich source of mesenchymal stromal or stem cells (MSCs) that can be used for developing allogeneic cell therapy to treat intractable diseases. In this report, we present evidence that umbilical cord-derived MSCs (UCMSCs) possess important immunomodulatory properties that may enable them to survive in an allogeneic environment. UCMSCs do not express human leukocyte antigen (HLA)-DR and co-stimulatory molecules CD80 and CD86 that are required for T-cell activation. More importantly, UCMSCs constitutively express a negative regulator of T-cell activation, B7-H1, and its expression is increased after interferon-γ (IFN-γ) treatment. In addition, IFN-γ treatment induced indoleamine 2,3-dioxygenase (IDO) and HLA-DR expression in UCMSCs. Neither control nor IFN-γ-treated UCMSCs stimulated allogeneic T-cell proliferation, and both cell populations inhibited third-party dendritic cell (DC)-mediated allostimulatory activity. Addition of a B7-H1-specific blocking antibody or an IDO inhibitor, 1 methyl tryptophan (1-MT) abrogated the T-cell immunosuppressive activity of these cells. Furthermore, UCMSCs prevented the differentiation and maturation of peripheral blood monocyte-derived DCs, and augmented the generation of regulatory T cells (Tregs) in culture. The immunosuppressive effects of UCMSCs are largely mediated by cell-to-cell contact, although some inhibitory activity was observed with cell-free supernatant. Our study suggests that these immunomodulatory properties of UCMSCs could potentially improve the outcome of allogeneic stem cell therapy.

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

To determine the potential for using stem cells in the treatment of ischemic injuries of the central nervous sys- tem, clinically relevant experiments were performed administering human adult adherent bone marrow derived stem cells into a rat model of ischemic stroke. Variables such as the requirement for immunosuppression, route of cell administration, window for therapeutic benefit and optimal cell dosage have all been examined in a series of relevant translational experiments in animals undergoing middle cerebral artery ligation stroke injury. Animals were tested for improvements in locomotor and neurological function at time points as late as 6 months post-cell transplantation and demonstrated sustained statistically significant benefit from a single dose of cells. Following sacrifice, immunohistochemistry was performed on tissues to determine stem cell engraftment and fate, as well as neuroprotection of endogenous tissue at the sites of ischemic injury. The results indicate locomotor and neu- rological improvement correlates with improved neuroprotection and limited retention of the transplanted stem cells, with limited neuronal fate. The observed benefit occurs in a cell dosage dependent fashion suggesting a pharmacological role for the cells when administered intravenously in these injury models.

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

Development of an allogeneic adherent stem cell therapy for treatment of ischemic stroke

Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI.

Outpatient Decitabine in Elderly Patients with Acute Myeloid Leukemia (AML).

Abstract 4144 BackgroundThe treatment of elderly patients with AML remains controversial due to the inferiority of outcomes associated with standard intensive induction regimens. Hypomethylating agents have been shown to improve quality of life and survival in patients with myelodysplastic syndromes and have activity in AML. We report our experience with decitabine in elderly patients with previously untreated or refractory AML. Patients and methodsWe conducted a retrospective analysis of 30 patients (11 males and 19 females) with AML who were ineligible for intensive induction chemotherapy and received decitabine (20 mg/m2 for 5 days every 28 days). Median age at diagnosis was 67 years (range 40 to 91 years), 28/30 (93.3%) patients were 60 years of age or older. Twelve (40%) patients had cytogenetic abnormalities (7 – unfavorable). ECOG performance status was 0-1 for 26 patients, 2 for 3 patients and 3 for 1 patient. Seven (23.3%) patients had secondary AML and 23 (76.7%) patients had de novo AML, of which 10 demonstrated evidence of multilineage dysplasia on bone marrow biopsy. Eleven (36.7%) patients progressed after prior therapy which included intensive induction therapy in 10 patients (followed by stem cell therapy in 4 patients) and tipifarnib in 1 patient. Nineteen (63.3%) patients received decitabine as first-line therapy. Clearance of blasts from the peripheral blood was monitored and used as an indicator of improved relapse-free survival in AML. Overall survival was defined as the time from the day 1 of decitabine treatment to death. ResultsPatients received a median of 5 cycles of decitabine. Seven patients (23.3%) received ≥10 cycles. All patients received decitabine in the outpatient setting. No hospitalizations were required to administer treatment. Peripheral blood blast clearance was documented in 23 (76.7%) patients including 7 patients who achieved a CR/CRi, and 2 PR. The median time to response was 2 months with median duration of 3 months. Seven patients (23.3%) did not respond to treatment. To date, 19 (63.3%) patients have died after 5-24 months of therapy and 11 (36.7%) remain alive. The median survival was 12 months in all patients (range 4 to 24 months) and 14 months in the 17 patients who received more than 4 cycles of therapy. Overall survival was 82.4% at 6 months and 47.9% at 12 months. Eleven (36.7%) patients survived for >1 year. Seven patients underwent allogeneic stem cell therapy after achieving CR/CRi on decitabine. Three patients received stem cells from siblings or offspring; 3 patients had a matched unrelated donor and 1 patient received umbilical cord stem cells. Three patients are alive after a median follow-up of 12 months. Three patients died of relapsed AML and 1 patient died of infectious complications of transplant.Decitabine was well tolerated. Ten patients experienced minimal nausea amenable to ondansetron with no documented episodes of vomiting. Seventeen patients developed grade 4 neutropenia and 3 patients grade 4 thrombocytopenia during the course of treatment. Fourteen (46.7%) patients underwent a total of 37 hospitalizations. Common reasons for hospitalizations were: febrile neutropenia (19), pneumonia (6) and thrombocytopenia (3). Sixteen (53.3%) patients never required hospitalization while undergoing treatment. No deaths were attributed to complications related to therapy.Decitabine administered as an outpatient is an effective treatment option for elderly and high risk patients with AML. It has a favorable chemotherapy-related toxicity profile and is associated with a decreased frequency of hospitalizations. Decitabine may facilitate a subsequent allogeneic transplant in eligible patients and should be considered a treatment option for high risk patients with AML. Disclosures:Off Label Use: decitabine in AML.

Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a chronic lung disease that leads to right ventricular (RV) hypertrophy (RVH), remodeling, and failure. We tested treatment with bone marrow-derived mesenchymal stem cells (MSCs) obtained from donor rats with monocrotaline (MCT)-induced PAH to recipient rats with MCT-induced PAH on pulmonary artery pressure, lung pathology, and RV function. This model was chosen to mimic autologous MSC therapy. On day 1, PAH was induced by MCT (60 mg/kg) in 20 female Wistar rats. On day 14, rats were treated with 10(6) MSCs intravenously (MCT + MSC) or with saline (MCT60). MSCs were obtained from donor rats with PAH at 28 days after MCT. A control group received saline on days 1 and 14. On day 28, the RV function of recipient rats was assessed, followed by isolation of the lungs and heart. RVH was quantified by the weight ratio of the RV/(left ventricle + interventricular septum). MCT induced an increase of RV peak pressure (from 27 + or - 5 to 42 +/- 17 mmHg) and RVH (from 0.25 + or - 0.04 to 0.47 + or - 0.12), depressed the RV ejection fraction (from 56 + or - 11 to 43 + or - 6%), and increased lung weight (from 0.96 + or - 0.15 to 1.66 + or - 0.32 g), including thickening of the arteriolar walls and alveolar septa. MSC treatment attenuated PAH (31 + or - 4 mmHg) and RVH (0.32 + or - 0.07), normalized the RV ejection fraction (52 + or - 5%), reduced lung weight (1.16 + or - 0.24 g), and inhibited the thickening of the arterioles and alveolar septa. We conclude that the application of MSCs from donor rats with PAH reduces RV pressure overload, RV dysfunction, and lung pathology in recipient rats with PAH. These results suggest that autologous MSC therapy may alleviate cardiac and pulmonary symptoms in PAH patients.

Ex Vivo Nanofiber Expansion and Genetic Modification of Human Cord Blood-Derived Progenitor/Stem Cells Enhances Vasculogenesis

The stem cell therapy for treating ischemic diseases is promising; however, the limited availability and compromised quality of progenitor cells in aged and diseased patients limit its therapeutic use. Here we report a nanofiber-based ex vivo stem cell expansion technology and proangiogenic growth factors overexpression of human umbilical cord blood (UCB)-derived progenitor cells to enhance angiogenic potential of therapeutic stem cells. The progenitor cells were expanded approximately 225-fold on nanofiber-based serum-free ex vivo expansion culture technique without inducing differentiation. The expanded cells express high levels of stem cell homing receptor, CXCR4, and adhesion molecule, LFA-1. The nanofiber-expanded stem cells uptake AcLDL effectively, and migrate efficiently in an in vitro transmigration assay. These expanded cells can also differentiate into endothelial and smooth muscle cells in vitro. In a NOD/SCID mouse hind limb vascular injury model, nanofiber-expanded cells were more effective in blood flow restoration and this effect was further augmented by VEGF(164) and PDGF-BB, growth factor overexpression. The data indicate that nanofiber-based ex vivo expansion technology can provide an essential number of therapeutic stem cells. Additionally, proangiogenic growth factors overexpression in progenitor cells can potentially improve autologous or allogeneic stem cell therapy for ischemic diseases.

Histocompatibility testing of cultivated human bone marrow stromal cells – A promising step towards pre-clinical screening for allogeneic stem cell therapy

Mesenchymal stem cells (MSCs) lack major histocompatibility complex (MHC)-II and only show minimal MHC-I expression. Despite MSCs demonstrating T-cell anergy, there are no established methods to evaluate their suitability. It is crucial to evaluate the complete mismatch of MHC compatibility in view of the hypo-immunogenic nature and immunomodulatory properties of MSCs with respect to their proliferation potential (PP) and utility in terms of passage number. With bone marrow (BM) being the major source of MSCs, the use of these cells becomes even more complicated, due to many other receptors coming to fore and triggering alternative pathways. This prospective study included five BM aspirates for MSC cultures and five allogeneic peripheral blood mono nuclear cells (PBMNCs) from healthy volunteers. MHC compatibility was assessed by polymerase chain reaction-sequence specific primer (PCR-SSP). The PP and a T-cell response to MSCs was addressed in mixed cultures and evaluated on the basis of their stimulation index (SI). Allogeneic circulatory antibodies against the donor MSCs was performed by cytotoxicity assay. The PP of MSCs during interactions with PBMNCs (T-cells) demonstrated T-cell anergy and the response to circulatory antibodies was minimal, in consonance with other published reports. Although, the results are encouraging for potential clinical application of MSC transplantation, autologous is always preferable to allogeneic, at least until the long-term safety of these cells is established in clinical trials.

Twisting immune responses for allogeneic stem cell therapy

Stem cell-derived tissues and organs have the potential to change modern clinical science. However, rejection of allogeneic grafts by the host's immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines. Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases. Traditional strategies usually involve suppressing the whole immune systems with drugs. There are many side effects associated with these methods. Here, we discuss an emerging strategy for manipulating the central immune tolerance by naturally "introducing" donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues. This strategy has two distinct stages. The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs (LHRH-A), keratinocyte growth factor (KGF), interleukin 7 (IL-7) and FMS-like tyrosine kinase 3 (FLT3). The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection. Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus. We also review several clinical cases to explain this new strategy.

Introduction to Cellular Therapy

Cell therapy represents a new frontier in the development of therapeutics for stroke. Aside from physical rehabilitation, few options exist to enhance recovery from stroke. Prior studies in the 1990s provided precedence for considering a cellular approach to treat neurological disorders with the pioneering work on transplantation in Parkinson disease. These trials furnished preliminary evidence for a modest benefit in young patients with a neurodegenerative disorder who underwent neural transplantation. From those initial studies, pilot work emerged on the application of cellular replacement in Huntington disease and other neurological disorders. In an entirely different area of medicine, stem cell transplantation in oncology provided support for the idea that stem cells could be administered intravenously for a range of disorders including stroke. Over the past decade, investigators accordingly began showing that intravenously injected stem cells from the bone marrow and umbilical cord could promote recovery in animal stroke models. Thus began a new area of investigation in which adult stem cells from other sources, rather than the brain, could be tested for therapeutic applications in stroke. As transplantation studies have been growing, it has also now clearly been established that the adult brain undergoes neurogenesis. Elegant work from Lindvall and Parent and others have shown that …