Hematopoietic stem cell therapy for malignant diseases
ABSTRACT Allogeneic bone marrow or blood stem cell transplantation (SCT) has changed its face in the last two decades. The introduction of nonmyeloablative conditioning regimens has reduced procedure toxicity and allowed the application of SCT in patients and conditions in which SCT was not offered in the past. In this review we will summarize the changes and accomplishments achieved in the past years in the field of stem cell transplantation for malignant disorders.
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ABSTRACT: Re-acquisition of immunocompetence after allogeneic bone marrow cell (BMC) transplantation depends on intrathymic maturation of the allogeneic T progenitor cells. We recently reported that CD44 promotes progenitor homing into the thymus and T-cell maturation and now elucidate the molecular mechanisms of CD44-supported thymocyte maturation. Lethally irradiated, tumor-bearing mice, allogeneically reconstituted with T-cell-depleted BMC and a small number of common lymphoid progenitor 2 cells (CLP2) from transgenic (TG) mice, that express ratCD44v4-v7 under the Thy1 promoter, showed accelerated immunocompetent T-cell recovery compared with mice reconstituted with non-transgenic (NTG) CLP2. In addition, graft-versus-host disease was strongly reduced after tumor vaccination. TG, but not NTG double-negative (DN) thymocytes showed high proliferative potential, accompanied by constitutive association of lck with CD44. Importantly, when thymocyte adhesion was strengthened by anti-CD44, co-cultures of DN thymocytes with thymic stroma supported DN thymocyte maturation. The close contact between DN thymocytes and thymic stroma promoted persisting activation of lck and ERK1/2, particularly in CD44v6(+) DN thymocytes. Thus, intrathymic T-cell maturation in allogeneically reconstituted, leukemia-bearing hosts can be considerably accelerated by high CD44v6 expression in early thymocytes, in which proliferation-supporting signals are initiated by a crosstalk between CD44v6 on thymocytes and panCD44 on the thymic stroma.Immunology and Cell Biology 09/2009; 88(2):136-47. DOI:10.1038/icb.2009.70 · 4.21 Impact Factor
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ABSTRACT: To assess the severity of xerostomia (subjective dry mouth) in haematopoietic stem cell transplantation (HSCT) patients and to investigate the association of xerostomia with other chronic oral complications. Cross-sectional study.Study participants and methods Participants were 48 patients with a history of HSCT recruited among members of the Dutch Stem Cell Transplantation Contact Group, and a comparison group of 41 age- and sex-matched individuals. Data were collected using the Xerostomia Inventory (XI score) and a seven-item oral health questionnaire. HSCT patients had a higher XI score than the comparison group, and a greater severity of several oral complaints: painful oral mucosa, altered taste, limited opening of the mouth and problems with tooth brushing. HSCT patients did not report greater pain during cold stimulation of teeth, chipped and cracked teeth or bleeding gums. In HSCT patients, the XI score correlated significantly with the severity of oral mucosal pain, altered taste, limited opening of the mouth, painful teeth following cold stimuli, chipped or cracked teeth, problems with tooth brushing and bleeding gums. In the comparison group, no correlations were observed between XI score and these oral problems. HSCT patients have more severe xerostomia, which is associated with other oral complaints. Dental professionals should monitor these patients post-transplant for oral complications. Symptoms of dry mouth should be relieved and secondary complications should be prevented.British dental journal official journal of the British Dental Association: BDJ online 11/2009; 207(9):E17; discussion 428-9. DOI:10.1038/sj.bdj.2009.977 · 1.08 Impact Factor
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ABSTRACT: We have previously reported that transplantation (Tx) of prevascularized donor islets as composite islet-kidneys (IK) reverses diabetic hyperglycemia in miniature swine. In order to test the potential clinical applicability of this strategy, we have extended it to a fully allogeneic nonhuman primate model. IKs were prepared in baboons by isolating islets from 50% to 70% partial pancreatectomies and injecting them under the autologous renal capsule, allowing vascularization before allogeneic Tx. Baboons with diabetes induced by stereptozotocin or total pancreatectomy, received composite IKs (n = 3) or free islets under the renal capsule or intraportally (n = 3), across fully allogeneic barriers with an immunosuppressive regimen consisting of ATG followed by MMF and tacrolimus. FBS of two of IK recipients decreased immediately after Tx and no insulin therapy was required throughout the experimental period (225 and 301 days). In contrast, all recipients of allogeneic free islets showed unstable FBS levels and required insulin within 2 months. We conclude that in addition to maintaining creatinine in the normal range, fully allogeneic IKs from single primate donors can achieve glucose regulation without insulin therapy, while free islets do not. These results support the feasibility of composite allogeneic IK Tx as a potential cure for end-stage diabetic nephropathy.American Journal of Transplantation 09/2011; 11(12):2603-12. DOI:10.1111/j.1600-6143.2011.03733.x · 6.19 Impact Factor