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PubMed1996

Induction of graft versus leukemia effects by cell-mediated lymphokine-activated immunotherapy after syngeneic bone marrow transplantation in murine B cell leukemia.

The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/ lymphoma. Allogeneic cell therapy, induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal residual disease provided that graft versus host disease can be prevented or adequately controlled.

Adjuvants, Immunologic↗
PubMed1995

Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1.

A 15-month-old boy with severe aplastic anemia developed veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT), in which the preparative regimen included 50 mg/kg/day cyclophosphamide and anti-lymphocyte globulin for 4 consecutive days. The diagnosis was made based on clinical symptoms and data including, hepatomegaly, right upper quadrant abdominal pain, jaundice, ascites, coagulopathy and thrombocytopenia which was refractory to transfusions of platelet concentrate. We gave 2, 3, 5 and 5 mg/day/body of recombinant tissue plasminogen activator (tPA) followed by heparin and prostaglandin E1 (PGE1) effectively and without significant side effect on days 9, 10, 13 and 14, respectively. Clinical and biochemical improvement was steady and dramatic. We suggest that tPA following continuous heparin and PGE1 infusion may be useful in the treatment of VOD even in infantile cases.

Alprostadil↗
PubMed1996

Repair capacity of mouse lung after total body irradiation alone or combined with cyclophosphamide.

PURPOSE: Cyclophosphamide (CTX) combined with fractionated total body irradiation (TBI) is frequently used in the conditioning of patients prior to bone marrow transplantation (BMT). This study was performed to investigate the effect of CTX on the repair capacity of lung tissue after TBI in a mouse model for BMT. MATERIALS AND METHODS: TBI was given as a single fraction, 3 fractions in 3 days (Fx 3) or 9 fractions in 3 days (Fx 9) either alone or 24 h after a single dose of CTX. The single fraction TBI was given at either high dose rate (HDR) of 0.71 Gy/min or low dose rate (LDR) of 0.08 Gy/min. All mice were transplanted 4-6 h after the last TBI fraction. Lung damage was assessed using ventilation rate (VR) and lethality between 28 and 180 days. The repair capacity of lung tissue was estimated using the direct analysis method with the probability of reaching the end point described by a logistic formulation of the linear quadratic model. RESULTS: The VR data confirmed the high repair capacity of lung tissue with an alpha/beta ratio of 4.4 Gy though with a wide 95% confidence interval (CI = 0.03-10.5). Giving CTX before fractionated TBI markedly reduced the doses needed to cause response in 50% of the animals. The sparing effect of using fractionated TBI was still evident in the combined CTX-TBI schedules. The estimated alpha/beta ratio was 1.6 Gy (CI = 0.01-4.7) which is within the range of values reported after thoracic radiation only. On the other hand, the sparing effect seen in going from single fraction HDR to LDR was completely abolished when CTX was given 24 h before TBI. The same pattern was repeated when lethality between 28-180 days was used. Yet, the use of lethality to estimate lung damage in a TBI model, markedly underestimated the repair capacity. CONCLUSIONS: These results confirm the high repair capacity of lung tissue after TBI and emphasize the value of using a specific end point in testing lung damage after TBI. It also shows that there can be a negative effect of CTX on the repair capacity of lung damage which is more pronounced when CTX is followed (24 h later) by single fraction TBI at LDR than by a fractionated TBI course over a few days.

Animals↗
PubMed1992

Conditioning regimens for allogeneic bone marrow transplantation.

Conditioning regimens for transplantation are important in determining transplant outcome. This review focuses on transplantation in aplastic anemia and leukemia using marrow from HLA-identical siblings. Results of conditioning with newer regimens such as busulfan plus cyclophosphamide and etoposide plus total body irradiation are reviewed and compared to results achieved with cyclophosphamide and total body irradiation. The potential for improved results using recent innovations such as dose adjustment of busulfan, agents which may decrease transplant-related toxicity, and directed radiation are discussed.

Anemia, Aplastic↗
PubMed1993

Bone marrow transplantation in sickle cell anaemia.

Sickle cell anaemia is a hereditary disorder commonly seen in the black population, due to a point mutation in the beta globin gene. The sickle mutation is responsible for an increased rigidity and adherence of the red blood cell leading to haemolytic anaemia and vaso-occlusive episodes. Symptoms include dactylitis, painful crisis, splenic sequestration and the development of multi-organ damage and failure. The progressive loss of splenic function increases the risk of infections. The morbidity and mortality can be reduced by the maintenance of an adequate nutrition, the prevention of infection and the treatment of complications. In some patients severely affected, a chronic transfusion program has to be instigated to maintain a level of haemoglobin S below 50%. New therapeutic strategies include the use of hydroxyurea and maybe, in the future, butyrates to increase the level of foetal haemoglobin. Further studies are needed to evaluate the benefits of such therapies. Bone marrow transplantation represents an attractive therapeutic tool and its role in other haemoglobinopathies like thalassaemia is now well demonstrated. As far as sickle anaemia is concerned, the first report concerned a child with acute myeloblastic leukaemia. The patient is now cured of both the sickle cell anaemia and the leukemia. Since April 1986, 21 patients underwent an allogeneic bone marrow transplantation for sickle cell anaemia in our department. 20 patients became asymptomatic and have an electrophoretic pattern of the haemoglobin similar to that of the donor. One patient died of bone marrow transplantation related complications.

Adolescent↗
PubMed1993

Hepatic veno-occlusive disease after bone marrow transplant.

Hepatic veno-occlusive disease (VOD) is a non-thrombotic obliteration of the lumina of small intrahepatic veins. VOD has been reported after exposure to a wide variety of pathogens. It has been suggested that the chemoradiotherapy used as the conditioning regimen for bone marrow transplant (BMT) is now the main cause of this disease. However, the pathogenesis of VOD after BMT is probably multifactorial. Endothelial injury of sinusoids and small hepatic veins is considered to be the initial event in genesis of VOD. This injury is followed by deposition of fibrin-related aggregates in the subendothelial zone. These aggregates, and the intramural entrapment of fluid and cellular debris, occlude progressively the hepatic venous outflow and generate a postsinusoidal intrahepatic hypertension. Clinically, VOD is characterized by jaundice, weight gain, ascites, painful hepatomegaly and platelet refractoriness developing early post transplant, although other posttransplant liver disturbances can produce a similar syndrome. VOD diagnosis is usually established by applying the clinical criteria proposed by the Seattle and Baltimore groups. When clinical diagnosis of VOD is uncertain, a transjugular liver study including a transvenous biopsy and measurement of the gradient between wedged and free hepatic venous pressure, is recommended in order to establish an accurate diagnosis. According to the literature data, the incidence of VOD ranges from 0 to 70% and its mortality from 20 to 50%. This very wide range is attributable to the different incidence of risk factors in the different series and to the differences in applying the diagnostic criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1992

Eliminating human immunodeficiency virus (HIV) from infected individuals and cells: is it possible?

The literature from 1984 to 1991 has been searched for reports of patients who have eliminated human immunodeficiency virus (HIV) from their system. While such reports are scarce, it appears that a small number of HIV-positive patients have reverted to a negative state either spontaneously or following radical immunosuppressive regimens for neoplastic disease. Although no carefully planned animal experiments or clinical trials have been reported, it would appear that bone marrow ablation and replacement may eliminate HIV from healthy, asymptomatic HIV-positive individuals. Although much of the clinical experience to date suggests that radical immunosuppression is not indicated in advanced AIDS patients in whom the virus has likely spread beyond the immune system, such cases do not represent evidence that immunosuppression is not indicated in healthy, HIV-positive individuals.

Adult↗
PubMed1993

What really cures in autologous bone marrow transplantation? A possible role for dimethylsulfoxide.

Dimethylsulfoxide has long been known to be a potent inducer of differentiation of various malignant cells in animals and human beings. It is a toxic agent, and high concentrations are needed to induce differentiation. Other compounds that also have methylene groups and a polar/apolar architecture, and are needed in much smaller concentrations to induce differentiation, like hexamethylene bisacetamide have been developed. They are already used in trials in human beings. However dimethylsulfoxide still has a very important role in bone marrow transplantation, being added to the frozen marrow as a cryoprotectant. We suggest that dimethylsulfoxide may induce differentiation of malignant cells present in the marrow or alternatively in the body when it is infused back with the transplanted marrow. This may be an additional factor contributing to the success rate achieved in various malignancies treated by transplantation, especially autologous, complementing the traditional explanations which are based mainly on the high dose chemotherapy and the immunological manipulations that occur during transplantation.

Acetamides↗
PubMedDate not supplied

Acute parkinsonian syndrome with demyelinating leukoencephalopathy in bone marrow transplant recipients.

A syndrome of rigidity, bradykinesia, spasticity, and often myoclonus and dementia developed acutely in 5 patients who had undergone successful engraftment of bone marrow transplants for the treatment of various hematologic diseases. Magnetic resonance imaging demonstrated widespread changes in white matter; brain biopsy disclosed mild demyelination associated with active phagocytosis of myelin. One patient, who was not treated, remains severely demented. Patients treated with very high-dose methylprednisolone had complete clinical recovery.

Adolescent↗
PubMed1996

An analysis of the elements essential in the development of a customized TBI program.

Bone marrow transplant, once a procedure carried out at a relatively small number of large medical centers, is being employed at an increasing number of non-academic hospitals. The use of total body photon irradiation for the purpose of marrow ablation and immunosuppression can be expected to accompany the outward growth of bone marrow transplantation at these same hospitals. An analysis of the fundamental physical factors associated with total body photon irradiation (TBI) should be of value to facilities considering the incorporation of a total body irradiation program into an existing radiation oncology department. By examining the existing resources of a radiotherapy center and the clinical objectives of the treatment, a facility considering TBI may determine whether or not their center already fulfills the necessary criteria, in addition to the avoidance of potential pitfalls in project implementation.

Bone Marrow Purging↗
PubMed1991

Hematopoietic stem cell processing and storage.

The techniques to collect, process, and store HSC in anticipation of transplantation are now widely available. Important unresolved issues revolve around the as yet imperfect identification and classification of totipotential progenitors. However, much progress has been and will continue to be made despite this limitation. Research priorities of present and future stem cell processing laboratories should include: 1. Optimization of liquid (nonfrozen) storage techniques. This will permit more complex cell-specific manipulations, such as T-lymphocyte subset selection, isolation of CD34+ populations, treatment in vitro with growth factors, gene transfer experiments, and long-range transport of HSC, to be performed while preserving HSC integrity. 2. A better understanding of the regulation and kinetics of peripheral blood and umbilical cord HSC, to allow optimum collection procedures that do not require marrow harvesting. 3. An intensive study into the optimum conditions of collection, processing, and storage of megakaryocytic progenitors to decrease the long platelet-transfusion dependency of the myeloablated patient. 4. A search for a simple in vitro correlate of engraftment potential of a stem cell preparation. This will greatly improve the quality control functions of the laboratory as well as contribute to better patient selection for transplantation.

Animals↗
PubMed2002

Future strategies for tolerance induction: a comparative study between hematopoietic stem cells and macrophages.

So far, clinical benefit of hematopoietic stem cell induced donor-specific tolerance across major histocompatibility complex (MHC) barriers was hampered by either graft rejection or graft-versus-host disease. An alternative approach focuses on the use of donor-derived cells that bear an inherent mechanism to circumvent allospecific rejection upon injection into non-immunosuppressed hosts. Using a myeloablative conditioning model in the rat, full donor chimeric recipients were generated and their potential to induce long-term cardiac allograft survival was compared with the fate of grafts transferred to non-immunosuppressed host rats pretreated with donor-macrophages derived from the peritoneal cavity in the LEW to DA inbred strain combination. The induction of full multilineage long-term donor-chimerism (> 150 days) after initial host conditioning using two doses of cyclophosphamide and one shot of busulphan prevented acute graft rejection, whereas non-chimeric animals experienced acute and complete rejection. Conversely, vigorous T-cell depletion is required to protect conditioned animals from lethal graft-versus-host disease. Instead, the use of donor intraperitoneal macrophages achieved a state of transient chimerism and subsequent long-term graft survival in fully immunocompetent rats without the need of lethal conditioning regimens. In conclusion, the complex immunologic interactions, observed after allogeneic bone marrow transplantation as a means to induce donor chimerism, and subsequent long-term graft acceptance can be avoided if appropriate cell populations can be identified that, by themselves, induce a transient state of donor chimerism prevailing long enough to deviate allospecific immune responses, as outlined in this study.

Animals↗