Showing papers on "Transplantation published in 1990"
TL;DR: The pacemaker role of the suprachiasmatic nucleus in a mammalian circadian system was tested by neural transplantation by using a mutant strain of hamster that shows a short circadian period to restore circadian rhythms to arrhythmic animals whose own nucleus had been ablated.
Abstract: The pacemaker role of the suprachiasmatic nucleus in a mammalian circadian system was tested by neural transplantation by using a mutant strain of hamster that shows a short circadian period. Small neural grafts from the suprachiasmatic region restored circadian rhythms to arrhythmic animals whose own nucleus had been ablated. The restored rhythms always exhibited the period of the donor genotype regardless of the direction of the transplant or genotype of the host. The basic period of the overt circadian rhythm therefore is determined by cells of the suprachiasmatic region.
1,772 citations
TL;DR: The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa.
Abstract: Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.
1,169 citations
TL;DR: The addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder after cardiac transplantation, and the risk increases sharply after cumulative doses greater than 75 mg.
Abstract: Background. A sudden increase in the incidence of post-transplantation lymphoproliferative disorder among the patients in our cardiac-transplantation program was temporally related to introduction of the immunosuppressive drug OKT3. This monoclonal antibody has come to be widely used in recent years both to prevent and to treat rejection after cardiac transplantation. Methods. In order to identify variables that predict the development of post-transplantation lymphoproliferative disorder, we analyzed retrospectively a series of 154 consecutive cardiac-transplant recipients at a single institution. Univariate analyses and multivariate analysis by logistic regression were performed. Results. Among 75 patients who did not receive OKT3, post-transplantation lymphoproliferative disorder developed in 1 (1.3 percent), as compared with 9 of 79 patients who received the drug (11.4 percent); the incidence among the OKT3-treated patients was ninefold higher (odds ratio, 9.5; 95 percent confidence interval, ...
865 citations
TL;DR: This was the first experience with the orthotopic reduced-size liver transplantation technique, which involved the retention of the recipient's inferior vena cava, and the principle of transplanting a portion of the liver from an adult into a child has been accepted in many centers.
Abstract: ORTHOTOPIC liver transplantation is an effective therapy for end-stage liver disease and has proved to be a major advance in the treatment of liver disease in children.1 The foremost obstacle faced by transplantation units worldwide has been the relative paucity of infant and child donors. The principle of transplanting a portion of the liver from an adult into a child has been accepted in many centers.2 3 4 In March 1987, an orthotopic reduced-size liver transplantation was performed in Brisbane, Australia. This was our first experience with the technique, which involved the retention of the recipient's inferior vena cava, to which the . . .
720 citations
TL;DR: The overall risk to develop a first tumor increased from 10% after 10 years to 40% after 20 years of graft survival, and the overall incidence was 250 times higher and that of BCC 10 times higher when compared with the general Dutch population.
Abstract: The incidence of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) was analyzed separately in all 764 patients who received a renal allograft between 1966 and 1988 at the Leiden University Hospital. The mean follow-up period was 8.7 posttransplant years (range 1-21 years). During this time period 176 skin cancers were diagnosed in 47 patients. The overall risk to develop a first tumor increased from 10% after 10 years to 40% after 20 years of graft survival. The overall incidence of SCC was 250 times higher and that of BCC 10 times higher when compared with the general Dutch population. Moreover the localization of SCCs and BCCs differed considerably. Solar radiation is thought to be an important risk factor for the development of skin cancer. However, the occurrence of skin cancer in long-term graft survivors forms also a major problem in a country with a higher geographical latitude and a moderate amount of sun-exposure, such as the Netherlands.
648 citations
TL;DR: It is concluded that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.
Abstract: We reviewed the results of transplantation of allogeneic marrow from HLA-identical donors in patients with beta-thalassemia who were less than 16 years old. Among the 222 consecutive patients who had received transplants since 1983, survival and event-free-survival curves leveled off about one year after transplantation, at 82 and 75 percent, respectively. Pretransplantation clinical characteristics were examined for their impact on survival, event-free survival, and the recurrence of thalassemia in the 116 consecutive patients who were treated with our current regimen, in use since June 1985. In a multivariate analysis, portal fibrosis and either the presence of hepatomegaly or a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly or portal fibrosis (class 1 had neither factor, class 2 had one, and class 3 had both). For class 1 patients the three-year probabilities of survival, event-free survival, and recurrence were 94, 94, and 0 percent, respectively. For class 2 patients the probabilities were 80, 77, and 9 percent, and for class 3 patients 61, 53, and 16 percent. We conclude that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.
587 citations
TL;DR: To study how ACE inhibition suppresses cardiac Ang II formation in man, ACE-dependent and ACE-independent Ang II-forming pathways were characterized in eight normal and 24 failing human hearts obtained at cardiac transplantation.
Abstract: Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang II on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring the conversion of [125I]angiotensin I (Ang I) to [125I]Ang II. LV [125I]Ang II-forming activity in normal hearts (35.5 +/- 2.7 fmol/min/mg, n = 8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5 +/- 2.9 fmol/min/mg, n = 9) and was 48% lower (p less than 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5 +/- 1.9 fmol/min/mg, n = 15).(ABSTRACT TRUNCATED AT 250 WORDS)
583 citations
TL;DR: Overall the various modalities of using graft reduction have resulted in postoperative results similar to those achieved with full-size grafts, while pretransplantation mortality has been limited to less than 2%.
Abstract: The University of Chicago program in pediatric liver transplantation continues actively to seek innovative surgical solutions to problems related to the management of children with end-stage liver disease. Among the most important problems facing these children is a shortage of donor organs, which results from three factors in addition to the actual supply of pediatric donors: the concentration of pediatric liver disease in the population younger than 2 years; the necessity for a graft that is small enough; and the epidemiology of accidents and other events that lead to organ donation. Transplantation using a liver lobe as a graft overcomes size disparity and shifts the available supply of organs from older donors to younger recipients. This work describes the technical aspects of recent innovations in the use of liver lobes in pediatric transplantation, simple reduced-size liver transplantation (RLT), split-liver transplantation (SLT), orthotopic auxiliary liver grafting (ALT), and transplantation using a living related donor (LRLT), and compares their results. Since November 1986 a total of 61 procedures have been performed in which a liver lobe was used as a graft: 26 RLT; 30 SLT, 25 in children and 5 in adults; 5 LRLT; and 1 ALT. Overall 62% of transplants performed in children have involved using a liver lobe as a graft. The rates of complications are somewhat higher than with whole-liver transplantation, but this may not be entirely the result of the complex procedures. Split liver transplantation is associated with the highest mortality and complication rates. Living related liver transplantation has been associated with complications in donors and recipients, but to date survival is 100%. Orthotopic auxiliary liver transplantation effectively corrected the metabolic defect in one patient with ornithine transcarbamylase deficiency. Overall the various modalities of using graft reduction have resulted in postoperative results similar to those achieved with full-size grafts, while pretransplantation mortality has been limited to less than 2%. Thus the use of grafts as liver lobes accomplishes the goal of reducing global mortality among children with end-stage liver disease, but at the cost of increased surgical complexity and more postoperative complications.
568 citations
TL;DR: The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.
556 citations
01 Jul 1990
TL;DR: These general guidelines will be of assistance to standardize the assessment of islet isolations, making it possible to better interpret and compare procedures from different centers.
Abstract: Recent progress in islet isolation from the pancreas of large mammals including man, accentuated the need for the development of precise and reproducible techniques to assess islet yield. In this report both quantitative and qualitative criteria for islet isolation assessment were discussed, the main topics being the determination of number, volume, purity, morphologic integrity andin vitro andin vivo function tests of the final islet preparations. It has been recommended that dithizone should be used as a specific stain for immediate detection of islet tissue making it possible to estimate both the total number of islets (dividing them into classes of 50 µ diameter range increments) and the purity of the final preparation. Appropriate morphological assessment should include confirmation of islet identification, assessment of the morphological integrity and of the purity of the islet preparation. The use of fluorometric inclusion and exclusion dyes together have been suggested as a viability assay to simultaneously quantitate the proportion of cells that are intact or damaged. Perifusion of islets with glucose provides a dynamic profile of glucose-mediated insulin release and of the ability of the cells to down regulate insulin secretion after the glycemic challenge is interrupted. Although perifusion data provides a useful guide to islet viability the quantity and kinetics of insulin release do not necessarily predict islet performance after implantation. Therefore, the ultimate test of islet viability is their function after transplantation into a diabetic recipient. For this reason,in vivo models of transplantation of an aliquot of the final islet preparation into diabetic nude (athymic) rodents have been suggested. We hope that these general guidelines will be of assistance to standardize the assessment of islet isolations, making it possible to better interpret and compare procedures from different centers.
555 citations
TL;DR: The ability to grow nonhemopoietic, connective tissue cells of marrow origin in vitro and the demonstration that these supported hemopoiesis upon transplantation to ectopic sites in vivo strengthened this premise.
Abstract: Hemopoietic precursors can be identified in a number of tissues, but the bone marrow is the only site in normal adult mammals in which myelopoiesis, erythropoiesis, and lymphopoiesis proceed simultaneously (1). When intrave ' nous injection of hemopoietic precursors occurs as in experimental or clinical bone marrow transplantation, long-term hemo poiesis still establishes only in the bone marrow. Local tissue influences critical for hemopoiesis thus appear to operate primarily in the medullary cavity (2). Such observations have led to considerable interest in understand ing the nature of these influences. A cellular basis for these tissue-specific effects evolved from morphologic studies that demonstrated a close association between blood cells and fixed tissue elements, collectively referred to as stromal cells (3-5). The ability to grow nonhemopoietic, connective tissue cells of marrow origin in vitro and the demonstration that these supported hemopoiesis upon transplantation to ectopic sites in vivo strengthened this premise (6, 7). The application of modern experimental techniques to problems in stromal cell biology has begun to define the mech anisms by which stromal cells mediate their effects. One major advance in the last decade has been the development of cell culture techniques that make it possible to grow selected stromal cells, to study their hemo poietic support capabilities, and to identify and clone genes that encode novel, stromal cell--derived growth and differentiation factors (8, 9). Stro-
TL;DR: In this paper, a model of hyperacute rejection was proposed and it was shown that if hyper-accurate rejection can be averted for a period after transplantation, prolonged xenograft survival is possible.
TL;DR: It is suggested that a decrease of the SR Ca2(+)-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure.
Abstract: A decrease in the myocardial level of the mRNA encoding the Ca2(+)-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human end-stage heart failure, we compared the SR Ca2(+)-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2(+)-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2(+)-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P less than 0.01 and -47%, P less than 0.05, respectively). The LV ratio of Ca2(+)-ATPase mRNA to 18S RNA positively correlated with cardiac index (P less than 0.02). The RV ratio correlated negatively with systolic, diastolic and mean pulmonary arterial pressures (P less than 0.02, P less than 0.02, and P less than 0.01, respectively). We suggest that a decrease of the SR Ca2(+)-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure.
TL;DR: Analysis of 5250 tumors that occurred in 4933 patients reported to the Cincinnati Transplant Tumor Registry (CTTR), a worldwide data base, reveals many striking findings.
Abstract: Since 1968, when an increased incidence of lymphomas was noted in renal-transplant recipients,1 evidence has accumulated that organ transplantation, and the immunosuppressive therapy associated wit...
TL;DR: Azotemic patients with diabetes are at high risk of developing contrast nephropathy even when less than 100 mL of radiocontrast agent is used, but this can be minimized by using less than 30 mL of Radiocont contrast agent.
TL;DR: Investigation of this assay system has shown that all three potential sources of stem cells can under appropriate circumstances contribute to long-term hematopoietic regeneration, thus establishing both the competitive pressure of hematoplastic stem cells in the cotransplanted compromised population and in the host, and the need to use genetic markers to track the specific contribution of the injected test cells.
Abstract: Although hematopoiesis is known to originate in a population of very primitive cells with both lymphopoietic and myelopoietic potential, a procedure for enumerating such cells has to date not been available. We now describe a quantitative assay for long-term repopulating stem cells with the potential for reconstituting all hematopoietic lineages. This assay has two key features. The first is the use of competitive repopulation conditions that ensure not only the detection of a very primitive class of hematopoietic stem cells but also the survival of lethally irradiated mice transplanted with very low numbers of such cells. The second is the use of a limiting-dilution experimental design to allow stem cell quantitation. The assay involves transplanting limiting numbers of male "test" cells into lethally irradiated syngeneic female recipients together with 1-2 x 10(5) syngeneic female marrow cells whose long-term repopulating ability has been compromised by two previous cycles of marrow transplantation. The proportion of assay recipients whose regenerated hematopoietic tissues are determined to contain greater than or equal to 5% cells of test cell origin (male) greater than or equal to 5 weeks later is then used to calculate the frequency of competitive repopulating units (CRU) in the original male test cell suspension (based on Poisson statistics). Investigation of this assay system has shown that all three potential sources of stem cells (test cells, compromised cells, and the host) can under appropriate circumstances contribute to long-term hematopoietic regeneration, thus establishing both the competitive pressure of hematopoietic stem cells in the cotransplanted compromised population and in the host, and the need to use genetic markers to track the specific contribution of the injected test cells. Analysis of the frequency of CRU in test marrow suspensions that varied widely in their CRU content gave similar values when endpoints of either 5 or 10 weeks posttransplantation were used and when either recipient marrow or thymus was used to identify progeny populations. In addition, repopulation of marrow and thymus was found to be associated in most mice injected with limiting numbers of test cells. These findings are consistent with the conclusion that the assay is highly selective for a very primitive, totipotent, reconstituting hematopoietic stem cell and should therefore be particularly useful in future gene therapy-oriented research as well as for more basic studies of hematopoietic stem cell regulation and differentiation.
TL;DR: Progress has been made in controlling CMV infection; hyperimmune anti-CMV globulin and certain antiviral drugs appear promising for prophylaxis, and the combination of hyperimmunoglobulin and ganciclovir appears promising for therapy.
Abstract: Cytomegalovirus (CMV) is the single most important infectious agent affecting recipients of organ transplants, with at least two-thirds of these patients having CMV infection 1-4 months after transplantation. Latently infected allografts are the major exogenous source of CMV infection in transplant recipients, although leukocyte-containing blood products can also transmit the virus. Three patterns of CMV infection are recognized: primary infection, reactivation infection, and superinfection. Primary infection has the greatest clinical impact. The clinical effects of CMV infection include infectious disease syndromes such as pneumonia and chorioretinitis; an immunosuppressed state that predisposes to potentially lethal opportunistic infection; and the initiation of a process that can result in allograft injury. Progress has been made in controlling CMV infection; hyperimmune anti-CMV globulin and certain antiviral drugs appear promising for prophylaxis, and the combination of hyperimmunoglobulin and ganciclovir appears promising for therapy.
TL;DR: There are two vital classes of engrafting cells: committed progenitors, which provide initial, unsustained engraftment, and PHSC, which produce delayed, but durable, engraft-ment, which allows the lethally irradiated host to survive initial aplasia.
Abstract: Long-term reconstitution of the lymphohaematopoietic cells of a mouse after lethal irradiation requires the transplantation of at least (5-10) x 10(3) bone marrow cells Several cell-separation techniques based on cell-surface characteristics have been used in attempts to identify the pluripotent haematopoietic stem cells (PHSC), and have allowed the long-term engraftment of lethally irradiated mice with an enriched fraction of fewer than 200 marrow cells But these techniques enrich not only for PHSC but also for haematopoietic progenitors, especially day-12 spleen colony-forming units (CFU-S) Although day-12 CFU-S have been postulated to be primitive multipotential haematopoietic progenitors, with day-8 CFU-S representing later, more committed progenitors, recent evidence suggests that neither of these CFU-S represents mouse PHSC Here we report that counterflow centrifugal elutriation, which sorts cells on the basis of size and density, can separate PHSC from these less primitive progenitors The fraction containing the largest cells was enriched for the granulocyte-macrophage colony-forming units (CFU-GM), but gave only transient, early engraftment and was therefore depleted of PHSC The intermediate fraction was enriched for CFU-S, but depleted of CFU-GM Despite being devoid of CFU-GM and CFU-S, the fraction consisting of only morphological lymphocytes gave sustained, albeit delayed, reconstitution of all lymphohaematopoietic cells, and was therefore enriched for PHSC We conclude that there are two vital classes of engrafting cells: committed progenitors, which provide initial, unsustained engraftment, and PHSC, which produce delayed, but durable, engraftment Therefore for late haematological reconstitution, PHSC must be transplanted with a distinguishable source of early engrafting cells, thereby allowing the lethally irradiated host to survive initial aplasia
TL;DR: It is concluded that the progression of diabetic polyneuropathy may be halted through the restoration of a euglycemic state by successful pancreatic transplantation.
Abstract: Reestablishment of the euglycemic state by successful transplantation of the pancreas might halt or reverse diabetic neuropathy. To test this possibility we evaluated neurologic function by clinical examination, nerve conduction studies, and autonomic-function tests in patients with insulin-dependent (Type I) diabetes mellitus before and after successful pancreatic transplantation. Sixty-one patients were studied before and 12 months after transplantation, 27 again after 24 months, and 11 again after 42 months. A control group of patients with Type I diabetes treated with insulin underwent the same studies at similar intervals — 48 patients before and after 12 months had elapsed, 21 again after 24 months, and 12 again after 42 months. In the control group, neuropathy tended to worsen during the follow-up period. The scores on the clinical examination indicated increased impairment after 12 months. Composite indexes of the degree of abnormality found on neurophysiologic testing of the function of ...
TL;DR: Cympathetic activity in patients with heart transplants or myasthenia gravis who were not being treated with cyclosporine was no different from that in Patients with essential hypertension or in normal controls, and cyclospora-induced hypertension is associated with sympathetic neural activation.
Abstract: Background. Hypertension is a frequent complication of cyclosporine-induced immunosuppression, but the underlying mechanism is unknown. In anesthetized animals, the administration of cyclosporine increases sympathetic-nerve discharge, which may contribute to hypertension. Methods. To determine whether cyclosporine-induced hypertension is accompanied by sustained sympathetic neural activation in patients, we recorded sympathetic action potentials using intraneural microelectrodes (in the peroneal nerve) in heart-transplant recipients receiving azathioprine and prednisone alone (n = 5) or in combination with cyclosporine (n = 14). We performed the same studies in eight patients with myasthenia gravis who were receiving cyclosporine and eight who were not, in five patients with essential hypertension, and in nine normal controls. Results. Heart-transplant recipients receiving cyclo-sporine had higher mean arterial blood pressure (±SE) than those not receiving cyclosporine (112±3 vs. 96±4 mm Hg; P<0....
TL;DR: The present study indicates, that the size of the apical foramen and possibly the avoidance of bacterial contamination during the surgical procedure are explanatory factors for pulpal healing.
Abstract: The purpose of the present investigation was to determine the long-term prognosis of autotransplanted premolars with respect to tooth survival and pulpal healing. The material consisted of 195 patients aged 7 to 35 years, with a total of 370 autotransplanted premolars with observation period ranged from 1 to 13 years. Teeth transplanted with incomplete and complete root formation showed 95 per cent and 98 per cent long-term survival respectively: Pulp healing as evaluated by sensibility testing and radiographic signs of partial pulp canal obliteration was usually verified 6 months after transplantation. The frequency of pulpal healing (versus pulp necrosis), appeared to be closely related to stage of root development at time of transplantation. Teeth transplanted with incomplete and complete root formation showed 96 per cent and 15 per cent pulp healing respectively. Another and associated factor which could equally well predict pulpal healing was the diameter of the apical foramen of the graft. Finally, in teeth with completed root formation, the use of bursa with internal cooling and no extra-alveolar storage prior to transplantation seemed to increase the chance for pulpal healing. The present study indicates, that the size of the apical foramen and possibly the avoidance of bacterial contamination during the surgical procedure are explanatory factors for pulpal healing.
TL;DR: The first type I diabetic patient with an established kidney transplant on basal cyclosporin immunosuppression who was able to eliminate the insulin requirement after human islet transplantation into the portal vein is reported, representing the first essential step required to determine the feasibility of islet transplants by future clinical trials.
Abstract: Effective clinical trials of islet transplantation have been limited by the inability to transplant enough viable human islets into patients with type I (insulin-dependent) diabetes mellitus to eliminate their exogenous insulin requirement. We report the first type I diabetic patient with an established kidney transplant on basal cyclosporin immunosuppression who was able to eliminate the insulin requirement after human islet transplantation into the portal vein. We successfully isolated approximately 800,000 islets that were 95% pure from 1.4 cadaver pancreases containing 121 U of insulin. Islets were proven viable by in vitro insulin response to glucose challenge. After 7 days of 24 degrees C culture, the islets were transplanted into the portal vein under local anesthesia. Seven days of Minnesota antilymphoblast globulin (20 mg/kg) administration followed the islet transplantation, with maintenance of the cyclosporin. Blood glucose was kept under strict control via intravenous insulin for 10 days posttransplantation, when all insulin therapy was stopped. Off insulin, the average 24-h blood glucose level remained less than 150 mg/dl, with the fasting glucose level at 115 +/- 6 mg/dl and the 2-h postprandial level at 141 +/- 8 mg/dl for 22 days posttransplantation (the time of this study). The C-peptide values post-Sustacal testing, although initially rising slower, exceeded the normal range, with peak values of 1.0-1.8 pmol/ml. This preliminary result represents the first essential step required to determine the feasibility of islet transplantation by future clinical trials.
TL;DR: This work has shown that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination or functional inactivation, and focused on understanding the cellular and molecular interactions that generate these forms of tolerance.
Abstract: During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.
TL;DR: The understanding of the physiological regulation of NGF synthesis in the CNS is the basis for a rational approach to its pharmacological modification and is an attractive alternative to the (long‐term) infusion ofNGF or the transplantation of N GF‐secreting cells with the goal of providing trophic support to the cholinergic neurons of the basal forebrain nuclei.
Abstract: In order to obtain information on the physiological regulation of NGF-synthesis in the central nervous system (CNS) we investigated the effects of a series of growth factors (known to be present in the CNS) in cultures of purified rat astrocytes and compared these effects with those observed after intraventricular injection of the same molecules. After preliminary experiments had shown that 10% fetal calf serum (FCS) produced a marked increase in NGF-mRNA levels in astrocytes (but neither in microglia nor oligodendrocytes) as demonstrated by Northern blot analysis and in situ hybridization the experiments were performed at low (0.5%) FCS concentrations. Supramaximal concentrations of IL-1 and various growth factors caused a 5- to 7-fold increase in NGF-mRNA after 6 h. By 24 h the NGF-mRNA levels approached control values again, most probably due to inactivation of the added factors since after readdition after 24 h the response was about the same as the initial one. Norepinephrine and 8-bromo-cAMP did not change NGF-mRNA levels. The growth factor-mediated changes in NGF-mRNA levels in astrocyte cultures were not consistently reflected by the changes observed after intraventricular injection. IL-1 produced by far the largest increase in hippocampal NGF-mRNA after intraventricular injection. This large response to IL-1 could result from a positive feedback mechanism, since IL-1beta injection not only increases NGF-mRNA but also IL-1beta-mRNA in the hippocampus. The understanding of the physiological regulation of NGF synthesis in the CNS is the basis for a rational approach to its pharmacological modification. This, in turn, is an attractive alternative to the (long-term) infusion of NGF or the transplantation of NGF-secreting cells with the goal of providing trophic support to the cholinergic neurons of the basal forebrain nuclei. These neurons are consistently affected in the early stages of Alzheimer's disease, their impaired function being essentially responsible for the cognitive deficits.
TL;DR: A state of donor-specific unresponsiveness was achieved that permitted survival of a second donor strain islet allograft transplanted to an extrathymic site and a potential strategy for specific modification of the peripheral immune repertoire.
Abstract: The application of isolated pancreatic islet transplantation for treatment of diabetes mellitus has been hampered by the vulnerability of islet allografts to immunologic rejection. Rat islet allografts that were transplanted into the thymus of recipients treated with a single injection of anti-lymphocyte serum survived indefinitely. A state of donor-specific unresponsiveness was achieved that permitted survival of a second donor strain islet allograft transplanted to an extrathymic site. Maturation of T cell precursors in a thymic microenvironment that is harboring foreign alloantigen may induce the selective unresponsiveness. This model provides an approach for pancreatic islet transplantation and a potential strategy for specific modification of the peripheral immune repertoire.
TL;DR: Passive immunotherapy with intravenous immunoglobulin decreases the risk of acute GVHD, associated interstitial pneumonia, and infections after bone marrow transplantation.
Abstract: Background. Graft-versus-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Since intravenous immunoglobulin has shown benefit in several immunodeficiency and autoimmune disorders, we studied its antimicrobial and immunomodulatory role after marrow transplantation. Methods. In a randomized trial of 382 patients, transplant recipients given immunoglobulin (500 mg per kilogram of body weight weekly to day 90, then monthly to day 360 after transplantation) were compared with controls not given immunoglobulin. By chance, the immunoglobulin group included more patients with advanced-stage neoplasms; otherwise, the study groups were balanced for prognostic factors. Results. Control patients seronegative for cytomegalovirus who received seronegative blood products remained seronegative, but seronegative patients who received immunoglobulin and screened blood had a passive transfer of cytomegalovirus antibody (median titer, 1:64). Among the 61 seronegativ...
TL;DR: The Thy/Liv implants provided a microenvironment in which to follow human hematopoietic progenitor cells for multiple lineages, indicating long-term maintenance, in vivo, of human progenitors for the T lymphoid, myelomonocytic, erythroid, and megakaryocytic lineages.
Abstract: Coimplantation of small fragments of human fetal thymus and fetal liver into immunodeficient SCID mice resulted in the formation of a unique structure (Thy/Liv). Thereafter, the SCID-hu mice showed reproducible and long-term reconstitution of human hematopoietic activity. For periods lasting 5-11 mo after transplantation, active T lymphopoiesis was observed inside the grafts and cells that were negative for T cell markers were found to have colony-forming units for granulocyte/macrophage (CFU-GM) and erythroid burst-forming unit (BFU-E) activity in the methylcellulose colony assay. In addition, structures similar to normal human bone marrow were observed inside the Thy/Liv grafts, consisting of blast cells, mature and immature forms of myelomonocytic cells, and megakaryocytes. These data indicate long-term maintenance, in vivo, of human progenitor cells for the T lymphoid, myelomonocytic, erythroid, and megakaryocytic lineages. The role of the implanted fetal liver fragments was analyzed using HLA-mismatched Thy/Liv implants. The HLA type of the liver donor was found on T cells and macrophages in the graft. In addition, cells grown in the methylcellulose colony assay and cells in a bone marrow-like structure, the "thymic isle," expressed the HLA type of the liver donor. Thus, the Thy/Liv implants provided a microenvironment in which to follow human hematopoietic progenitor cells for multiple lineages. The formation of the Thy/Liv structures also results in a continuous source of human T cells in the peripheral circulation of the SCID-hu mouse. Though present for 5-11 mo, these cells did not engage in a xenograft (graft-versus-host) reaction. This animal model, the first in which multilineage human hematopoietic activity is maintained for long periods of time, should be useful for the analysis of human hematopoiesis in vivo.
TL;DR: Analysis of clinical features associated with complete response (CR) to acute GVHD therapy identified more favorable responses to therapy in patients without either liver or skin involvement, patients with acute lymphoblastic leukemia, and donor/recipient pairs other than male patients with female donors.
TL;DR: The results showed that significant numbers of adipocytes were ruptured after suction procedures, and adipocytes appeared to survive better for a short term in a more vascularized bed (rectus muscle) than in a low vascular area (ear dermis).
Abstract: In recent years, adipocytes obtained by suction-assisted lipectomy have been used for implantation by injection methods. This study is designed to assess the appearance of suctioned and excised adipose tissue and its survival after being injected or implanted into different tissues (0.5 cc into the rectus muscle and 0.5 cc into the dorsal ear skin) of New Zealand White rabbits. The results showed that significant numbers of adipocytes were ruptured after suction procedures. The intact cells represented approximately 10 percent of the fat cell population. Fat cells in aspirated and excised samples remained intact and did not differ histologically. After being injected into tissue, adipocytes appeared to survive better for a short term in a more vascularized bed (rectus muscle) than in a low vascular area (ear dermis). Long-term studies at 6- to 9-month intervals revealed transplanted adipose tissue, taken by suction or excision, being replaced with fibrosis, although cystic spaces and only a small number of surviving adipocytes were still present. Insulin did not show any protective effects on survival of the adipocytes during their transplantation.
TL;DR: DDD pacing could represent an alternative approach to the management of chronic heart failure due to dilated cardiomyopathy, especially for heart transplant candidates and patients who are not accepted for cardiac transplantation, but no longer respond to drug therapy.
Abstract: The beneficial effects of physiologic dual-chamber (DDD) pacing in the treatment of end-stage idiopathic dilated cardiomyopathy were evaluated in 16 patients in whom conventional drug therapy had failed. Candidates for cardiac transplantation as well as patients not accepted for transplantation participated. During DDD pacing at an atrioventricular delay of 100 ms, left ventricular ejection fraction increased from 16.0 ± 8.4 to 25.6 ± 8.6% (p