Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Multipotent mesenchymal stromal cells (MSC) have immunomodulatory effects. The aim of this study was to demonstrate safety and feasibility of MSC transfusion in pediatric patients who had undergone allogeneic stem cell transplantation from MMFD, MUD, MMUD and MSD. Patients with posttransplant complications based on deregulated immune effector cells who may benefit from an immunomodulatory effect of MSC had been selected. MSC were isolated from the hematopoietic stem cell donors in five cases and from a third party parental donor in two cases. We transfused ex vivo-expanded MSC in 11 doses into seven pediatric patients. Cell doses were escalated based on availability from 0.4x10(6) to 3.0x10(6) per kg bodyweight No adverse effects were detected with a maximum follow-up of 29 months. One out of three patients showed slight improvement of chronic GVHD. Two patients with severe acute GvHD did not progress to cGvHD. One patient received MSC to stabilize graft function after secondary haploidentical transplantation. One patient recovered from trilineage failure due to severe hemophagocytosis. This is the first case of a pediatric patient treated with MSC for trilineage failure after haploidentical stem cell transplantation from her father. We report the first series of 11 transfusions of expanded MSC in pediatric patients with immunological complications after allogeneic transplantation. Transfusion of MSC was safe and encouraging improvements in some patients were observed.
Blood Cells Mol Dis
PMID:Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. 1786 50

Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150-200 mg/m(2)), thiotepa (10 mg/kg), melphalan (120 mg/m(2)) and OKT-3 (5 mg/day, day -5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age=42 (range, 21-59) years) have been transplanted with this regimen. Diagnosis were AML (n=16), ALL (n=7), NHL (n=3), MM (n=2) and CML (n=1). Patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6x10(6) (range, 3.4-17x10(6)) CD34+ cells/kg, 4.4x10(4) (range, 0.006-44x10(4)) CD3+ T cells/kg and 7.2x10(7) (range, 0.02-37.3x10(7)) CD56+ cells/kg. Donor-recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2-3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m(2) fludarabine, the dose was reduced to 150 mg/m(2). Engraftment was rapid with a median time to >500 granulocytes/microL of 12 (range, 10-21) days, >20,000 platelets/microL of 11 (range, 7-38) days and full donor chimerism after 2-4 weeks in all patients. Incidence of grade II-IV degrees GVHD was 48% with grade II degrees =10, III degrees =2 and IV degrees =2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n=1), mucormycosis (n=1), pneumonia (n=3) or GVHD (n=1). Overall survival is 9/29 patients (31%) with deaths due to infections (n=7), GVHD (n=1) and relapse (n=12) with a median follow-up of 241 days (range, 112-1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.
Blood Cells Mol Dis
PMID:Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. 1786 47

Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for patients to benefit from HCT when a human leukocyte antigen (HLA) genotypically matched sibling is not available. Initial results with the use of mismatched allograft has been disappointing due to the high incidence of graft-versus-host disease (GVHD) and infectious complications resulting in an unacceptable treatment-related morbidity and mortality. Recent advances with effective T-cell depletion, the use of 'megadose' of stem cells and reduced intensity conditioning has significantly decreased the early transplant related mortality and GvHD, while enabling robust and prompt engraftment, and hence enhancing the therapeutic benefits of haploidentical transplantation. However, the cardinal problems related to delayed immune reconstitution causing posttransplant infectious complications and relapse remain, limiting the efficacy of haploidentical transplant. Preliminary data have demonstrated the great potential in the use of adoptive cellular immunity and selective allodepletion in rapidly reconstituting immunity without GvHD. The encouraging reports from haploidentical transplant using noninherited maternal antigen (NIMA)-mismatched donors or natural killer alloreactive donors may greatly increase the donor availability and open a way to more appropriate donor selection in HLA-haploidentical HSCT. Future challenges remain in determining the safest approach for haploidentical transplant to be performed with minimal risk of GvHD, while preserving effective graft-versus-leukemia activity and promoting prompt immune reconstitution.
Blood Cells Mol Dis
PMID:Nonmyeloablative allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors: a review. 1788 41

Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.
Blood Cells Mol Dis
PMID:Enhancing T cell reconstitution after hematopoietic stem cell transplantation: a brief update of the latest trends. 1790 11

Although adoptive transfer of donor lymphocytes protects from infections and relapse after allogeneic hematopoietic stem cell transplantation in both mice and in men, it is associated with a high risk of graft versus host disease (GvHD) which rises with HLA mismatching and the number of T lymphocytes that are infused. Elimination/reduction of alloreactive donor T lymphocytes is an appealing approach and several strategies have been proposed. Here we describe generation of anti-3rd party T lymphocytes under conditions of IL-2 deprivation and their effects in a pre-clinical murine model. Our results clearly indicated that anti-3rd party T lymphocytes generated on a large scale by means of IL-2 deprivation maintain a broad T cell repertoire, do not proliferate in a mixed lymphocyte reaction and do not cause GvHD in NOD-SCID mice. These anti-3rd party lymphocytes contain a large adaptive T regulatory cell subset which might contribute to in vitro and in vivo immune modulation.
Blood Cells Mol Dis
PMID:Large-scale generation of human allodepleted anti-3rd party lymphocytes. 1793 16

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. The success of HSCT is greatly reduced by the development of complications, which include graft-versus-host disease (GVHD), relapse and infection. Human leukocyte antigen (HLA) matching of patients and donors is essential, but does not completely prevent these complications; non-HLA genes may also have an impact upon transplant outcome. Polymorphisms within genes that are associated with an individual's capability to mount an immune response to alloantigen and infectious pathogens and/or response to drugs (pharmacogenomics) are all currently being studied for their association with HSCT outcome. This review summarises the potential role of non-HLA polymorphisms in predicting HSCT outcome, from studies on retrospective transplant cohorts of HLA-identical siblings and matched unrelated donors. The clinical relevance and interpretation of non-HLA genetics, and how these could be used alongside clinical risk factors in HSCT, are also discussed.
Expert Rev Mol Med 2007 Nov 02
PMID:Haematopoietic stem cell transplantation: can our genes predict clinical outcome? 1797 48

Human umbilical cord blood (CB) has recently been used as a source of stem cells in transplantation. NK cells derived from CB are the key effector cells involved in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). It was reported that the activity of CB NK cells was lower than that of adult peripheral blood (PB) NK cells. In this study, we analyzed the expression of some NK cell receptors and cytotoxicity-related molecules in CB and PB NK cells. The expressions of activating NK receptors, CD16, NKG2D and NKp46, did not show significant difference between CB and PB NK cells. But the expression of inhibitory receptor NKG2A/CD94 was significantly higher on CB NK cells. As to the effector function molecules, granzyme B was expressed significantly lower in CB NK cells, but the expressions of intracellular perforin, IFN-gamma, TNF-alpha and cell surface FasL and TRAIL did not show difference between CB and PB NK cells. The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of CB NK cells.
Cell Mol Immunol 2007 Oct
PMID:High expression of NKG2A/CD94 and low expression of granzyme B are associated with reduced cord blood NK cell activity. 1797 18

After haploidentical stem cell transplantation immune recovery is inevitably slow and infectious related mortality is about 30-40%. Immune reconstitution could be improved by infusing donor T cells, but the obstacle is graft-versus-host disease. In a mixed lymphocyte reaction, alloantigen-stimulated T cells uptake 4,5-dibromorhodamine methyl ester (TH9402), a compound that is structurally similar to rhodamine. TH9402 preferentially localizes in mitochondria and when exposed to 500- to 600-nm wavelength visible light delivered through the Theralux device (Kiadis Pharma, Amsterdam, The Netherlands), it becomes highly cytotoxic through oxidative damage. This study investigated a range of parameters, and combinations thereof, with the aim of achieving optimal T cell allodepletion and preservation of pathogen-specific responses. We report on 11 clinical scale dry runs which reproducibly yielded the following results. Blood mononuclear cells were stimulated with haploidentical irradiated (20 Gy). Blood mononuclear cells in a mixed lymphocyte reaction. Cells were then incubated with TH9402 and exposed to light delivered through the Theralux device. Optimal conditions for T cell allodepletion emerged as (1) duration of mixed lymphocyte reaction: 24 h; (2) responder cell concentration: 3-5x10(6)/ml; (3) TH9402 concentration: 5 microM; (4) quantity of internalized TH9402, as measured by mean fluorescence intensity (MFI): 20,000-25,000 MFI; (5) energy delivered: 0.1 J/cm(2). Only under these conditions were the frequencies (by limiting dilution analyses) of alloantigen-specific T cells maximally reduced, i.e., 2467+/-639 (mean+/-SD) times, when compared with non-TH9402-treated cells. Pathogen-specific responses to pathogen antigens such as Cytomegalovirus, Adenovirus, Varicella Zoster Virus, Herpes Simplex Virus, Aspergillus fumigatus, Candida albicans, Toxoplasma gondii were retained, although with a 19+/-9.7 times reduction in frequency. This remarkable drop in frequency of alloreactive T cells is expected to allow safe infusion of relatively large numbers of T cells across histocompatibility barriers for adoptive transfer of donor immunity. Consequently, a clinical trial is planned to incorporate infusion of photo-allodepleted donor T cells after haploidentical stem cell transplantation with the aim of decreasing infection-related mortality.
Blood Cells Mol Dis
PMID:Photodynamic purging of alloreactive T cells for adoptive immunotherapy after haploidentical stem cell transplantation. 1797 31

Mesenchymal stem cells (MSCs) are multipotent progenitor cells isolated by various relatively easily accessible tissues, such as bone marrow and cord blood. MSCs gained attention because of their ease for in vitro expansion together with their multilineage potential. More recently, in vitro and in vivo immunosuppressive properties have been ascribed to them, as they are able to modulate the function of all major immune cell populations, thus impeding immune responses. The underlying mechanisms of their differentiation and function are not thoroughly understood, but still they represent important candidates for tissue regeneration and manipulation of the immune response in graft rejection, graft versus host disease, and autoimmune disorders. Characteristics and immunogenic profile of MSCs, their interface with immune system and their potential use as immunosuppressive elements in cellular therapeutic protocols are reviewed in this chapter.
Methods Mol Biol 2007
PMID:Immune properties of mesenchymal stem cells. 1845 59

Allogeneic hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with malignant and non-malignant immunohematopoietic diseases. Matched unrelated donors are increasingly used and improved HLA matching has led to increased survival. In addition, stem cells derived from peripheral blood and cord blood are being utilized to a greater extent. During the last decade, reduced-intensity conditioning, which is preferentially used in older patients or those with organ dysfunction, was introduced as an alternative to standard myeloablative regimens. In addition, the isolation of patients after transplant has been challenged by allowing patients to be treated at home after ASCT. Analysis of mutations in caspase recruitment domain containing protein 15 and levels of regulatory T-cells may be important in identifying patients at risk for acute graft-versus-host disease (GVHD). Mesenchymal stem cells that have immunomodulatory effects home in to injured tissues and may be used in the treatment of patients with steroid-refractory GVHD. In addition, the graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) effect (ie, the attack of the transplanted immune system against the tumor or leukemia), is of major importance for the success of ASCT in patients with malignant disease. GVT and GVL effects may be improved by utilizing differences in minor histocompatibility antigens between the patients and the donor or by using natural killer cell alloreactivity. ASCT has shown GVT effects in patients with solid tumors. New developments in clinical ASCT have been highlighted in this review.
Curr Opin Mol Ther 2008 Aug
PMID:Recent progress in allogeneic stem cell transplantation. 1868 98


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