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Stem-cell therapy holds great promise for the treatment of ischemic heart disease. However, the benefit of cardiac cell therapy has not yet been proven in long-term clinical trials. Poor engraftment and survival of transplanted cells is one of the major concerns for the successful application of stem cells in cardiac cell therapy. Cell and cardiac pre-conditioning are now being explored as new approaches to support cell survival and enhance the therapeutic efficacy. In this paper, we summarize the state-of-the-art methods of cell delivery and cell survival post-delivery, with a focus on the pre-conditioning approaches that have been attempted to support the survival of transplanted cells. [ABSTRACT FROM AUTHOR]

The following commentary was developed by the National Marrow Donor Program Cord Blood Advisory Group and is intended to provide an overview of umbilical cord blood (UCB) processing, summarize the current state of potency assays used to characterize UCB, and define limitations of the assays and future needs of the cord blood banking and transplant community. The UCB banking industry is eager to participate in the development of standardized assays to uniformly characterize cellular therapy products that are manufactured in a variety of ways. This paper describes the desired qualities of these assays and how the industry proposes to co-operate with developers to bring relevant assays to market. To that end, the National Marrow Donor Program (NMDP) Cord Blood Bank Network is available to serve as a resource for UCB testing material, research and development consulting, and product/assay testing in an accredited UCB manufacturing environment. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are multipotent cells that differentiate into osteoblasts, myocytes, chondrocytes and adipocytes as well as insulin-producing cells. The mechanism underlying their in vivo differentiation is not clear and is thought to be caused by spontaneous cell fusion or factors present in the microenvironment. However, their ease of isolation, high 'ex-vivo' expansion potential and ability to differentiate into multiple lineages make them attractive tools for potential use in cell therapy. MSC have been isolated from several tissues, including bone/bone marrow, fat, Wharton's jelly, umbilical cord blood, placenta and pancreas. The 'immunosuppressive' property of human MSC makes them an important candidate for cellular therapy in allogeneic settings. Use of allogeneic MSC for repair of large defects may be an alternative to autologous and allogeneic tissue-grafting procedures. An allogeneic approach would enable MSC to be isolated from any donor, expanded and cryopreserved, providing a readily available source of progenitors for cell replacement therapy. Their immunomodulatory properties have raised the possibility of establishing allogeneic MSC banks for tissue regeneration. These facts are strongly reflected in the current exponential growth in stem cell research in the pharmaceutical and biotechnology communities. Current knowledge regarding the immunobiology and clinical application of MSC needs to be strengthened further to establish MSC as a safe and effective therapeutic tool in regenerative medicine. This paper discusses human MSC with particular reference to the expression of their surface markers, their role as immunomodulators and their multilineage differentiation potential and possible use in tissue regeneration and repair. [ABSTRACT FROM AUTHOR]

Introduction Mesenchymal stromal cells (MSC) represent an attractive cell population for tissue engineering purposes. As MSC are described as immunoprivileged, non-autologous applications seem possible. A basic requirement is the survival of MSC after transplantation in the host. The purpose of the current paper was to evaluate the survival of undifferentiated and osteogenically induced human MSC from different origins after transplantation in immunocompetent mice. Methods Human MSC were isolated from bone marrow (BMSC) and adipose tissue (ASC). After cultivation on mineralized collagen, MSC were transplanted subcutaneously into immunocompetent mice (n=12). Undifferentiated MSC (group A) were compared with osteogenic-induced MSC (group B). Human-specific in situ hybridization and anti-vimentin staining was used to follow MSC after transplantation. Quantitative evaluation of lymphocytes and macrophages was performed as a measure of immunologic rejection. Unloaded scaffolds served as controls (group C). Specimens were harvested at 4 and 8 weeks. Results Undifferentiated BMSC and ASC were detected in the majority of cases after xenogenic transplantation (group A, a total of 22 out of 24 cases), while osteogenic-induced MSC (group B) could be detected in only three of 24 cases. Quantification of lymphocytes and macrophages revealed significantly higher cell numbers in group B compared with group A (P<0.05). Discussion Our results suggest that undifferentiated MSC are candidates for non-autologous cell transplantation, while osteogenic-induced MSC seem to be eliminated by the host's immune system. This observation seems independent of the origin of MSC and applies to BMSC and ASC. [ABSTRACT FROM AUTHOR]

Background Little is known about human mesenchymal stromal cell (hMSC) phenotypic and functional subsets in response to environmental stimuli. The strategy used in this study focused on defining hMSC functional subpopulations based in particular on their Thy-1 (CD90) antigen (Ag) surface expression. Methods The effect of different in vitro microenvironmental conditions on the isolation and expansion of bone marrow-derived (BM) hMSC from hematologic malignancies (HM) and normal samples (NS) was assayed. hMSC clonogenic and differentiation potential, phenotypic profile and long-term capacity to sustain in vitro hemopoiesis were considered in relation to the different expansion protocols. Results The results showed that angiogenic supplements used in combination with low serum content gave rise to the appearance of Thy-1- HM-MSC with high proliferative potential, capable of restoring the typical HM stromal impairment. The expression of the CD271 was partially maintained. We further report an enhancement towards the osteogenic and adipogenic differentiation capacity by the Thy-1- HM-MSC subset. Despite the angiogenic treatment, the Thy-1- MSC stopped short of full endothelial differentiation. Discussion In this paper we provide evidence that in vitro angiogenic stimuli generate HM-MSC lacking CD90 Ag expression. The Thy-1- MSC subset is characterized by peculiar functional and phenotypic characteristics, thus supporting the role played by the microenvironment in selecting particular hMSC subsets maintaining normal tissue homeostasis or inducing pathologic processes. [ABSTRACT FROM AUTHOR]

This article presents abstracts of several papers related to cell preservation. One of the abstracts is "Involvement of Mitochondrial-Associated Athway of Apoptosis in Cryopreservation Failure," by R.G. van Buskirk and J.G. Baust. Cell viability and function following cryopreservation remains sub-optimal for many cell systems. This has long been accepted overlooked by researchers due to a lack of options. Recent focus on delayed-onset cell death has begun to provide an explanation for these observed failures. In conclusion examination of mitochondrial proteins levels following cryopreservation revealed distinct temporal profiles between differing cryopreservation protocols.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematologic malignancies and inherited disorders of the hematopoietic system. Ex vivo T-cell depletion (TCD) of the graft and post-transplantation immunosuppression efficiently prevents the development of GvHD in no- MHC-identical settings. However, the consequence of these non-specific strategies is a long-lasting immunodeficiency associated with increased incidence of disease relapse, graft rejection and reactivation of viral infections. Donor lymphocyte infusion, which is used for treating leukemic relapse after allogeneic HSCT, can result in severe GvHD. Several strategies are being optimized specifically to inactivate anti-host T cells while preserving anti-leukemic or anti-microbial immunocompetence. Based on the ex vivo or in vivo elimination of anti-host T cells, or on the modulation of their anti-host activity, these approaches, which have been explored extensively in pre-clinical studies and tested in some preliminary clinical trials, are discussed in this paper. [ABSTRACT FROM AUTHOR]

GvHD, the most important cause of morbidity and mortality after allogeneic stem cell transplantation, depends primarily on the ability of a donor T-cell subset to react to immunogenic host Ag. Recently developed culture conditions and treatment strategies may bring us closer to the selective elimination of such alloreactive T cells, often considered the holy grail of transplantation. Among the various therapeutic modalities, photodynamic therapy (PDT) offers a biological and global approach to the eradication of unwanted allo-activated T cells by combining mitochondrial targeting, P-glycoprotein inhibition and reactive oxygen species production. Indeed, the high potency of PDT against malignant cells has been harnessed to exert selective and extensive elimination of alloreactive T-cell subsets mediating GvHD, while preserving resting T cells with the ability to reconstitute the immune system for GvL activity and prevent or suppress viruses and fungi. The present paper reviews the basis of the PDT strategy, and the methodology employed. In vitro and in vivo studies that formed the proof of principle as a basis for human studies to investigate the clinical potential of PDT in the context of GvHD will be presented together with insights into future clinical applications of this versatile treatment platform. [ABSTRACT FROM AUTHOR]

IL-15 is a pleiotropic cytokine that plays an important role in both the innate and adaptive immune system. IL-15 promotes the activation of neutrophils and macrophages, and is critical to DC function. In addition, IL-15 is essential to the development, homeostasis, function and survival of natural killer (NK) cells, NK T (NKT) cells and CD8 + T cells. Based on these properties, IL-15 has been proposed as a useful cytokine for immunotherapy. It is currently being investigated in settings of immune deficiency, for the in vitro expansion of T and NK cells, as well as an adjuvant for vaccines. In this paper, we will review the targeting of IL-15 for immunotherapy, with a particular emphasis on its effects on CD8 + T cells. [ABSTRACT FROM AUTHOR]

Background Hematopoietic progenitor stem cells (HPSC) are a specialized transfusion product used for transplantation. Microbial contamination may occur during harvest or subsequent manipulation of these cells. The same difficulties in ensuring a safe, sterile, final product are faced in the preparation of other cell-therapy products directly obtained from donors. Detection of contamination is problematic, and the clinical significance of infusing contaminated HPSC is controversial. Methods Chimeric Therapies' manufacturing and clinical experience with BM HPSC products and validation of a culture method for detection are described. In addition, this paper reviews the literature concerning contaminated blood products, including rates and circumstances of contamination, organisms, methods of detection, and the clinical significance of infusion of contaminated products. Results Seven of 33 BM harvest products received at Chimeric Therapies were culture positive for skin commensal organisms. Three of seven were culture positive in the infused product. This compares with literature reports of 0—42%. No patients had significant infusion reactions or evidence of infection related to the contamination. Discussion The risks associated with microbial contamination with skin commensals are insignificant compared with other components of transplantation. Contamination with pathogens can be eliminated with careful good manufacturing practices (GMP). A series of practical recommendations are presented for the reduction of contamination in HPSC and cell-therapy products. [ABSTRACT FROM AUTHOR]

Presents abstracts from papers in the medical field. Self-powered device for harvesting white blood cell (WBC) from UC blood during centrifugation; Results of the first public cord bank established in South America (Brazil); Evaluation of the Stem Quick E filter system from Asahi Medical for processing UC blood; Report on the American Red Cross Cord Blood Bank (ARCCBB) raising the level of minimum cell count required from donors.

Recent studies demonstrate the capacity of BM-derived cells to engraft as differentiated cells of a variety of organs, including lung. In this paper, we review the current state-of-the-art in this area. We also summarize our work demonstrating that cultured adherent marrow cells can serve as progenitors of lung alveolar epithelium. [ABSTRACT FROM AUTHOR]

Background Previously, we demonstrated that murine mesenchymal stem cells (MSCs) injected intracranially into neonatal mice expand throughout the central nervous system (CNS). This paper describes real-time PCR (RT-PCR) assays that enable accurate quantification of transplanted cells in vivo . Methods RT-PCR assays that amplify sequences in the mouse Y chromosome or human Alu repeats were developed and used to quantify the number of male, murine or human MSCs in the CNS at various times after intracranial injection into neonatal mice, or in various organs of adult mice after i.p. injection of cells into 13 day-old embryos. Results In the CNS, levels of male mouse DNA in female transplant recipients increased on average 30-fold between 3 and 60 days post-injection, but then was unchanged at 140 days post-transplant (P=0.107). Male DNA accounted for up to 0.309% of the total DNA content of brain, representing maximally 600 000 donor cells. Human DNA was detected in the CNS up to 300 days post-transplant, but levels never exceeded 7.63×10 -4 % of total brain DNA content. After in utero transplantation, human DNA levels ranged from 0.36×10 -5 % to 2.14×10 -5 % of the total DNA content of liver, kidney and spleen. Significantly higher levels were found in heart (P=0.06), femur and brain (P=0.02), and lung (P=0.0025). Discussion RT-PCR assays were developed to quantify levels of male, murine and human cells in vivo following sex-mismatched or xeno-transplants. Due to their accuracy, precision, and sensitivity, these assays provide a versatile alternative to measuring stem-cell engraftment in vivo. [ABSTRACT FROM AUTHOR]

Background Priming with autologous tumor vaccine followed by ex vivo expansion of activated T cells is a feasible experimental strategy. This paper describes the application of this cellular therapy to treat patients with late-stage non-small-cell lung cancr (NSCLC). Methods Twenty-one patients with Stages III and IV NSCLC were treated. Tumor samples were obtained surgically (five patients) or by using a co-axial biopsy needle (16 patients). Each course of vaccination consisted of irradiated tumor cells, mixed with GM-CSF and injected intradermally on Day 1, followed by GM-CSF only on Days 2–5. The course was repeated 10–14 days later. Lymphocytes were collected 10–14 days after the second course and ex vivo expanded using IL-2 and anti-CD3 Ab. The expansion products were then re-infused into the patients. Results Twelve out of 16 biopsies resulted in optimal cell numbers for vaccine preparation. Nineteen out of 21 patients achieved a delayed type hypersensitivity (DTH) response after two courses of vaccination. In 18/21 patients, the ex vivo expansion products contained >1.6×10 10 cells. Subset analysis showed 77.0–97.2% T cells with a CD4:CD8 ratio of 0.65–4.0; natural killer cells were 2.0–18.6%. There were no significant toxicities. The median survival of all 21 patients was 18.6 months, with a 1-year survival of 51.6%. Conclusion Autologous tumor cell-vaccination may be combined with ex vivo expansion of lymphocytes as adoptive cellular immunotherapy for advanced NSCLC. Overall survival in this cohort of poor prognosis patients compared favorably with results reported in the literature. [ABSTRACT FROM AUTHOR]

Presents abstracts of papers related to cytotherapy. "Cord Blood-Derived Mesenchymal Progenitor Cells Can Present Distinct Hematopoietic Supportive Capacity," by Z. C. Alfonso; "Large-Scale Transcriptional Analysis of ex vivo Expanded Human T Cells," by H. Haddad; "Extensive Purging of NHL Cells Using a Photodynamic Strategy," by N. Dallaire.

Presents abstracts of papers presented at the 2001 International Symposium on Minimal Residual Cancer. "Growth Factor Signaling in Carcinoma Progression," by J. P. Thiery; "Cell Adhesion Molecules in Angiogenesis," by C. Wagener; "Anti-Angiogenesis and Hypoxia," by A. L. Harris.

Corrections to "The effect of type I collagen on steochondrogenic differentiation in adipose-derived stromal cells in vivo," a paper by M. Alonso, S. Claros, and colleagues that appeared in the volume 10 of this journal, are presented.

A recent paper in Cytotherapy presented an interesting soft-tissue augmentation technique that caught our attention. We believe that the method is creative but complicated to practice. We note that the authors used platelet-rich plasma (PRP) solely as the source of growth factors. In fact, PRP itself can serve as a scaffold to carry cells. Considering the unique properties of PRP, we propose an alternative technique that may not only simplify the procedure but also yield promising results. The specific reasons are explained in this letter. In addition, we comment on the use of heparin as an anticoagulant for PRP production. [ABSTRACT FROM AUTHOR]

The article reviews developments in the research of regulatory Treg (T) cells in the treatment of autoimmunity. A research paper in the issue on attempts to improve the isolation of Treg cells through the addition of CD8-depletion techniques to those currently being practiced is mentioned. The author describes the possible benefits that can arise from Treg cell transfers and the clinical trials that should be performed to evaluate them.

The author reflects on the various studies in regenerative medicine that focuses on mesenchymal stromal cells (MSC) as the building blocks of new tissues for repair of injury or replacement of pathologic tissues in the treatment of genetic and acquired disease. He indicates that the issue of Cytotherapy includes four papers on MSC biology and pre-clinical model of MSC therapy that highlights the growing importance of the cell. A brief discussion of the four studies was also presented by the author.

The author reflects on the initiative of the medical journal "Cytotherapy" to improve its impact factor to the readers. He says that the journal is aware of the fierce competition between medical publications, and will progressively increase its readership impact through submitted paper selection. Furthermore, he says that the journal has other goals aside from improving its readership impact like serving as the official publication of the International Society of Cell Therapy (ISCT).

The article announces that this 11th volume of "Cytotherapy" marks a relaunch of the journal. It describes the new cover and improved format of the journal. It also notes that the font size was made smaller and the line spacing closer to publish the increased number of papers accepted for publication in a timely fashion. It adds that each issue has 25% more contents than previous without any increase in bulk.

Introduces a series of papers presented at the 2001 International Symposium on Minimal Residual Cancer, published in the July 2001 issue of "Cytotherapy" journal. State of the knowledge and use of monoclonal antibodies in the study of cancer; Advantages of smaller meetings among experts in the cancer field.