Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction - (TOPCARE-AMI)

Background - Experimental studies suggest that transplantation of blood-derived or bone marrow–derived progenitor cells beneficially affects postinfarction remodeling. The safety and feasibility of autologous progenitor cell transplantation in patients with ischemic heart disease is unknown

Evidence for engraftment of human bone marrow cells in non-lethally irradiated baboons

Background. Prior to organ harvesting, an attempt was made to modulate the donor's immune responses against prospective xenogeneic recipients by infusion of 'recipient-type' bone marrow. Methods. For this purpose, baboons conditioned with total lymphoid irradiation were given 6x108 unmodified human bone marrow cells/kg body weight with no subsequent treatment. Results. Animals survived until they were euthanized at 18 months. Using primers specific for human chorionic gonadotrophin gene, the presence of human DNA was confirmed by polymerase chain reaction in the blood of one animal for up to 18 months after cell transplantation; in the other animal, xenogeneic chimerism became undetectable in the blood at 6 months after bone marrow infusion. However, tissue samples obtained from both animals at the time they were euthanized bad evidence of donor (human) DNA. Additionally, the presence of donor DNA in individually harvested colonies of erythroid and myeloid lineages suggested that infused human bone marrow cells had engrafted across the xenogeneic barrier in both baboons. Conclusions. Bone marrow transplantation from human to baboon leads to establishment of chimerism and modulation of donor-specific immune reactivity, which suggests that this strategy could be reproducibly employed to crease 'surrogate' tolerogenesis in prospective donors for subsequent organ transplantation across xenogeneic barriers

A clinical trial combining donor bone marrow infusion and heart transplantation: intermediate-term results.

BACKGROUND: Donor chimerism (the presence of donor cells of bone marrow origin) is present for years after transplantation in recipients of solid organs. In lung recipients, chimerism is associated with a lower incidence of chronic rejection. To augment donor chimerism with the aim to enhance graft acceptance and to reduce immunosuppression, we initiated a trial combining infusion of donor bone marrow with heart transplantation. Reported herein are the intermediate-term results of this ongoing trial. METHODS: Between September 1993 and August 1998, 28 patients received concurrent heart transplantation and infusion of donor bone marrow at 3.0 x 10(8) cells/kg (study group). Twenty-four contemporaneous heart recipients who did not receive bone marrow served as controls. All patients received an immunosuppressive regimen consisting of tacrolimus and steroids. RESULTS: Patient survival was similar between the study and control groups (86% and 87% at 3 years, respectively). However, the proportion of patients free from grade 3A rejection was higher in the study group (64% at 6 months) than in the control group (40%; P =.03). The prevalence of coronary artery disease was similar between the two groups (freedom from disease at 3 years was 78% in study patients and 69% in controls). Similar proportions of study (18%) and control (15%) patients exhibited in vitro evidence of donor-specific hyporesponsiveness. CONCLUSIONS: The infusion of donor bone marrow reduces the rate of acute rejection in heart recipients. Donor bone marrow may play an important role in strategies aiming to enhance the graft acceptance

The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis.

Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation

Population Pharmacokinetic Study of a Test Dose Busulfan Patients Undergoing Hematopoietic Stem Cell Transplantation

UNIFESP (Universidade Federal de São Paulo), BrazilOnco-Hematology Unit, Instituto da Criança - HC - FMUSP, Sao Paulo, BrazilHospital Israelita Albert Einstein, BrazilHematology and Bone Marrow Transplantation Dept, Hospital Israelita Albert Einstein, BrazilHematology and Bone Marrow Transplantation Dept, UNIFESP (Universidade Federal de Sao Paulo), BrazilPediatric Bone Marrow Transplantation Center, Instituto de Oncologia Pediatrica, São Paulo, BrazilHematology and Bone Marrow Transplantation Dept, Hospital Israelita Albert Einstein, Sao Paulo, BrazilInstituto de Oncologia Pediátrica, São Paulo, BrazilClinical Research Center, Instituto de Oncologia Pediátrica, São Paulo, BrazilDepartment of Medicine - Bone Marrow Transplant Program, Case Western Reserve University, ClevelandUNIFESP (Universidade Federal de São Paulo), BrazilHematology and Bone Marrow Transplantation Dept, UNIFESP (Universidade Federal de Sao Paulo), BrazilWeb of Scienc

Perioperative donor bone marrow infusion augments chimerism in heart and lung transplant recipients

Background.: We and others have demonstrated that a low level of donor cell chimerism was present for years after transplantation in tissues and peripheral blood of heart and lung recipients; it was associated, in the latter, with a lower incidence of chronic rejection. To augment this phenomenon, we initiated a trial combining simultaneous infusion of donor bone marrow with heart or lung allotransplantation. Methods.: Between September 1993 and January 1995, 15 nonconditioned patients received either heart (n = 10) or lung (n = 5) allografts concurrently with an infusion of unmodified donor bone marrow (3.0 × 108 cells/kg), and were maintained on an immunosuppressive regimen consisting of tacrolimus and steroids. Results.: There was no complication associated with the infusion of donor bone marrow. Chimerism was detectable in 73% of bone marrow-augmented patients up to the last sample tested. Of the 5 control recipients who did not receive bone marrow infusion, only 1 had detectable chimerism by flow on postoperative day 15, which dwindled to an undetectable level by postoperative day 36. None of the patients had evidence of donor-specific immune modulation by mixed lymphocyte reaction. Conclusions.: The combined infusion of donor bone marrow and heart or lung transplantation, without preconditioning of the recipient, is safe and is associated with an augmentation of donor cell chimerism. © 1995 The Society of Thoracic Surgeons

Outcome analysis of 71 clinical intestinal transplantations

Objective: The aim of the study was to determine risk factors associated with graft failure and mortality after transplantation of the intestine alone or as pad of an organ complex. Summary Background Data: Even with modern immunosuppressive therapies, clinical intestinal transplantation remains a difficult and unreliable procedure. Causes for this and solutions are needed. Methods: Between May 1990 and February 1995, 71 intestinal transplantations were performed in 66 patients using tacrolimus and low-dose steroids. The first 63 patients, all but one treated 1 to 5 years ago, received either isolated grafts (n = 22), liver and intestinal grafts (n = 30), or multivisceral grafts (n = 11). Three mere recipients of allografts who recently underwent surgery and one undergoing retransplantation were given unaltered donor bone marrow cells perioperatively as a biologic adjuvant. Results: Of the first 63 recipients, 32 are alive: 28 have functioning primary grafts and 4 have resumed total parenteral nutrition after graft enterectomy. Thirty-five primary grafts were lost to technical and management errors (n = 10), rejection (n = 6), and infection (n = 19). Regression analysis revealed that duration of surgery, positive donor cytomegalovirus (CMV) serology, inclusion of graft colon, OKT3 use, steroid recycle, and high tacrolimus blood levels contributed to graft loss. All four intestine and bone marrow recipients are alive for 2-3 months without evidence of graft- versus-host disease. Conclusion: To improve outcome after intestinal transplantation with previous management protocols, it will be necessary to avoid predictably difficult patients, CMV seropositive donors, and inclusion of the graft colon. Bone marrow transplantation may further improve outcome by ameliorating the biologic barriers of rejection and infection and allowing less restrictive selection criteria

Organ and tissue transplantation

A report is delivered on the First International Congress of the Transplantation Society (Paris 1967). The recent interest in transplantation of organs is largely due to the technical advances in surgical procedures making it possible to replace organs in the human, as well as to an increased understanding of the basic biological problems underlying the rejection of such grafts. At this first International Congress, widely ranging topics were discussed, including organ transplantation, mechanism of graft rejection, methods of immunosuppression, genetics of transplantation, bone marrow transplantation, and cancer as homograft. New techniques of organ transplantation, new concepts in the antigenic structure of cells, new methods of purifying subcellular fraction of antilymphocytic serum, new drugs to combat rejection phenomena, and above all a fresh outlook on the mode of action of these drugs at a molecular level, will doubtless render this an exciting new approach to biology in general and to clinical problems in particular.peer-reviewe

Bone remodeling after renal transplantation

Bone remodeling after renal transplantation. Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation

Transplantation tolerance from a historical perspective

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy